Clinical UM Guideline

This document addresses gene mutation testing to determine whether an individual is at risk for the development of malignant tumors (including but not limited to breast, colon, lung, pancreatic and ovarian cancers) and to guide cancer management or targeted cancer therapy in individuals with malignant conditions. This document also addresses the use of circulating tumor DNA testing to assess gene mutations.

Note(s):

• This document does not address gene panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider). For information on these tests, please see the following:
  • GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling
• This document does not address circulating tumor cell (CTC) tests. For information on these tests, please see LAB.00015 Detection of Circulating Tumor Cells.
• This document does not provide coverage criteria for drugs including but not limited to chemotherapeutic agents or associated therapeutic products.
• For information on genetic testing for inherited diseases (including preconception or prenatal genetic testing and testing for germline genetic diseases), see CG-GENE-13 Genetic Testing for Inherited Diseases.
• When an individual genetic test is addressed in a separate medical policy or clinical utilization management guideline (CUMG), that policy or CUMG applies. For additional information, please see the following related documents:
  • CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis
  • CG-GENE-16 BRCA Genetic Testing
  • CG-GENE-19 Measurable Residual Disease Assessment in Lymphoid Cancers Using Next Generation Sequencing
  • GENE.00025 Proteogenomic Testing for the Evaluation of Malignancies
  • GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

Medically Necessary:

1. Gene Mutation Testing for Cancer Susceptibility (See Table A below)
   Gene mutation testing for cancer susceptibility is considered medically necessary when all of the following criteria are met:
   1. The genetic disorder is associated with a potentially significant cancer; and
   2. The risk of the significant cancer associated with the genetic disorder cannot be identified through biochemical or other testing; and
   3. A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the risk of developing malignancy; and
   4. The results of the genetic test may impact the medical management (for example, surveillance; life-style) of the individual; and
   5. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
2. Gene Mutation Testing to Guide Cancer Management or Targeted Cancer Therapy (See Table B below)
   Gene mutation testing used to identify individuals for cancer management or to guide targeted cancer therapy is considered medically necessary when all of the following criteria are met:
   1. The individual is a candidate for treatment (for example, targeted therapy using a pharmaceutical or biologic treatment) or other cancer management strategies, and the mutation status of a specific gene, or set of mutations, is required prior to initiating, or as part of treatment; and
   2. A specific mutation, or set of mutations, has been established in the scientific literature to identify those most likely to benefit from treatment.
3. Circulating Tumor DNA (Liquid Biopsy) to Guide Cancer Management or Targeted Cancer Therapy (See Table C below)
   Use of a circulating tumor DNA (ctDNA) test for cancer management or to guide targeted cancer therapy in individuals with solid tumors is considered medically necessary when the mutation(s) meets criteria “B” above and when formalin-fixed paraffin-embedded tumor tissue (FFPET) is inadequate in quality or quantity or is unavailable for testing.

Note: For information on circulating tumor DNA panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider), see GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.

Not Medically Necessary:

1. Gene Mutation Testing for Cancer Susceptibility
   Gene mutation testing for cancer susceptibility is considered not medically necessary in individuals not meeting all of the Section A criteria above.
2. Gene Mutation Testing to Guide Cancer Management or Targeted Cancer Therapy
   Gene mutation testing used to identify individuals for cancer management or to guide targeted cancer therapy is considered not medically necessary when the medically necessary criteria in Section B above are not met.
3. Circulating Tumor DNA (Liquid Biopsy) to Guide Cancer Management or Targeted Cancer Therapy
   Use of a circulating tumor DNA (ctDNA) test for cancer management or to guide targeted cancer therapy in individuals with solid tumors is considered not medically necessary when the medically necessary criteria in Section C above is not met, including to detect the recurrence of a solid tumor, including colorectal cancer, and to test for solid tumor cancer susceptibility.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met.

When services are also Not Medically Necessary:
For the following procedure codes, or when the code describes a procedure designated in the Clinical Indications section as not medically necessary.

A. Gene Mutation Testing for Cancer Susceptibility in Individuals with Cancer (See Table A below)

Genetic testing for cancer susceptibility is used to predict an individual’s risk of cancer development in the future and to identify carriers (individuals who do not have the cancer but have a copy of a genetic variant which has been associated with the development of cancer). It has been estimated that approximately 5-10% of all cancers are considered to be hereditary (the result of inherited genetic susceptibility).

Genetic testing for cancer susceptibility (a form of predictive genetic testing) is generally carried out in asymptomatic individuals who are considered to be at high risk for developing cancer due to a strong family medical history of the disease, or other factors. Predictive genetic testing can be further divided into two categories: presymptomatic and predispositional. Presymptomatic predictive genetic testing confirms or denies the development of the disease in those at risk as the condition's genetic variant is highly penetrant and there is little or no variable expression. Predispositional predictive genetic tests provide information about an individual's risk of developing a specific disorder in the future. Predispositional predictive genetic testing is generally carried out for incompletely penetrant conditions and the results are not indicative of the inevitable occurrence of a condition or disease, nor are they a guarantee that a disease will not develop in the future.

One of the limitations of predictive genetic testing is the challenge in interpreting positive test results. Some individuals who test positive for a disease-associated variant may never develop the disease. In order to be useful in the clinical setting, the results of predictive genetic testing should have a high positive predictive value (PPV) and evidence should demonstrate that such results improve either disease prevention or management, as compared with care without genetic testing. Please refer to CG-GENE-13 Genetic Testing for Inherited Diseases for more information on the specific types of genetic tests, including but not limited to predictive genetic testing.

A position statement published by the American Society of Clinical Oncology (ASCO) indicates that genetic testing for cancer susceptibility is appropriate when the:

1) Individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the genetic test can be adequately interpreted, and 3) the test results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer (ASCO, 2003).

ASCO also recommends that genetic testing only be provided in the setting of pre- and post-test counseling, which should include a discussion of the risks and benefits of cancer early detection and prevention modalities (ASCO, 2003).

In assessing the value of a specific genetic test for susceptibility to a particular malignant condition, consideration should be given to the peer-reviewed, published literature addressing the analytical validity, clinical validity, and clinical utility of the test. Each genetic test must be carefully evaluated to determine whether or not the identified variant reliably identifies a specific type of cancer, and that the results of the genetic test, whether affirmative or negative, will impact the clinical management of the individual (for example, guide treatment decisions, surveillance recommendations or preventive strategies). The results of genetic testing are also expected to improve net health outcomes, (that is, the anticipated health benefits of the interventions outweigh any harmful effects [medical or psychological] of the intervention).

The National Comprehensive Cancer Networks (NCCN) guidelines do not contain recommendations for the general strategy of testing a tumor for a wide range of biomarkers. However, the guidelines do contain recommendations for specific genetic testing for individual cancers, when there is a known drug-biomarker combination that has demonstrated benefits for that particular type of tumor, such as non-small cell lung cancer (NCCN NSCLC).

Multiple Endocrine Neoplasia Type 2 (MEN 2) and Thyroid Cancer

Thyroid cancer (carcinoma) is relatively uncommon. In the United States, the lifetime risk of being diagnosed with thyroid cancer is approximately 1%. An estimated 44,280 cases of newly diagnosed thyroid cancer are expected in the United States in 2021 (National Cancer Institute [NCI]).

Multiple endocrine neoplasia type 2 (MEN 2) is a genetic condition which can be passed from generation to generation in a family. The gene associated with MEN 2 is called RET (RET proto-oncogene). A mutation in the RET gene increases an individual’s risk of developing medullary thyroid cancer and other tumors associated with MEN 2.

Three major types of tumors are associated with MEN 2: medullary thyroid cancer, parathyroid tumors, and pheochromocytoma. MEN 2 is classified into three subtypes based on clinical features: MEN 2A, which affects 60% to 90% of MEN 2 families; MEN 2B, which affects 5% of MEN 2 families; and FMTC, which affects 5% to 35% of MEN 2 families (ASCO, 2013). The most common sign of multiple endocrine neoplasia type 2 is medullary thyroid cancer.

Based on histological findings, thyroid cancer includes the following categories: (1) differentiated (follicular, papillary and Hurthle); (2) medullary; and (3) anaplastic (aggressive undifferentiated tumor). Medullary thyroid cancer (MTC) develops from the “C” or parafollicular cells of the thyroid gland which produce calcitonin. Approximately 80% of the cases of MTC are sporadic. The remaining inherited syndromes include multiple endocrine neoplasia (MEN) type 2A (also known as MEN 2A), MEN 2B and familial MTC (FMTC). All three of these subtypes, MEN 2A, MEN 2B and FMTC are inherited in an autosomal dominant pattern and involve an elevated risk for the development of medullary carcinoma of the thyroid. MEN 2A and MEN 2B have an increased risk for the development of pheochromocytoma. MEN 2A has an elevated risk for parathyroid adenoma or hyperplasia. Additional features in MEN 2B include distinctive facies with enlarged lips, mucosal neuromas of the lips and tongue and ganglioneuromatosis of the gastrointestinal tract. MTC generally occurs in early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in FMTC (Moline, 2013).

Mutations in the RET proto-oncogene are found in at least 95% of individuals with MEN 2A and 88% of FMTC. Mutations associated with MEN 2A and familial MTC have been most frequently identified in several codons of the extracellular domains of exon 10, 11 and 13, while MEN 2B and some FMTC mutation have been identified within the intracellular exons 14 to 16. Somatic mutations in exons 11, 13 and 16 have also been identified in at least 25% of sporadic MTC tumors. Approximately 6% of individuals with clinical sporadic MTC are carriers of a RET germline mutation (National Comprehensive Cancer Network® [NCCN], 2021).

The management of MEN 2 depends on the type of MEN 2 diagnosed and whether the condition was identified prior to clinical signs and symptoms. If treated prior to regional lymph node metastases, MEN2 can usually be cured surgically. However, the majority of individuals (up to 75%) have lymph node involvement at the time of diagnosis. Because the development of invasive MTC is usually preceded by C-cell hyperplasia and can be detected by the oversecretion of calcitonin in response to a chemical challenge, annual surveillance employing biochemical testing has been used to monitor those with inherited disease before it progresses beyond the earliest stages. Genetic assays for RET mutations may be utilized as an alternative to annual biochemical testing for C-cell hyperplasia in individuals with a known family history of MEN 2A, 2B, or FMTC. Annual biochemical screening can be discontinued in those individuals who test negative for RET mutations. Individuals who test positive for RET mutations may elect to undergo immediate thyroidectomy or defer thyroidectomy until biochemical tests suggest the development of MTC. Genetic assays for RET oncogene mutations have also been used to determine if new cases of MTC without a known family history are truly sporadic in origin. Positive test results in this setting may prompt the evaluation of family members or initiate screening for pheochromocytoma.

The American Thyroid Association (ATA) developed four MTC risk levels based on correlations between RET genotype and MEN 2 phenotype, and made specific recommendations regarding the ideal timing for prophylactic thyroidectomy (ATA, 2015). For individuals with RET variants associated with MEN 2B, who have the highest risk for early-onset MTC, thyroidectomy is recommended within the first year of life. For individuals at the next highest risk level (i.e., those with variants involving RET codon 634), thyroidectomy is recommended in the first 5 years of life. For individuals with genotypes at the third highest level of risk, thyroidectomy should be considered prior to the age of 5 years, but may be delayed if stringent clinical criteria are met. For individuals with genotypes in the lowest risk category, thyroidectomy may be delayed after age 5 in the context of normal screening results and a family history consistent with less aggressive MTC.

According to the recommendations set forth in the guidelines by the NCCN (NCCN, 2021), genetic testing for RET-proto-oncogene mutations is recommended for all newly diagnosed individuals with clinically apparent sporadic MTC, and for screening children and adults in known relatives with inherited forms of MTC.

In summary, there is adequate data to show that genetic tests for point mutation in the RET gene can identify those with an inherited susceptibility for MTC prior to the onset of clinical manifestations. Test results affect individual management by prompting age-appropriate prophylactic thyroidectomy, the early diagnosis and treatment of pheochromocytoma and/or hyperparathyroidism, continued biochemical monitoring in affected individuals, and by prompting discontinuation of monitoring in individuals who test negative.

PTEN Hamartoma Tumor Syndrome

Germline mutations in PTEN have been identified in a variety of rare syndromic manifestations that are collectively known as PTEN hamartoma tumor syndrome (PHTS). The defining clinical feature of PHTS is the presence of hamartomatous tumors, benign tumors resulting from an overgrowth of normal tissue. The phenotypic spectrum of PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and adult Lhermitte-Dulcos disease (ALDD). Notably, germline mutations in PTEN are also associated with adult Lhermitte-Dulcos disease, autism spectrum disorders with macrocephaly, and possibly intellectual disability/developmental delay with macrocephaly. The estimated penetrance of PTEN mutation is approximately 80%, although risk estimates vary.

CS is characterized by multiple hamartomas and/or an increased risk of developing cancerous lesions in various tissues and organs, including the skin, mucous membranes, breast, thyroid, endometrium and brain. Other cancers associated with CS include colorectal cancer, kidney cancer, and possibly melanoma. Additional conditions associated with CS include macrocephaly and Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development or intellectual disability. The features of CS overlap with those of BRRS.

The BRRS variant of Cowden syndrome/PHTS is characterized by the presence of macrocephaly, gastrointestinal hamartomatous polyps, multiple lipomas, hemangiomas, developmental delay, and in males, pigmented macules of the glans penis. The signs of BRRS that may be present at birth include macrocephaly and macrosomia. Developmental delays may present in early childhood. Other signs associated with BRRS include pectus excavatum, hypotonia, hyperextensibility of joints, thyroid disorders, seizures and scoliosis.

Adult Lhermitte-Dulcos disease (ALDD, also known as dysplastic gangliocytoma of the cerebellum) is characterized by the development of slow-growing, benign hamartomatous outgrowths of the cerebellum. The lesions typically arise in the cerebellar hemispheres, most frequently in the left hemisphere. This condition is most frequently seen in adults, with the average age at diagnosis of 34 years. Developmental abnormalities including macrocephaly and intellectual developmental disorder are common. A presumptive diagnosis of PHTS may be made based on clinical findings; however, a definitive diagnosis of PHTS is made when genetic testing identifies a germline mutation.

The diagnostic criteria for CS are multifaceted. The NCCN guidelines include testing criteria and clinical diagnostic criteria for CS. According to the NCCN guidelines, the CS/PHTS testing algorithm was established to assist in determining which individuals are candidates for testing for PTEN pathogenic or likely pathogenic variants and can be used to evaluate the need for further risk assessment and genetic testing. The revised clinical diagnostic criteria can be used to identify clinical features associated with CS/PHTS. Individuals who meet the revised clinical diagnostic criteria for CS/PHTS are candidates for testing for PTEN pathogenic or likely pathogenic variants (NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, 2022).

According to the NCCN guidelines, the testing criteria for CS/PHTS are divided into three categories (see criteria below). An individual is considered for testing for PTEN pathogenic or likely pathogenic variants based on whether he or she meets specific criteria or combinations of criteria from these three categories.

1. The first category includes any individual with a personal history of BRRS, adult LDD, autism spectrum disorder with macrocephaly, or two or more biopsy-proven trichilemmomas. Additionally, individuals with a family history positive for the presence of a known PTEN pathogenic or likely pathogenic variant.
2. The next category represents “major” features which have been associated with CS/PHTS. An individual exhibiting at least two of the major criteria where one of these is macrocephaly meets the threshold for genetic testing. Similarly, an individual exhibiting three or more of the major criteria without macrocephaly or an individual who meets one of the major criteria and three or more of the minor criteria, would also meet the genetic testing threshold. If an individual has two or more major criteria but does not have macrocephaly, then one of the major criteria may be included as one of the three minor criteria in order to meet the testing threshold. Lastly, an individual with a first-degree relative diagnosed with CS/PHTS or BRRS for whom testing has not been performed would also fulfill the threshold for PTEN testing if the individual meets at least one major criterion and two or more minor criteria. With respect to the presence of mucocutaneous lesions, the panel did not consider the published evidence sufficient to specify an exact number or extent of these lesions required for the condition to be defined as a major criterion for Cowden syndrome. The NCCN panel also felt that evidence from the literature was not sufficient to include fibrocystic breast disease, uterine fibroids or fibromas as part of the testing criteria.
3. The final category of criteria includes features with a “minor” association with CS/PHTS. In order to fulfill the genetic testing criteria in this category, an individual would need to meet at least four or more of the minor criteria or three or more minor criteria and one of the major criteria.  

It is also worth noting that an individual with a first-degree relative diagnosed with CS or BRRS for whom testing has not been completed would also meet the PTEN gene mutation testing criteria provided the individual meets at least one of the major criteria and two or more of the minor criteria (NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, 2022).

The testing criteria below provides a summary of NCCN’s testing criteria for CS/PHTS as well as the major and minor criteria.

TABLE A: Testing for conditions listed in the table below without a “Yes” in the column for “Clinical Utility of Gene Mutation Testing for Cancer Susceptibility Demonstrated” have not been shown to be useful in making determinations regarding cancer susceptibility. In many cases, this is because knowledge of the genetic status does not change management. The following table lists commonly requested gene testing targets along with an assessment of whether or not they have been shown to be useful in determining if an individual is at increased risk for the development of a specific type of malignancy or in guiding clinical management in an at-risk individual (for example, increased cancer surveillance).

TABLE A Gene Mutation Testing for Cancer Susceptibility
(Return to Clinical Indications) – (Return to Discussion/General Information)

B.  Gene Mutation Testing for Cancer Management or to Guide Targeted Therapy in Individuals with a Malignant Condition (See Table B below)

Increased understanding of the human genome has made it possible to identify genomic variation in both normal and malignant tissues. Newer therapies may be targeted to specific variants ("targeted biologic therapy") and may not have been evaluated in individuals without the specific variant or be considered unlikely to benefit individuals without the specific variant.

Examples of targeted therapies include those that:

• Block specific enzymes and growth factor receptors involved in cancer cell proliferation. These drugs are also called signal transduction inhibitors.
• Modify the function of proteins that regulate gene expression and other cellular functions.
• Induce cancer cells to undergo apoptosis.
• Block the growth of blood vessels and blood supply to tumors.
• Help the immune system to destroy cancer cells.

The Food and Drug Administration (FDA) has approved numerous companion diagnostic devices to detect variants in specific genes for the targeted treatment of cancer. Methodologies include, but are not necessarily limited to: immunohistochemistry (IHC), real-time or multiplex polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). As an example of a targeted cancer therapy, in 2017, the FDA approved IDHIFA^® (enasidenib) for the treatment of relapsed or refractory acute myeloid leukemia (AML). However, the FDA drug label also stipulated that IDHIFA should only be used in individuals with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA approved test.

In some cases, genetic testing, also called molecular characterization, is recommended for risk stratification and treatment planning (cancer management), which affects choice of chemotherapeutic regimen, surveillance considerations, and minimal (measurable) disease detection.

Targeted Therapy and Treatment Planning for Leukemias

Leukemia, which is sometimes referred to as a blood cancer, is a type of cancer that affects the blood and bone marrow. The disease occurs when blood cells produced in the bone marrow grow out of control Frequently, leukemia starts the white blood cells, but some leukemias start in other blood cell types. There are various forms of leukemia, which are generally categorized based on whether the leukemia is acute (fast growing) or chronic (slower growing), and whether it starts in myeloid cells or lymphoid cells. As an example, acute lymphoblastic leukemia (AML) and chronic myeloid leukemia (CML) are both blood and bone marrow cancers that affect the same types of white blood cells. While the onset of AML occurs suddenly as very immature cells quickly crowd out normal cells in the bone marrow, CML has a delayed onset, with the CML cells slowly growing out of control. Targeted therapy may be used for the treatment of various types of leukemias.

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (also known lymphoblastic lymphoma [ALL/LBL] and acute lymphocytic leukemia) refers to blood malignancies of lymphoid precursor cells. These entities are described as ALL/LBL because in this setting, leukemia and lymphoma display overlapping clinical presentations of the same disease; the systems for classification and diagnosis do not distinguish between leukemia and lymphoma. Broadly, ALL/LBL is divided into tumors of B cell and T cell descent; tumors of natural killer (NK) cell lineage are also recognized but occur less frequently. Because the various subtypes are morphologically indistinguishable, immunophenotyping is required to determine the lineage.

Most cases of ALL/LBL have molecular and/or cytogenetic abnormalities that are associated with unique phenotypes, prognostic features, and/or influence the choice of treatment. The World Health Organization (WHO) classification system uses immunophenotype and cytogenetic/molecular features to delineate specific categories of ALL/LBL.

With regards to gene mutation testing in individuals suspected of having ALL/LBL, the NCCN recommends:

The Ph-like phenotype is associated with recurrent gene fusions and mutations that activate tyrosine kinase pathways and includes gene fusions involving ABL1, ABL2, CRLF2, CSFIR, EPOR, JAK2, and PDGFRD and mutations involving FLT3, IL7R, SH2B3, JAK1, JAK3, and JAK2 (in combination with CRLF2 gene fusions). Testing for these abnormalities at diagnosis may aid in risk stratification. The safety and efficacy of targeted agents in this population is an area of active research… In cases of hypodiploid ALL where germline TP53 mutations are common, testing should be considered (NCCN ALL, 2021). 

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) refers to a group of leukemias that arise from a myeloid precursor in the bone marrow. Although AML is fairly rare overall, accounting for only about 1% of all cancers it is still one of the most common types of leukemia in adults. Cytogenetically normal AML is the largest defined subclass of AML and accounts for approximately 45% of all AML cases. In spite of the lack of cytogenetic abnormalities, these cases frequently have genetic variants that influence outcomes. The incidence of AML increases with age, with a median age at diagnosis of 68 years. Clinical signs and symptoms include but are not limited to, anemia, neutropenia, and thrombocytopenia. AML is also known as acute myelocytic leukemia, acute myelogenous leukemia, acute granulocytic leukemia, acute non-lymphocytic leukemia) (ACS, 2022).

Management of individuals with AML relies on the results of genetic testing to inform diagnosis, prognosis, and predict response to therapy. Abnormalities in specific genes, such as mutations in ASXL1, BCR-ABL, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA (biallelic), IDH1, IDH2, PML-RARA, RUNX1, and TP53 confer prognostic significance in adults with AML. In addition to prognostic implications, some gene may impact medical decision making or have therapeutic significance in AML (NCCN AML 2022).

The revised 2008 World Health Organization (WHO) AML classification scheme emphasizes the importance of genetic testing in AML Similarly, NCCN recommends that all individuals suspected of having AML be tested for specific gene mutations. Because numerous mutations are associated with AML, testing using multiplex gene panels and comprehensive next-generation sequencing (NGS) analysis may be used for the ongoing management of AML and various phases of treatment (NCCN AML 2022; Swerdlow, 2008). For information on gene panel testing in MDS, please refer GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.

AML is vigorously treated upon detection with chemotherapy and stem cell transplantation.

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variation of AML. In particular, individuals with APL typically present with symptoms related to complications of anemia, neutropenia, and thrombocytopenia. Other signs and symptoms include combinations of weakness and easy fatigability, infections of variable severity, and/or hemorrhagic findings such as gingival bleeding, ecchymoses, menorrhagia or epistaxis. Unique to APL is a presentation with bleeding caused by disseminated intravascular coagulation. Frequently, by the time that individual seeks medical care, the situation has become a life-threatening emergency because of the risk of catastrophic bleeding. Often, at diagnosis, the marrow is nearly 100 percent replaced by malignant promyelocytes, which results in severe anemia, thrombocytopenia, and neutropenia.

APL represents a medical emergency with a high rate of mortality due to hemorrhage. Treatment of the bleeding disorder is usually initiated as soon as the diagnosis is suspected based on cytologic criteria, and even before definitive cytogenetic or molecular confirmation of the diagnosis has been made. Gene mutation testing is not required to diagnose or treat APL. Diagnosis of APL may be made based on an evaluation of the clinical presentation, cell morphology, immunophenotyping, identification of PML/RARα rearrangements using karyotyping, real-time polymerase chain reaction (RT-PCR), or fluorescence in situ hybridization (FISH), and immunofluorescence with anti-PML monoclonal antibodies.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoid neoplasms (lymphoproliferative disorders) that is characterized by a progressive accumulation of functionally incompetent lymphocytes, which are usually of monoclonal origin. CLL is considered identical (that is, one disease with different manifestations) to small lymphocytic lymphoma (SLL). The term CLL is used when the disease manifests predominately in the blood, whereas the term SLL is used when involvement is predominately nodal.

The evaluation of suspected cases of CLL varies according to the presentation. The diagnosis of CLL is generally suspected in asymptomatic individuals when a routine blood count reveals an absolute lymphocytosis. Evaluation of such individuals would usually include a complete blood count with differential and peripheral blood immunophenotyping using flow cytometry. Tests to identify genetic changes that occur in CLL might include but are not necessarily limited to FISH and PCR to identify chromosomal deletions, 13 [del(13q)], and trisomy 12.

The NCCN guidelines on Chronic Lymphocytic Leukemia indicate that TP53 mutation status is associated with low response rates to chemoimmunotherapy and recommends that TP53 mutation testing be done to inform prognosis and/or therapy determination.

Del(17p), which reflects the loss of the TP53 gene and is frequently associated with mutations in the remaining TP53 allele, is associated with short treatment-free interval, short median survival (32 months), and poor response to chemotherapy. TP53 abnormalities can occur in the absence of del(17p) and TP53 mutations have been identified as predictors of resistance to fludarabine-based or bedamustine-based regimens and poor survival, independent of 17p chromosome status (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

Additionally, the NCCN also recommends that IGHV mutation status be determined prior to initiating treatment for CLL:

The choice of first-line treatment for CLL/SLL should be based on the disease stage, presence or absence of del(17p) or TP53 mutation, IGHV mutation status (if considering chemoimmunotherapy), patient’s age, performance status, comorbid conditions, and the agent’s toxicity profile. (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

The mutation status of at least two other genes have been identified as playing an important role in the selection of targeted therapies for the treatment of CLL. In individuals with CLL/SLL who do not have del(17p)/TP53 mutation, the NCCN states “testing for BTK and PLCG2 mutations may be useful in patients with disease progression or no response while on BTK inhibitor therapy. BTK and PLCG2 mutation status alone is not an indication to change treatment” (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

CLL is an extremely diverse disease with certain subsets of individuals having survival rates without treatment that are similar to the normal population. With the possible exception of allogeneic hematopoietic cell transplantation (HCT), there currently is no treatment option that can cure CLL. According to the NCCN: “Long-term results from several prospective studies have shown that allogeneic hematopoietic cell transplant (HCT) can provide long-term disease control and also overcome the poor prognosis associated with del(17p) and TP53 mutations” (NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 2022).

Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML), also known as chronic myelogenous, chronic myelocytic or chronic granulocytic leukemia) is a myeloproliferative neoplasm in which the bone marrow makes too many myeloid cells. These blood cells are abnormal and can build up in the blood and bone marrow so there is less room for the healthy white blood cells. CML is a relatively uncommon disease, primarily affecting older adults at an average age of 64 years. CML it is not an inherited disease. Instead, the DNA mutations associated with CML occur over an individual’s lifetime, rather than being present from birth.

CML is associated with the BCR-ABL mutation that is formed by the combining of two genes: BCR (on chromosome 22) and ABL1 (on chromosome 9), resulting in the BCR-ABL1 fusion gene (also known as the Philadelphia chromosome). The presence of the BCR-ABL1 fusion gene confirms the diagnosis of CML. CML patients who have the Philadelphia chromosome (Ph+ CML) have a more favorable prognosis than those without the Philadelphia chromosome (Ph- CML). Testing for the BCR-ABL abnormality can be done using cytogenetics (chromosome analysis or karyotyping), FISH and RT-PCR (to detect and measure the BCR-ABL1 RNA transcripts in leukemic cell). DNA sequencing methods may be used to identify secondary mutations within BCR-ABL1 that are known to cause resistance to therapy.

Prior to the availability of protein tyrosine kinase inhibitors (TKIs), the only curative option for CML was high-dose chemotherapy with hematopoietic stem cell transplantation (HSCT). but with the emergence of BCR-ABL-targeted TKIs, the role of HSCT has become less clear. Protein TKIs are typically utilized in the treatment of CML. Point mutations in the BCR-ABL1 kinase domain are a frequent mechanism of secondary resistance to TKI therapy and are associated with poor prognosis and higher risk of disease progression.

Several drugs in the protein TKI class have now been approved by the United States Food and Drug Administration for the treatment of CML Most individuals have a good response to this first-line of therapy. However, some individuals develop secondary (acquired) resistance to the first-line therapeutic agent, which may be due to secondary mutations of the BCR-ABL gene. BCR-ABL1 kinase domain (KD) mutation status can be used to guide selection of alternative TKIs for CML patients who experience resistance to or intolerance to initial TKI therapy. The NCCN recommends that in individuals who present with advanced phase CML, the selection of TKI should be based on prior therapy and/or BCR-ABL1 mutation profile.

Additionally, according to the NCCN, “NGS allows for the detection of low-level BCR-ABL1 kinase domain mutations as well as resistance mutations in genes other than BCR-ABL1 that may confer resistance to TKIs or portend disease progression” and “NGS with myeloid mutation panel should be considered for patients with no identifiable BCR-ABL1 mutations” (NCCN Chronic Myeloid Leukemia, V1 2023).

The NCCN also recommends gene mutational analysis when allogeneic hematopoietic cell transplantation is being considered for patients with advanced phase CML.

Hairy Cell Leukemia

Hairy cell leukemia (HCL) is a relatively uncommon chronic B cell lymphoproliferative disorder (lymphoid neoplasm) characterized by the build-up of small mature B cell lymphoid cells with abundant cytoplasm and "hairy" projections inside the peripheral blood, bone marrow, and splenic red pulp. This typically causes splenomegaly and a variable decline in the production of normal red blood cells, platelets, mature granulocytes, and monocytes. The amplified production of malignant cells, along with a decrease in these mature elements, results in a variety of systemic consequences, including, but not limited to, anemia, splenomegaly, bleeding, and an increased risk of infection.

The etiology of HCL is not completely understood. Most cases of HCL are believed to arise from a late, activated memory B cell somatic BRAF V600E gene mutation. The resultant abnormal activation of the RAF-MEK-ERK signaling pathway leads to a distinct phenotype and prolonged cell survival.

Exposures to environmental hazards such as ionizing radiation and pesticides have been mentioned as possible causes. Exposure to cigarette smoke, alcohol consumption, solvents and obesity do not appear to be risk factors for the development of HCL.

The diagnosis of HCL is generally made based on the results of bone marrow biopsy and aspirate in conjunction with immunophenotyping by flow cytometry. The aberrant (“hairy”) cells exhibit expression of pan-B cell antigens (for example, CD19, CD20, CD22) along with CD103, CD11c, and CD25. Gene mutation testing is typically not required to make the diagnosis of HCL.

Because this malignancy progresses very slowly and sometimes doesn't progress at all, it is not always necessary to begin treatment for HCL immediately after the diagnosis is confirmed.

Systemic Mastocytosis

Systemic mastocytosis is a rare disorder characterized by the expansion and focal accumulation of neoplastic mast cells (MC) in various organs, including the skin, spleen, liver, bone marrow and gastrointestinal tract. The World Health Organization (WHO) categorizes mastocytosis into cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma (MCS). WHO also further delineates SM into additional categories based on disease-specific features:

1. Indolent SM (ISM)
2. Smoldering SM (SSM)
3. Aggressive SM (ASM)
4. SM with an associated hematopoietic neoplasm (SM-AHN) and
5. MC leukemia (MCL).

MCS is a rare, localized, aggressive MC tumor that typically progresses to MCL within a short time. Advanced SM (ASM, SM-AHN, MCL) and MCS have unfavorable prognoses. Without successful therapy, the estimated median survival time in these individuals is less than 3 years. Once the diagnosis of SM has been made, the subtype (variant) of disease must be identified, as treatment and prognosis differ for each disorder\ (Valent, 2021).

Systemic mastocytosis is frequently diagnosed after affected individuals seek medical care for symptoms caused by the disorder. Symptoms of systemic mastocytosis may include cutaneous lesions, flushing, itching, hives, abdominal pain, diarrhea, nausea or vomiting, bone or muscle pain, anemia, bleeding disorders, splenomegaly, lymphadenopathy, depression, mood changes and problems concentrating.

A somatic mutation in the KIT gene is the most common genetic alteration found in systemic mastocytosis. The KIT gene encodes a protein that helps regulate cell growth and division. When the KIT gene is mutated, it can cause uncontrolled production of MCs which then accumulate in various organs of the body.

With regards to gene mutation testing for individuals suspected of having systemic mastocytosis, the NCCN recommends that:

If a diagnosis of SM is suspected, molecular testing for KIT D816V using an assay with high sensitivity (eg, ASO-qPCR or digital droplet PCT) can first be undertaken on the peripheral blood, in combination with measurement of the serum tryptase level and evaluation of clinical signs and/or symptoms suggestive of SM-related organ involvement.

Following a positive test of peripheral blood, KIT mutational analysis may also be performed on the bone marrow aspirate. Fresh bone marrow is aspirate is preferable but formalin-fixed paraffin-embedded tissue can also be used. Decalcified tissue typically interferes with DNA/RNA assays, and thus, decalcified BM should not be used for mutational analysis. If initial screening of the peripheral blood fails to detect the KIT D816V mutation in a patient with suspected SM, testing of the bone marrow should be undertaken with a highly sensitive assay (eg, ASO-qPCR or digital droplet PCR).

Additionally, the NCCN recommends:

Myeloid mutation panel testing should be performed on the bone marrow, but can be performed on the peripheral blood in the presence of an AHN and/or circulating mast cells. Myeloid mutation panels alone are not recommended for the detection of KIT D816V. Next-generation sequencing (NGS) assays can exhibit low sensitivity and higher-sensitivity assays should always be performed (NCCN Systemic Mastocytosis, 2021).

Currently, there is no treatment of systemic mastocytosis. Treatment is targeted at relieving the effects of MC overgrowth and avoiding environmental and dietary triggers.

Targeted Therapy and Treatment Planning for Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) consist of a group of blood malignancies characterized by clonal hematopoiesis, one or more cytopenias (ie, anemia, neutropenia, and/or thrombocytopenia), and atypical cellular maturation. MDS shares some pathologic and clinical features with AML, but MDS has a lower percentage of blasts in bone marrow and peripheral blood (by definition, < 20 percent). Individuals with MDS are at risk for symptomatic anemia, infection, bleeding, and transformation to AML. Because the clinical presentation of MDS in individuals varies significantly, diagnosis and disease stratification are based on multiple factors including clinical data, morphology of peripheral blood and bone marrow, cytogenetics, fluorescence in situ hybridization (FISH), flow cytometry and next-generational sequencing myeloid mutations studies. The primary clinical challenge in these disorders are morbidities caused by cytopenias and the potential for MDS to evolve into acute myeloid leukemia (AML). Additionally, there are complications that may arise as a result of chronic transfusions, treatment toxicity and in some cases systemic inflammatory conditions (NCCN Myelodysplastic Syndromes, 2022).

Genetic frequently somatically mutated in MDS include: ASXL1, BCOR, CALR, CBL, DDX41, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1, ZRSR2. However, it is important to note that several MDS-associated genes, (including but not limited to DNMT3A, EZH2, NRAS, SF3B1, TP53 and TET2) can occur in non-disease states and no single gene mutation is diagnostic of MDS. Additionally, mutations in several genes can occur in neoplasms other than MDS including malignancies of lymphoid origin such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Therefore, mutations should not be considered presumptive evidence of MDS when the diagnostic criteria for MDS have not been met. Instead, gene mutation testing may be used to inform the diagnosis of MDS (NCCN Myelodysplastic Syndromes, 2022). For information on gene panel testing in MDS, please refer GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.

Mutations in several genes have prognostic value. As an example, mutations of ASXL1, ETV6, EZH2, RUNX1 and TP53 have been associated with decreased overall survival, while only mutations in SF3B1 have been associated with a more favorable prognosis in several, but not all studies NCCN Myelodysplastic Syndromes, 2022). 

Therapeutic options for individuals with MDS include supportive care, low-intensity therapy, high-intensity therapy (including allogeneic HCT) and participation in clinical trials.

Targeted Therapy and Treatment Planning for Myeloproliferative Neoplasms (MPNs)/Myeloproliferative Disorders (MPDs)

The MPDs/MPNs are a large group of relatively rare pathogenetically related diseases arising in the bone marrow and characterized by the proliferation of one or more myeloid cell lines in the bone marrow resulting in increased numbers of relatively mature neoplastic cells in the peripheral blood. According to the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissue, MPNs include chronic myelogenous leukemia (BCR-ABL1 positive [CML]), PV, PMF and ET. However, CML is unique in that it is the only one of these conditions that is positive for the BCR-ABL1 translocation. The others, PV, MF and ET are considered part of the operational sub-category of BCR-ABL1 negative conditions (Swerdlow, 2017).

MPNs are characterized by a complex collection of symptoms. The symptoms vary within and between each MPN subtype, but typically include constitutional symptoms such as fatigue, weight loss, pruritus, symptoms associated with splenomegaly, and a variety of laboratory abnormalities, including leukocytosis, thrombocytosis and erythrocytosis. And while there are a number of shared clinical features across the conditions, each of the three BCR-ABL–negative MPNs is considered a distinct clinical entity. ET is characterized by elevation in platelet count and megakaryocyte proliferation in the bone marrow. PV is distinguished by an increase in red blood cell production, with resulting increases in RBC mass and hemoglobin and hematocrit levels. Frequently, platelet and white blood cell count are also elevated. PMF is characterized by anemia, progressive splenomegaly and bone marrow fibrosis, and multi-organ extramedullary hematopoiesis. Most of these features, however, are not diagnostically specific, and secondary causes of erythrocytosis, thrombocytosis and bone marrow fibrosis must be excluded.

The BCR-ABL1–negative MPNs are genetically characterized by the overlapping presence of mutations in three driver genes—JAK2, CALR, and MPL. Mutations in either of these driver genes results in increased activity in the JAK/STAT signal transduction pathway.

The diagnosis and monitoring of individuals with BCR-ABL–negative MPN can be challenging because several of the clinical and laboratory features of the classic forms of these diseases-PV, ET, or PMF-can be mimicked by other conditions such as myeloid fibrosis. Additionally, these diseases cannot always be identified with certainty on morphologic bone marrow exam, and diagnosis can be complicated by altering disease patterns. As an example, PV and ET can undergo a leukemic transformation or evolve into PMF.

The 2017 WHO guidelines on the Classification of Tumours of Haematopoietic and Lymphoid Tissue were revised in 2017 to reflect the recent discovery of genetic abnormalities involved in the pathogenesis of BCR-ABL1 negative MPN. The WHO diagnostic criteria include a combination of clinical, laboratory cytogenetic, and molecular testing. The diagnosis of PMF requires the individual to meet 3 major and 2 minor criteria. The diagnosis of PV requires meeting both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria, whereas the diagnosis of ET requires meeting all 4 criteria The 2017 WHO criteria recommends that JAK2V617F and other clonal markers be tested in individuals suspected of having ET and PMF. WHO also recommends that testing for JAK2V617F and JAK2 exon 12 variants be conducted in individuals suspected of having PV. These guidelines also provide the following information regarding JAK2 mutation testing:

JAK2 mutations are not specific for any single clinical or morphologic MPN phenotype, and are also reported in some cases of myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and acute myeloid leukaemia (AML). Thus, an integrated, multidisciplinary approach is necessary for the classification of myeloid neoplasms (Swerdlow, 2017).

The National Comprehensive Cancer Network (NCCN) guidelines on Myeloproliferative Neoplasms recommends that molecular testing for JAK2V617F mutations be performed in all individuals suspected of having ET, MF or PV. For individuals suspected of having PV, when JAK2V617F mutation testing is negative, molecular testing for the JAK2 exon 12 mutation should also be conducted. These NCCN guidelines include MPL mutation testing in the initial workup of all individuals suspected of having an MPN. The NCCN recommends that when JAK2 V617F mutation testing is negative, molecular testing for MPL and CALR mutations should be performed for individuals with MF and ET (NCCN, 2021).

Table B below contains a list of targeted cancer therapies, the associated cancer and the genetic variant that may be tested in order to direct targeted cancer therapy, including to guide recommended treatment planning. This information may be used to determine the appropriateness of a requested genetic test when considering the medical necessity criteria in the section above labeled: Gene Mutation Testing to Guide Targeted Cancer Therapy. Table B is current as of the publish date of this document. FDA approvals after the publish date (for example new drugs or new indications for existing drugs), will not be reflected in Table B until the next publish date. Reviewers should not rely solely on the absence of a drug/gene combination in Table B when determining whether a particular gene test meets the medical necessity criteria. For additional information and periodic updates on drug and companion diagnostic device approvals/clearances, visit the FDA websites at: https://labels.fda.gov/ and https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools.

TABLE B Gene Mutation Testing for Cancer Management or to Guide Targeted Cancer Therapy
(Return to Clinical Indications) – (Return to Discussion/General Information)

C.  Circulating Tumor DNA (Liquid Biopsy)

Cancer develops from genetic alterations in DNA that affect the way cells grow and divide. A tissue biopsy is the gold standard for detecting DNA alterations that can be used to identify cancer, determine treatment options, or evaluate responsiveness to treatment. Tissue biopsies have several disadvantages: the biopsy procedure may be painful, such as the insertion of a long needle or a surgical procedure; the retrieved tissue may be too small for analysis; or an individual may not be able to physically tolerate the procedure. In addition, because tissue biopsies only represent cellular samples from parts of a tumor, important diagnostic data could be missed.

Circulating tumor DNA (ctDNA), also known as liquid biopsy, is proposed as a less-invasive method for cancer identification, surveillance, and treatment guidance. The National Cancer Institute (NCI) defines liquid biopsy as “A test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood.” Tests of ctDNA detect small fragments of mutated DNA that are released from tumors into blood, presumably by apoptosis and/or necrosis. These tests are being explored as a less-invasive diagnostic alternative to tissue biopsies to improve the selection of targeted therapeutic agents for late-stage cancers and for post-cancer monitoring.

There are several limitations of liquid biopsies. Regarding cancer management, many cancers do not have specific DNA variants that can be identified and, when present, can be different in individuals with the same cancer. The DNA found in the fluid sample may not fully represent the tumor and mislead treatment decisions. The genetic variants found may not be “driver” variants and may not provide useful information about the cancer. Regarding cancer detection, liquid biopsies can test positive for cancer when no cancer is present (false-positive) or test negative when cancer is present (false-negative). Because cancer cells release more mutated DNA fragments in later cancer stages, the test may not identify early cancer. Likewise, a liquid biopsy can detect cancerous cells that may never actually cause harm, leading to overtreatment (NCI, 2018). While liquid biopsies are promising, a great deal of research is still needed to determine when these tests improve outcomes for individuals with cancer. Nonetheless, in circumstances when tumor tissue is inadequate in quality or quantity or is unavailable for testing, and the presence or absence of a variant is likely to guide drug treatment, it is reasonable to test for ctDNA given that no alternative exists.

Liquid biopsies are regulated by the Clinical Laboratory Improvement Amendments (CLIA) program, which oversees and certifies the laboratories conducting FDA-approved and non-FDA approved tests. The FDA approval or clearance does not necessarily imply that the test improves clinical outcomes or should be used for clinical management. Testing for ctDNA performed in CLIA-certified laboratories also do not require evidence of clinical utility; only analytical and clinical validity of the test must be demonstrated prior to clinical use.

This document does not address ctDNA panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider). For information on ctDNA panel testing, see GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.  

EGFR Mutation Testing to Select Targeted Therapy in Individuals with Non-small Cell Lung Cancer

Liquid biopsy tests for ctDNA are targeted for specific gene variants. For example, in the instance of NSCLC, a targeted liquid biopsy may be used to identify the presence of the epidermal growth factor receptor (EGFR) variant and determine if individuals may benefit from kinase inhibitor medication.

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology released a joint guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors (TKI) (Lindeman, 2018). This document has a strong recommendation stating, “In lung adenocarcinoma patients who harbor sensitizing EGFR mutations and have progressed after treatment with an EGFR-targeted TKI, physicians must use EGFR T790M mutational testing when selecting patients for third-generation EGFR-targeted therapy.” Regarding circulating tumor cell testing (also referred to as circulating plasma cfDNA, plasma cfDNA and cfDNA), they state the following:

• There is currently insufficient evidence to support the use of circulating plasma cfDNA molecular methods for establishing a primary diagnosis of lung adenocarcinoma (no recommendation; insufficient evidence, confidence, or agreement to provide a recommendation).
• In some clinical settings in which tissue is limited and/or insufficient for molecular testing, physicians may use a cfDNA assay to identify EGFR mutations (recommendation; some limitations in quality of evidence).
• Physicians may use plasma cfDNA methods to identify EGFR T790M mutations in lung adenocarcinoma patients with progression or secondary clinical resistance to EGFR-targeted TKIs; testing of the tumor sample is recommended if the plasma result is negative (expert consensus opinion; serious limitations in quality of evidence).

The NCCN has the following category 2A recommendation regarding ctDNA testing to identify the EGFR variant in individuals with NSCLC: “If there is insufficient tissue to allow testing for all of EGFR, ALK, ROS1 and BRAF, repeat biopsy and/or plasma testing should be done.” (NCCN NSCLC V2.2021).

The FDA has approved at least two tests for detecting the EGFR variant in individuals with NSCLC. For example:

• cobas EGFR Mutation Test v2 (Roche Molecular Systems Inc., Pleasanton, CA, USA)
  • Solid tumor tissue testing:
    On June 1, 2016, the FDA in PMA (P150047) expanded the approval of the cobas^® Mutation Test v2 (Roche Molecular Diagnostics, Pleasanton, CA), a tissue biopsy test, to be used as a real-time polymerase chain reaction (PCR) blood plasma test that detects defined mutations of the epidermal growth factor receptor (EGFR) gene in individuals with non-small cell lung cancer (NSCLC). The test is indicated as a companion diagnostic to identify individuals who have exon 19 deletions or L858R mutations and would benefit from treatment with Tarceva® (erlotinib), a kinase inhibitor. According to the FDA, individuals who test negative with the cobas plasma test should undergo a tissue biopsy for confirmation (FDA 2016[b]).
  • ctDNA testing:
    On September 28, 2016, the FDA approved the cobas plasma test for detecting the EGFR T790M mutation for individuals who would benefit from treatment with Tagrisso (osimertinib), a kinase inhibitor recommended after progression of NSCLC during first-line treatment (P150044). The FDA states that the efficacy of the plasma test for targeting Tagrisso is limited, and plasma specimens should only be used when a tissue biopsy is not possible (FDA 2016[c]).

In addition to the FDA-approved companion diagnostic tests, some commercially available tests (performed at a CLIA certified laboratories) are available which detect EGFR variants in individuals with non-small cell lung cancer are also available. As an example, OncoBEAM^™ (Sysmex Inostics, Mundelein, IL) has developed the Lung1 EGFR ctDNA test which may be used to identify individuals with non-small cell lung cancer who may benefit from treatment with an EGFR-targeted tyrosine kinase inhibitor.

PIK3CA Mutation Testing to Select Targeted Therapy in Individuals with Breast Cancer

Mutations in the phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene have been implicated in the pathogenesis of several cancers, including but not limited to colon, gastric, breast, endometrial, and lung cancer. Researchers are exploring the role of PIK3CA mutations in the initiation, progression and management of various cancers.

Mutations in the PIK3CA gene can also lead to the development of a group of rare, non-malignant disorders collectively known as PIK3CA-related overgrowth spectrum (PROS). PROS disorders include fibroadipose hyperplasia, CLOVES syndrome, megalencephaly-capillary malformation (MCAP) syndrome, hemihyperplasia‐multiple lipomatosis (HHML) syndrome, hemimegalencephaly and facial infiltrating lipomatosis. This document does not address PROS.

Other names for PIK3CA include but are not limited to:

• catalytic subunit alpha polypeptide gene
• PI3K
• PI3KCA
• PI3K-alpha
• PI3-kinase p110 subunit alpha.

The FDA approved the companion diagnostic test therascreen PIK3CA RGQ PCR Kit (QIAGEN Germantown, MD) to detect the PIK3CA variants in both, a breast tumor tissue specimen and a plasma specimen (ctDNA). According to the FDA, individuals who are negative by the therascreen test using the ctDNA should undergo tumor biopsy for PIK3CA variant testing. Use of the ctDNA test has not been evaluated in a prospective clinical study; approval was based on a retrospective secondary analysis of participants enrolled in the SOLAR-1 clinical trial. The SOLAR-1 trial evaluated alpelisib on the basis of tumor-tissue PIK3CA mutation status.

The May 24, 2019 FDA Summary and Effectiveness Data (SSED) includes a discussion of the concordance of the PIK3CA variant results of the therascreen PIK3CA RGQ PCR Kit (P190004) which uses plasma samples and the therascreen PIK3CA RGQ PCR Kit, which uses tissue samples (P190001). Of the 328 PIK3CA tissue positive subjects, only 179 were plasma PIK3CA positive. Of the 215 PIK3CA tissue negative subjects, 209 were plasma PIK3CA negative. The negative percent agreement (NPA) was 97.2% while the positive percent agreement (PPA) was only 54.6%. It was noted that five PIK3CA variants (H1047Y, Q546R, Q546E, E545D and E545A) were not identified by the therascreen PIK3CA RGQ PCR Kit using plasma clinical samples. FDA approval of the PIK3CA RGQ PCR Kit is contingent upon additional post market accuracy studies of those variants. Because of the high false negative rate (the plasma test failed to discover approximately 46% of the variants identified in the tumor tissue test), reflex testing of plasma mutation negative samples using tissue specimens is required.

The NCCN Clinical Practice Guidelines on Breast Cancer (V2.2022) recommends that in individuals with HR-positive/HER2-negative breast cancer, PIK3CA mutation testing using tumor tissue or ctDNA in peripheral blood (liquid biopsy) be conducted in order to identify candidates for alpelisib plus fulvestrant, (category 1 rating). If liquid biopsy results are negative, tumor tissue testing is recommended.

With regard to treatment regimens for men with breast cancer, the NCCN indicates the following:

Management of advanced breast cancer in males is similar to that in females; however, it is preferred that when an aromatase inhibitor is used, a GnRH analog should be given concurrently. Available data suggest single-agent fulvestrant has similar efficacy in males as in females. Newer agents such as CDK4/6 inhibitors in combination with an aromatase inhibitor or fulvestrant, mTOR inhibitors, and PIK3CA inhibitors have not been systematically evaluated in clinical trials in males with breast cancer. However available real-world data suggest comparable efficacy and safety profiles and it is reasonable to recommend these agents to males based on extrapolation of data from studies comprised largely of female participants with advanced breast cancer.

Testing to Detect the Recurrence of Colorectal Cancer

Colvera^™ (Clinical Genomics Pathology, Bridgewater, NJ) has been explored as a liquid biopsy test to detect the recurrence of colorectal cancer (CRC). In 2017, Murray and colleagues investigated the analytical and clinical validity of the Colvera plasma test for the detection of methylated BCAT1 and IKZF1 in individuals with CRC. The researchers randomized 264 plasma samples and 120 buffer samples, divided the samples into 8 batches of 48, and processed the samples over 8 days using 2 equipment lines. Clinical validity was analyzed by using Colvera on 222 archived plasma samples (n=26 with known CRC) from individuals who were scheduled for colonoscopy as part of a previous trial (Pedersen, 2015). The researchers found that the limit of detection (LOD) was 12.6 pg/ml (95% confidence interval [CI], 8.6 to 23.9), the equivalent of 2 diploid genomes/ml of plasma. Colvera tested positive for 19/26 known cancer cases for an agreement of 73% (95% CI, 52% to 88%). For the 196 nonneoplastic subjects, Colvera had an agreement of 89% (95% CI, 84% to 93%). Total agreement was 87% (194/222; 95% CI, 82% to 91%). Limitations of the study included a small sample size.

In 2020, Musher and colleagues published a cross-sectional study evaluating the diagnostic accuracy of the Colvera test compared with carcinoembryonic antigen (CEA) for identifying recurrence of CRC. The study enrolled 537 adults who were undergoing surveillance after treatment for stage II or III CRC. Blood samples were collected at a single time point, within 6 months of surveillance radiological imaging, and evaluated using the Colvera test and CEA. A total of 322 (60%) individuals were included in the final analysis; 20 (3.7%) were excluded because they did not meet eligibility criteria and 195 (36.3%) were excluded for insufficient information. Among the evaluable participants, CRC recurrence occurred in 27 (8.4%) of individuals. The sensitivity of the Colvera test for detecting CRC recurrence (63%) was significantly higher than CEA testing (48.1%), p=0.046. However, the specificity of CEA testing (96.3%) was significantly higher than Colvera testing (91.5%), p=0.012. While the Colvera test appears to be a promising diagnostic tool to predict the recurrence of CRC, the study has several limitations which prevent drawing conclusions regarding its diagnostic accuracy. For example, as discussed above, a substantial proportion (40%) of study participants were excluded from the analysis. Additionally, the authors acknowledge that although this study demonstrated that the specificity of CEA in the 295 subjects without cancer recurrence was higher than that of Colvera, the significance of a false positive result in this study is uncertain due to the relatively short follow-up period. Because the Colvera and CEA results were correlated with only one imaging test, it is possible that some individuals thought to be without recurrence might later prove to have recurrent disease after further imaging. Additional well-designed prospective, randomized controlled trials with longer follow-up are needed to determine whether, Colvera, when compared to CEA facilitates earlier diagnosis of CRC recurrence and, in turn, improves cancer-related outcomes.

TABLE C Circulating Tumor DNA Testing to Guide Targeted Cancer Therapy in Individuals with Solid Tumor(s) (when Criteria B in the Clinical Indications section are met). (Return to Clinical Indications)

Note: This document does not address ctDNA panel testing (defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider. For information on ctDNA panel testing for indications other than selecting targeted therapy agents in individuals with cancer, see:

• GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling.  

Associated Therapeutic Product (ATP): The therapeutic, preventive, and prophylactic drugs and biological products approved in association with an IVD (FDA, 2016).

Biallelic Mutation: A mutation in both copies of a particular gene that affects the function of both copies.

Bone marrow: The inner, soft part of certain bones, where new blood cells are made.

Circulating tumor DNA (ctDNA): Also known as a liquid biopsy, this test detects small fragments of mutated DNA that are released from tumors into blood, presumably by apoptosis and/or necrosis.

Cytogenetics: The branch of genetics that examines the structure of DNA within the cell nucleus, (the number and morphology of chromosomes).

Epidermal growth factor receptor (EGFR): A cell receptor that is associated with regulation of cell growth.

First-degree relative: Any relative who is a parent, sibling, or offspring of an individual.

The National Human Genome Research Institute of the National Institutes of Health (NIH) defines the following terms in the context of potential transmission of inherited conditions associated with genetic mutations as follows:

• First-degree relative: Any relative who shares approximately 50% of an individual’s genetic material, such as an individual’s parent (father or mother), full sibling (brother or sister), or offspring.
• Second-degree relative: Any relative who shares approximately 25% of an individual’s genetic material, such as an individual’s grandparent, grandchild, uncle, aunt, niece, nephew, or half-sibling.
• Third-degree relative: Any relative who shares approximately 12.5% of an individual’s genetic material, such as an individual’s first cousin, great grandparent, great grandchild, great uncle, great aunt, half-uncle, half-aunt, half-niece, or half-nephew.

Genome: The total genetic composition of an organism.

In Vitro Companion Diagnostic Devices (IVD): An in vitro device or an imaging tool that provides information essential for the safe and effective use of a corresponding therapeutic product. The use of an IVD companion diagnostic device with a particular therapeutic product is stipulated in the instructions for use in the FDA labeling of both the diagnostic device and the corresponding therapeutic product, as well as in the FDA labeling of any generic equivalents and biosimilar equivalents of the therapeutic product (FDA, 2016).

Lymphoid cells: Cells derived from the lymphatic system, including lymphocytes, lymphoblasts, and plasma cells.

Lymphoid tissue: Relating to the tissue responsible for producing antibodies and lymphocytes. Examples of lymphoid tissue includes but is not limited to the lymph nodes, thymus, tonsils, and spleen.

Mast cells: Immune cells of the myeloid lineage that are present in connective tissues. Mast cells are also known as mastocytes.

Mast cell sarcoma: A particularly aggressive form of sarcoma.

Myeloid cells: A subgroup of lymphocytes (white blood cells) derived from the bone marrow, and which play a major role in innate immunity. Myeloid cells include granulocytes, monocytes, macrophages, and dendritic cells.

Next-generation sequencing (NGS): Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.

Point mutation: A change within a gene that results in one base pair in the DNA sequence being altered

Sarcoma: A tumor that is mad of connective tissue cell.

Targeted cancer therapy: Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer. They recognize a specific feature of the cancer cell, attach to it, and destroy it. Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names (NCI, 2014).

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8. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006; 20(10):1767-1773.
9. Jabbour EJ, Cortes JE, Kantarjian HM. Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options. Clin Lymphoma Myeloma Leuk. 2013; 13(5):515-529.
10. Khorashad JS, Anand M, Marin D, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia. 2006; 20(4):658-663.
11. Kolibaba KS. Molecular monitoring of response in patients with chronic myeloid leukemia. Manag Care. 2013; 22(7):40, 50-61.
12. Leotta S, Markovic U, Pirosa MC, et al. The role of ponatinib in adult BCR-ABL1 positive acute lymphoblastic leukemia after allogeneic transplantation: a real-life retrospective multicenter study. Ann Hematol. 2021; 100(7):1743-1753.
13. Maino E, Sancetta R, Viero P. Current and future management of Ph/BCR-ABL positive ALL. Expert Rev Anticancer Ther. 2014; 14(6):723-740.
14. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008; 112(12):4437-4444.
15. Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009; 114(24):4944-4953.
16. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res.2005; 65(11)4500-4505.
17. Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007; 92(3):401-404.
18. Soverini S, De Benedittis C, Papayannidis C, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer. 2014; 120(7):1002-1009.
19. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011 Aug; 118(5):1208-1215.
20. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naïve patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005; 106(6):2128-2137.
21. Yoo HL, Kim SH, Choi SY, et al. Optimal time points for BCR-ABL1 tyrosine kinase domain mutation analysis on the basis of European LeukemiaNet recommendations in chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2019; 19(7):406-412

BRAF Mutation Analysis

1. Aguilera D, Janss A, Mazewski C, et al. Successful retreatment of a child with a refractory brainstem ganglioglioma with vemurafenib. Pediatr Blood Cancer. 2016; 63(3):541-543.
2. Andrulis M, Penzel R, Weichert W, et al. Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia. Am J Surg Pathol. 2012; 36(12):1796-1800.
3. Arcaini L, Zibellini S, Boveri E, et al. The BRAF V600E mutation in hairy cell leukemia and other mature B-cell neoplasms. Blood. 2012; 119(1):1888-1891.
4. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011; 104(3):392-398.
5. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001; 19(16):3622-3634.
6. Bautista F, Paci A, Minard-Colin V, et al. Vemurafenib in pediatric patients with BRAFV600E mutated high-grade gliomas. Pediatr Blood Cancer. 2014; 61(6):1101-1103.
7. Bokemeyer C, Bondarenko I, Hartmann JT, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol. 2011; 22(7):1535-1546.
8. Bokemeyer C, Cutsem EV, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012; 48(10):1466-1475.
9. Bokemeyer C, Kohne C, Rougier P, et al. Cetuximab with chemotherapy (CT) as first-line treatment for metastatic colorectal cancer (mCRC): analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. J Clin Oncol 2010; 28:15s. (Abstr 3506).
10. Boyd EM, Bench AJ, van 't Veer MB, et al. High resolution melting analysis for detection of BRAF exon 15 mutations in hairy cell leukaemia and other lymphoid malignancies. Br J Haematol. 2011; 155(5):609-612.
11. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011; 364(26):2507-2516.
12. Davies H, Bignell GR, Cox C, Stephens P, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-954.
13. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010; 11(8):753-762.
14. Diamond EL, Subbiah V, Lockhart AC, et al. Vemurafenib for BRAF V600-mutant Erdheim-Chester disease and Langerhans cell histiocytosis: analysis of data from the histology-independent, Phase 2, open-label VE-BASKET study. JAMA Oncol. 2019; 5(1):122.
15. Dietrich S, Glimm H, Andrulis M, et al. BRAF inhibition in refractory hairy-cell leukemia. N Engl J Med. 2012; 366(21):2038-2040.
16. Di Nicolantonio F, Martini M, Molinari F, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008; 26(35):5705-5712.
17. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-819.
18. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012; 367(2):107-114.
19. Follows GA, Sims H, Bloxham DM, et al. Rapid response of biallelic BRAF V600E mutated hairy cell leukaemia to low dose vemurafenib. Br J Haematol. 2013; 161(1):150-153.
20. Gautschi, O, Pauli, C, Strobel, K, et al. A patient with BRAF V600E lung adenocarcinoma responding to vemurafenib. J Thorac Oncol. 2012; 7(10): e23-24.
21. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013; 121(9):1495-1500.
22. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012; 380(9839):358-365.
23. Héritier S, Emile JF, Barkaoui MA, et al. BRAF mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy. J Clin Oncol. 2016; 34(25):3023-3030.
24. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015; 373(8):726-736.
25. Kaley T, Touat M, Subbiah V, et al. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J Clin Oncol. 2018; 36(35):3477-3484.
26. Khan MA, Andrews S, Ismail-Khan R, et al. Overall and progression-free survival in metastatic melanoma: analysis of a single-institution database. Cancer Control. 2006; 13(3):211-217.
27. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009; 27(35):5924-5930.
28. Li J, Sasane M, Zhang J, et al. Is time to progression associated with post-progression survival in previously treated metastatic non-small cell lung cancer with BRAF V600E mutation? A secondary analysis of phase II clinical trial data. BMJ Open. 2018; 8(8):e021642.
29. Lin JS, Webber EM, Senger CA, et al. Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer. Am J Cancer Res 2011; 1(5):650-662.
30. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017; 377(19):1813-1823.
31. López-Rubio M, Garcia-Marco JA. Current and emerging treatment options for hairy cell leukemia. Onco Targets Ther. 2015; 8:2147-2156.
32. Mao C, Liao RY, Qiu LX, et al. BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. Mol Biol Rep 2011; 38(4):2219-2223.
33. Marks AM, Bindra RS, DiLuna ML, et al. Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib. Pediatr Blood Cancer. 2018; 65(5):e26969.
34. McClain KL, Picarsic J, Chakraborty R, et al. CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. Cancer. 2018; 124(12):2607-2620.
35. Ogino S, Shima K, Meyerhardt JA, et al. Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803. Clin Cancer Res. 2012; 18(3):890-900.
36. Peters S, Michielin O, Zimmermann S. Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. J Clin Oncol. 2013; 31(20):e341-344.
37. Peyrade F, Re D, Ginet C, et al. Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation. Haematologica. 2013; 98(2):e20-22.
38. Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2015; 51(5):587-594.
39. Planchard D, Besse B, Groen HJM, et al. An open-label phase 2 trial of dabrafenib plus trametinib in patients with previously treated BRAF V600E-mutant metastatic non-small cell lung cancer. Lancet Oncol. 2016; 17(7):984-993.
40. Oneal PA, Kwitkowski V, Luo L, et al. FDA approval summary: Vemurafenib for the treatment of patients with Erdheim-Chester Disease with the BRAFV600 Mutation. Oncologist. 2018; 23(12):1520-1524.
41. Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009; 27(35):5931-5937.
42. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015; 372(1):30-39.
43. Robinson SD, O'Shaughnessy JA, Cowey CL, et al. BRAF V600E-mutated lung adenocarcinoma with metastases to the brain responding to treatment with vemurafenib. Lung Cancer. 2014; 85(2):326-330.
44. Rowland A, Dias MM, Wiese MD, et al. Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer. Br J Cancer. 2015; 112(12):1888-1894.
45. Rush S, Foreman N, Liu A. Brainstem ganglioglioma successfully treated with vemurafenib. J Clin Oncol. 2013; 31(10):e159-e160.
46. Seymour MT, Brown SR, Richman S, et al. Addition of panitumumab to irinotecan: results of PICCOLO, a randomized controlled trial in advanced colorectal cancer (aCRC) [abstract]. ASCO Meeting Abstracts 2011; 29:3523.
47. Shahabi V, Whitney G, Hamid O, et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother. 2012; 61(5):733-737.
48. Shao H, Calvo K, Gronborg M, et al. Distinguishing hairy cell leukemia variant from hairy cell leukemia: development and validation of diagnostic criteria. Leuk Res 2013; 37(4):401-409.
49. Sharma SG, Gulley ML. BRAF mutation testing in colorectal cancer. Arch Pathol Lab Med. 2010; 134(8):1225-1228.
50. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012; 366(8):707-714.
51. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and Trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018; 36(1):7-13.
52. Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011; 364(24):2305-2315.
53. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011; 29(15):2011-2019.
54. Vasen HF, Moslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007; 44(6):353-362.
55. Vultur A, Villanueva J, Herlyn M. BRAF inhibitor unveils its potential against advanced melanoma. Cancer Cell. 2010; 18(4):301-302.
56. Wilson PM, Labonte MJ, Lenz HJ. Molecular markers in the treatment of metastatic colorectal cancer. Cancer J. 2010; 16(3):262-272.
57. Xi L, Arons E, Navarro W, et al. Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation. Blood. 2012; 119(14):3330-3332.

Circulating Tumor DNA

1. Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686). Clin Cancer Res. 2016; 22(10):2386-2395.
2. Murray DH, Rohan TB, Gaur S, et al. Validation of a circulating tumor-derived DNA blood test for detection of methylated BCAT1 and IKZF1 DNA. J Appl Lab Med. 2017; 2(2)165-175.
3. Musher BL, Melson JE, Amato G et al. Evaluation of circulating tumor DNA for methylated BCAT1 and IKZF1 to detect recurrence of stage II/stage III colorectal cancer (CRC). Cancer Epidemiol Biomarkers Prev. 2020 Sep 21. Epub ahead of print.
4. Perakis S and Speicher MR. Emerging concepts in liquid biopsies. BMC Med. 2017; 15(1):75.
5. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018; 36(9):841-849.
6. Thress KS, Brant R, Carr TH, et al. EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. Lung Cancer. 2015; 90(3):509-515.

EGFR Mutation Analysis

1. An N, Zhang Y, Niu H, et al. EGFR-TKIs versus taxanes agents in therapy for nonsmall-cell lung cancer patients: a PRISMA-compliant systematic review with meta-analysis and meta-regression. Medicine (Baltimore). 2016; 95(50):e5601.
2. Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006; 95(8):998-1004.
3. Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005; 23(31):8081-8092.
4. Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011; 29(31):4113-4120.
5. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst. 2005; 97(9):643-655.
6. Cappuzzo F, Ligorio C, Jänne PA, et al. Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization-positive/phospho-Akt-positive or never smoker patients with advanced non-small-cell lung cancer: the ONCOBELL trial. J Clin Oncol. 2007a; 25(16):2248-2255.
7. Cappuzzo F, Ligorio C, Toschi L, et al. EGFR and HER2 gene copy number and response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2007b: 2(5):423-429.
8. Cascinu S, Berardi R, Salvagni S, et al. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. Br J Cancer. 2008; 98(1):71-76.
9. Clark GM, Zborowski DM, Culbertson JL, et al. Clinical utility of epidermal growth factor receptor expression for selecting patients with advanced non-small cell lung cancer for treatment with erlotinib. J Thorac Oncol. 2006; 1(8):837-846. da Cunha Santos G, Dhani N, Tu D, et al. Molecular predictors of outcome in a phase 3 study of gemcitabine and erlotinib therapy in patients with advanced pancreatic cancer: National Cancer Institute of Canada Clinical Trials Group Study PA.3. Cancer. 2010; 116(24):5599-5607.
10. Dacic S, Flanagan M, Cieply K, et al. Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol. 2006; 125(6):860-865.
11. D’Angelo SP, Pietanza, MC, Johnson ML, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J Clin Oncol. 2011; 29(15):2066-2070.
12. Douillard JY, Pirker R, O'Byrne KJ, et al. Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer. J Thorac Oncol. 2014; 9(5):717-724.
13. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010; 28(5):744-752.
14. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small cell lung cancer treated chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005; 23(25):5900-5909.
15. Feld R, Sridhar SS, Shepherd FA, et al. Use of the epidermal growth factor receptor inhibitors gefitinib and erlotinib in the treatment of non-small cell lung cancer: a systematic review. J Thorac Oncol. 2006; 1(4):367-376.
16. Franek J, Cappelleri JC, Larkin-Kaiser KA, et al. Systematic review and network meta-analysis of first-line therapy for advanced EGFR-positive non-small-cell lung cancer. Future Oncol. 2019; 15(24):2857-2871.
17. Fukuoka M, Wu YL, Thongprasert S, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011; 29(21):2866-2874.
18. Geyer JR, Stewart CF, Kocak M, et al. A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas. Eur J Cancer. 2010; 46(18):3287-3293.
19. Han SW, Kim TY, Hwang PG, et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2005; 23(11):2493-2501.
20. Helman E, Nguyen M, Karlovich CA, et al. Cell-free DNA next-generation sequencing prediction of response and resistance to third-generation EGFR inhibitor. Clin Lung Cancer. 2018; 19(6):518-530.
21. Hirsch FR, Varella-Garcia M, Cappuzzo F, et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib. Ann Oncol. 2007; 18(4):752-760.
22. Hirsch FR, Varella-Garcia M, McCoy J, et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol. 2005; 23(28):6838-6845.
23. Huang SF, Liu HP, Li LH, et al. High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004; 10(24):8195-8203.
24. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 2006; 24(21):3340-3346.
25. Janne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015; 372(18):1689-1699.
26. Jenkins S, Yang JC, Ramalingam SS, et al. Plasma ctDNA analysis for detection of the EGFR T790M mutation in patients with advanced non-small cell lung cancer. J Thorac Oncol. 2017; 12(7):1061-1070.
27. John T, Akamatsu H, Delmonte A, et al. EGFR mutation analysis for prospective patient selection in AURA3 phase III trial of osimertinib versus platinum-pemetrexed in patients with EGFR T790M-positive advanced non-small-cell lung cancer. Lung Cancer. 2018; 126:133-138.
28. Karlovich C, Goldman JW, Sun JM, et al. Assessment of EGFR mutation status in matched plasma and tumor tissue of NSCLC patients from a phase I study of rociletinib (CO-1686). Clin Cancer Res. 2016; 22(10):2386-2395.
29. Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non–small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013; 31(27):3335-3341.
30. Krug AK, Enderle D, Karlovich C, et al. Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma. Ann Oncol. 2018; 29(3):700-706.
31. Laurent-Puig P, Cayre A, Manceau G, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009; 27(35):5924-5930.
32. Li C, He Q, Liang H et al. Diagnostic accuracy of droplet digital PCR and amplification refractory mutation system PCR for detecting EGFR mutation in cell-free DNA of lung cancer: A meta-analysis. Front Oncol. 2020; 10:290.
33. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350(21):2129-2139.
34. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362(25):2380-2388.
35. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012; 13(5):528-538.
36. Mitsudomi T, Kosaka T, Endoh H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol. 2005; 23(11):2513-2520.
37. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010; 11(2):121–128.
38. Mok TS, Wu Y-L, Ahn M-J, et al.; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017; 376(7):629-640.
39. Mok T, Wu YL, Lee JS, et al. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated Erlotinib and chemotherapy. Clin Cancer Res. 2015; 21(14):3196-3203.
40. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-957.
41. Mok TS, Wu YL, Yu CJ, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27(30):5080-5087.
42. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676):1497-1500.
43. Papadimitrakopoulou VA, Han JY, Ahn MJ, et al. Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: Osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer. Cancer. 2020; 126(2):373-380.
44. Park CK, Cho HJ, Choi YD, et al. A Phase II Trial of Osimertinib in the second-line treatment of non-small cell lung cancer with the EGFR T790M mutation, detected from circulating tumor DNA: LiquidLung-O-Cohort 2. Cancer Res Treat. 2019; 51(2):777-787.
45. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: Initial results from the chrysalis phase I study. J Clin Oncol. 2021; 39(30):3391-3402.
46. Parra HS, Cavina R, Latteri F, et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004; 91(2):208-212.
47. Passiglia F, Rizzo S, Di Maio M et al. The diagnostic accuracy of circulating tumor DNA for the detection of EGFR-T790M mutation in NSCLC: a systematic review and meta-analysis. Sci Rep. 2018; 8(1):13379.
48. Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012; 13(1):33-42.
49. Ramalingam SS, O'Byrne K, Boyer M, et al. Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. Ann Oncol. 2016; 27(3):423-429.
50. Rosell R, Carcereny E, Gervais R, et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012; 13(3):239-246.
51. Rosell R, Moran T, Queralt C, et al.; Spanish Lung Group. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009a; 361(10):958-967.
52. Rosell R, Perez-Roca L, Sanchez JJ, et al. Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS One. 2009b; 4(5):e5133.
53. Saarilahti K, Bono P, Kajanti M, et al. Phase II prospective trial of gefitinib given concurrently with cisplatin and radiotherapy in patients with locally advanced head and neck cancer. J Otolaryngol Head Neck Surg. 2010; 39(3):269-276.
54. Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007; 12(1):90-98.
55. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31(27):3327-3334.
56. Srividya MR, Thota B, Arivazhagan A, et al. Age-dependent prognostic effects of EGFR/p53 alterations in glioblastoma: study on a prospective cohort of 140 uniformly treated adult patients. J Clin Pathol. 2010; 63(8):687-691.
57. Sundaresan TK, Sequist LV, Heymach JV, et al. Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses. Clin Cancer Res. 2016; 22(5):1103-1110.
58. Takano T, Ohe Y, Sakamoto H, et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol. 2005; 23(28):6829-6837.
59. Tan EH, Ramlau R, Pluzanska A, et al. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann Oncol. 2010; 21(2):217-222.
60. Tanaka T, Matsuoka M, Sutani A, et al. Frequency of and variables associated with the EGFR mutation and its subtypes. Int J Cancer. 2010; 126(3):651-655.
61. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med. 2005; 353(2):133-144.
62. Usui K, Yokoyama T, Naka G, et al. Plasma ctDNA monitoring during epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatment in patients with EGFR-mutant non-small cell lung cancer (JP-CLEAR trial). Jpn J Clin Oncol. 2019; 49(6):554-558.
63. Van Damme N, Deron P, Van Roy N, et al. Epidermal growth factor receptor and K-RAS status in two cohorts of squamous cell carcinomas. BMC Cancer. 2010; 10:189.
64. van Zandwijk N, Mathy A, Boerrigter L, et al. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer. Ann Oncol. 2007; 18(1):99-103.
65. Wang Z, Cheng Y, An T, et al. Detection of EGFR mutations in plasma circulating tumour DNA as a selection criterion for first-line gefitinib treatment in patients with advanced lung adenocarcinoma (BENEFIT): a phase 2, single-arm, multicentre clinical trial. Lancet Respir Med. 2018; 6(9):681-690.
66. Weber B, Meldgaard P, Hager H, et al. Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays. BMC Cancer. 2014; 14:294.
67. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol. 2017; 18(11):1454-1466.
68. Wu YL, Zhong WZ, Li LY, et al. Epidermal growth factor receptor mutations and their correlation with gefitinib therapy in patients with non-small cell lung cancer: a meta-analysis based on updated individual patient data from six medical centers in mainland China. J Thorac Oncol. 2007; 2(5):430-439.
69. Yang JC, Hirsh V, Schuler M, et al. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations J Clin Oncol. 2013; 31(27):3342-3350.
70. Yang JC, Sequist LV, Geater SL, et al. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015; 16(7):830-838.
71. Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012; 13(5):539-548.
72. Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol. 2007; 2(1):22-28.
73. Yung WK, Vredenburgh JJ, Cloughesy TF, et al. Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study. Neuro Oncol. 2010; 12(10):1061-1070.
74. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8):735-742.
75. Zhu CQ, da Cunha Santos G, Ding K, et al.; National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol. 2008; 26(26):4268-4275.

Multiple Endocrine Neoplasia Type 2 (MEN 2) and Thyroid Cancer

1. Alvandi E, Akrami SM, Chiani M, et al. Molecular analysis of the RET proto-oncogene key exons in patients with medullary thyroid carcinoma: a comprehensive study of the Iranian population. Thyroid. 2011; 21(4):373-382.
2. Benej M, Bendlova B, Vaclavikova E, Poturnajova M. Establishing high resolution melting analysis: method validation and evaluation for c-RET proto-oncogene mutation screening. Clin Chem Lab Med. 2011; 50(1):51-60.
3. Cascón A, Pita G, Burnichon N, et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab. 2009; 94(5):1701-1705.
4. Elisei R, Romei C, Cosci B, et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007; 92(12):4725-4729.
5. El Lakis M, Nockel P, Gaitanidis A, et al. Probability of positive genetic testing results in patients with family history of primary hyperparathyroidism. J Am Coll Surg. 2018; 226(5):933-938.
6. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996; 276(19):1575-1579.
7. Frank-Raue K, Buhr H, Dralle H, et al. Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol. 2006; 155(2):229-236.
8. Gertner ME, Kebebew E. Multiple endocrine neoplasia type 2. Curr Treat Options Oncol. 2004; 5(4):315-325.
9. Huang SM, Tao BL, Tzeng CC, et al Prenatal molecular diagnosis of RET proto-oncogene mutation in multiple endocrine neoplasia type 2A. J Formos Med Assoc. 1997; 96:542-544.
10. Iacobone M, Schiavi F, Bottussi M, et al. Is genetic screening indicated in apparently sporadic pheochromocytomas and paragangliomas? Surgery. 2011; 150(6):1194-1201.
11. Jimenez C, Cote G, Arnold A, Gagel RF. Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab. 2006; 91(8):2851-2858.
12. Krawczyk A, Hasse-Lazar K, Pawlaczek A, et al. Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas. Endokrynol Pol. 2010; 61(1):43-48.
13. Leboulleux S, Baudin E, Travagli JP, et al. Medullary thyroid carcinoma. Clin Endocrinol. 2004; 61(3):299-310.
14. Mannelli M, Castellano M, Schiavi F, et al.; Italian Pheochromocytoma/Paraganglioma Network. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009; 94(5):1541-1547.
15. Martinelli P, Maruotti GM, Pasquali D, et al. Genetic prenatal RET testing and pregnancy management of multiple endocrine neoplasia Type II A (MEN2A): a case report. J Endocrinol Invest. 2004; 27(4):357-360.
16. Offit K, Kohut K, Clagett B, et al. Cancer genetic testing and assisted reproduction. J Clin Oncol. 2006; 24:4775-4782.
17. Offit K, Sagi M, Hurley K. Preimplantation genetic diagnosis for cancer syndromes: a new challenge for preventive medicine. JAMA. 2006; 296(22):2727–2730.
18. Plaza-Menacho I, Burzynski GM, de Groot JW, et al. Current concepts in RET-related genetics, signaling and therapeutics. Trends Genet. 2006; 22(11):627-636.
19. Romei C, Mariotti S, Fugazzola L, et al.; ItaMEN network. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010; 163(2):301-308.
20. Romei C, Tacito A, Molinaro E, et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol (Oxf). 2015; 82(6):892-899.
21. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011; 61(4):212-236.
22. Waldmann J, Langer P, Habbe N, et al. Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas. Endocrine. 2009; 35(3):347-355.

Myeloproliferative Neoplasms/Myeloproliferative Disorders

1. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464):1054-1061.
2. Campbell P. Green, A. The myeloproliferative disorders. N Engl J Med 2006; 355(23):2452-2466.
3. Campbell PJ, Scott LM, Buck G, Definition of subtypes of essential thrombocythemia and relation to polycythaemia vera based on JAK2^V617F mutation status: a prospective study. Lancet. 2005; 366(9501):1945-1953.
4. De Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature. 1982; 300(5894):765-767.
5. Guglielmelli P, Pancrazzi A, Bergamaschi G, et al. Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. Br J Haematol. 2007; 137(3):244-247.
6. Guglielmelli P, Rotunno G, Fanelli T, et al. Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis. Blood Cancer J. 2015; 5:e360.
7. James c, et al, Detection of JAK2^V617F as first intention diagnostic test for erythrocytosis. Leukemia. 2006; 20(2):350-353.
8. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352(17):1779-1790.
9. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005; 7(4):387-397.
10. McLornan D, Percy M, McMullin M. JAK2^V617F: a single mutation in the myeloproliferative group of disorders. Ulster Med J. 2006; 75(2):112-119.
11. Mejía-Ochoa M, Acevedo Toro PA, Cardona-Arias JA. Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000-2018. BMC Cancer. 2019; 19(1):590.
12. Michiels JJ, Bernema Z, Van Bockstaele D, et al. Current diagnostic criteria for the chronic myeloproliferative disorders (MPD) essential thrombocythemia (ET), polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF). Pathol Biol. 2007; 55(2):92-104.
13. Michiels JJ, De Raeve H, Hebeda K, et al. WHO bone marrow features and European clinical, molecular, and pathological (ECMP) criteria for the diagnosis of myeloproliferative disorders. Leuk Res. 2007; 31(8):1031-1038.
14. Milosevic Feenstra JD, Nivarthi H, Gisslinger H, et al. Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms. Blood. 2016; 127(3):325-332.
15. Nelson ME, Steensma DP. JAK2^V617F in myeloid disorders: what do we know now, and where are we headed? Leuk Lymphoma. 2006; 47(2):177-194. 
16. Nussenzveig RH, Swierczek SI, Jelinek J, et al. Polycythemia vera is not initiated by JAK2^V617F mutation. Exp Hematol. 2007; 35(1):32-38.
17. Pardanani A, Lasho TL, Finke C, et al. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia. 2007; 21(9):1960-1963.
18. Passamonti F, Elena C, Schnittger S, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011; 117(10):2813-2816.
19. Rumi E, Pietra D, Pascutto C, et al. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood. 2014; 124(7):1062-1069.
20. Scott LM. The JAK2 exon 12 mutations: a comprehensive review. Am J Hematol. 2011; 86(8):668-676.
21. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007; 356(5):459-468.
22. Siemiatkowska A, Bieniaszewska M, Hellmann A, Limon J. JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms. Leuk Res. 2010; 34(3):387-389.
23. Sokol K, Tremblay D, Bhalla S, et al. Implications of mutation profiling in myeloid malignancies-part 2: myeloproliferative neoplasms and other myeloid malignancies. Oncology (Williston Park). 2018; 32(5):e45-e51.
24. Speletas M, Katodritou E, Daiou C, et al. Correlations of JAK2^V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders. Leuk Res. 2007; 31(8):1053-1062.
25. Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2003; 200-224.
26. Tefferi A. Classification, diagnosis and management of myeloproliferative disorders in the JAK2^V617F era. Hematology Am Soc Hematol Educ Program. 2006; 240-245.
27. Tefferi A, Gilliland DG. Oncogenes in myeloproliferative disorders. Cell Cycle. 2007; 6(5):550-556.
28. Tefferi A, Gilliland DG, Villeval JL, et al. The JAK2^V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. Mayo Clin Proc. 2005; 80(7):947-958.
29. Tefferi A, Lasho TL, Finke CM, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28(7):1472-14777.
30. Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2^V617F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007; 110(3):840-846.
31. Villeval JL, James C, Pisani DF, et al. New insights into the pathogenesis of JAK2^V617F positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost. 2006; 32(4):341-351.
32. Walz C, Cross NC, Van Etten RA, Reiter A. Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders. Leukemia. 2008; 22(7):1320-1334.
33. Wolanskyj AP, Lasho TL, Schwager SM, et al. JAK2 mutation in essential thrombocythemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005; 131(2):208-213.

Non-small Cell Lung Cancer

1. Gerber DE, Minna JD. ALK inhibition for non-small cell lung cancer: from discovery to therapy in record time. Cancer Cell. 2010; 18(6):548-551.
2. Li Y, Ye X, Liu J, et al. Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. Neoplasia. 2011; 13(1):1-11.

PIK3CA Mutation Analysis

1. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019; 380(20):1929-1940.
2. Arsenic R, Treue D, Lehmann A, et al. Comparison of targeted next-generation sequencing and Sanger sequencing for the detection of PIK3CA mutations in breast cancer. BMC Clin Pathol. 2015; 15:20.
3. Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology. 2017; 18(7):904-916.
4. Cappuzzo F, Varella-Garcia M, Finocchiaro G, et al. Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. Br J Cancer. 2008; 99(1):83-89.
5. Chae YK, Davis AA, Jain S, et al. Concordance of genomic alterations by next-generation sequencing in tumor tissue versus circulating tumor DNA in breast cancer. Molecular cancer therapeutics. 2017; 16(7):1412-1420.
6. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9):2371-2376.
7. De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010; 11(8):753-762.
8. De Stefano A, Carlomagno C. Beyond KRAS: Predictive factors of the efficacy of anti-EGFR monoclonal antibodies in the treatment of metastatic colorectal cancer. World J Gastroenterol. 2014; 20(29):9732-9743.
9. Ellis MJ, Lin L, Crowder R, et al. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2010; 119(2):379-390.
10. Fiala O, Pesek M, Finek J, et al. Gene mutations in squamous cell NSCLC: insignificance of EGFR, KRAS and PIK3CA mutations in prediction of EGFR-TKI treatment efficacy. Anticancer Res. 2013; 33(4):1705-1711.
11. Hahn AW, Gill DM, Maughan B, et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget. 201; 8(20):33614-33620.
12. Henry NL, Schott AF, Hayes DF. Assessment of PIK3CA mutations in human epidermal growth factor receptor 2–positive breast cancer: clinical validity but not utility. J Clin Oncol. 2014; 32(29):3207-3209.
13. Higgins MJ, Jelovac D, Barnathan E, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clinical cancer research. 2012; 18(12):3462-3469.
14. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-354.
15. Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009; 15(16):5049-5059.
16. Karapetis CS, et al. PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer- results from NCIC CTG/AGITG CO. 17. Clin Cancer Res. 2014; 20(3):744-53.
17. Kawano O, Sasaki H, Endo K, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer. 2006; 54(2):209-215.
18. Kidess E., Heirich K., Wiggin M., et al. Mutation profiling of tumor DNA from plasma and tumor tissue of colorectal cancer patients with a novel, high-sensitivity multiplexed mutation detection platform. Oncotarget, 6(4), p.2549-2561.
19. Kodahl AR, Ehmsen S, Pallisgaard N, et al. Correlation between circulating cell‐free PIK 3 CA tumor DNA levels and treatment response in patients with PIK 3 CA‐mutated metastatic breast cancer. Molecular oncology. 2018; 12(6):925-935.
20. Krasinskas AM. EGFR Signaling in Colorectal Carcinoma. Patholog Res Int. Pathology Research International, vol. 2011, Article ID 932932, 6 pages, 2011.
21. Lin JS, Webber EM, Senger CA, et al. Systematic review of pharmacogenetic testing for predicting clinical benefit to anti-EGFR therapy in metastatic colorectal cancer. Am J Cancer Res. 2011; 1(5):650-662.
22. Loi S, Michiels S, Lambrechts D, et al. Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. J Natl Cancer Inst. 2013, 105(13):960-967.
23. Mao C, Yang ZY, Hu XF, et al. PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Ann Oncol. 2012; 23(6):1518-1525.
24. Normanno N, Rachiglio AM, Lambiase M, ET AL. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann Oncol. 2015; 26(8):1710-1714.
25. Ogino S, Liao X, Imamura Y, et al. Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial. J Natl Cancer Inst. 2013; 105(23):1789-1798.
26. Ogino S, Nosho K, Kirkner GJ, et al. PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol. 2009; 27(9):1477-1484.
27. Papaxoinis G, Kotoula V, Alexopoulou Z, ET AL. Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study. PLoS One. 2015; 10(10):e0140293.
28. Prenen H, De Schutter J, Jacobs B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009; 15(9):3184-3188.
29. Razis E, Bobos M, Kotoula V, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011, 128(2):447-456.
30. Rothe F, Laes JF, Lambrechts D, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014; 25(10):1959-1965.
31. Sartore-Bianchi A, Martini M, Molinari F, et al. PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res. 2009; 69(5):1851-1857.
32. Tol J, Dijkstra JR, Klomp M, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer. 2010; 46(11):1997-2009.

RAS Mutation Analysis

1. Al-Jehani RM, Jeyarajah AR, Hagen B, et al. Model for the molecular genetic diagnosis of endometrial cancer using K-ras mutation analysis. J Natl Cancer Inst. 1998; 90(7):540-542.
2. Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26(10):1626-1634.
3. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000).
4. Bokemeyer C, Cutsem EV, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 2012; 48(10):1466-1475.
5. Caduff RF, Johnston CM, Frank TS. Mutations of the Ki-ras oncogene in carcinoma of the endometrium. Am J Pathol 1995; 146(1):182-188.
6. Cervantes A, Macarulla T, Martinelli E, et al. Correlation of KRAS status (wild type [wt] vs. mutant [mt]) with efficacy to first-line cetuximab in a study of cetuximab single agent followed by cetuximab + FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC). J Clin Oncol 26: 2008 (May 20 suppl; abstr 4129).
7. Cuatrecasas M, Villanueva A, Matias-Guiu X, Prat J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer. 1997; 79(8):1581-1586.
8. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008; 19(3):508-515.
9. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol. 2010; 28(5):744-752.
10. Duggan BD, Felix JC, Muderspach LI, et al. Early mutational activation of the c-Ki-ras oncogene in endometrial carcinoma. Cancer Res. 1994; 54(6):1604-1607.
11. Eberhard DA, Johnson BE, Amler LC et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005; 23(25):5900-5909.
12. Esteller M, García A, Martínez-Palones JM, et al. The clinicopathological significance of K-RAS point mutation and gene amplification in endometrial cancer. Eur J Cancer. 1997; 33(10):1572-1577.
13. Fujimoto I, Shimizu Y, Hirai Y, et al. Studies on ras oncogene activation in endometrial carcinoma. Gynecol Oncol. 1993; 48(2):196-202.
14. Hogdall EV, Hogdall CK, Blaakaer J, et al. K-ras alterations in Danish ovarian tumour patients. From the Danish "Malova" Ovarian Cancer study. Gynecol Oncol. 2003; 89(1):31-36.
15. Hunt JD, Mera R, Strimas A, et al. KRAS mutations are not predictive for progression of preneoplastic gastric lesions. Cancer Epidemiol Biomarkers Prev. 2001; 10(1):79-80.
16. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008; 359(17):1757-1765.
17. Khalid A, McGrath KM, Zahid M, et al. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol. 2005; 3(10):967-973.
18. Khalid A, Zahid M, Finkelstein SD et al. Pancreatic cyst fluid DNA analysis in evaluating pancreatic cysts: a report of the PANDA study. Gastrointest Endosc. 2009; 69(6):1095-1102.
19. Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2010; 28(6):918-927.
20. Mao C, Qiu LX, Liao RY, et al. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 2010; 69(3):272-278.
21. Messersmith WA, Ahnen DJ. Targeting EGFR in colorectal cancer. N Engl J Med. 2008; 359(17):1834-1836.
22. Olsen C, Schefter T, Chen, et al. Results of a phase I trial of 12 patients with locally advanced pancreatic carcinoma combining gefitinib, paclitaxel, and 3-dimensional conformal radiation: report of toxicity and evaluation of circulating K-ras as a potential biomarker of response to therapy. Am J Clin Oncol. 2009; 32(2):115-121.
23. Peeters M, Douillard JY, Van Cutsem E, et al. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol. 2013; 31(6):759-765.
24. Rockacy MJ, Zahid M, McGrath KM, et al. Association between KRAS mutation, detected in pancreatic cyst fluid, and long-term outcomes of patients. Clin Gastroenterol Hepatol. 2013; 11(4):425-429.
25. Schneider CP, Heigener D, Schott-von-Romer K et al. Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer. J Thorac Oncol. 2008; 3(12):1446-1453.
26. Semczuk A, Postawski K, Przadka D et al. K-ras gene point mutations and p21ras immunostaining in human ovarian tumors. Eur J Gynaecol Oncol. 2004; 25(4):484-488.
27. Sorich MJ, Wiese MD, Rowland A, et al. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015; 26(1):13-21.
28. Van Cutsem E, Lang I, D'haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Clin Oncol 26: 2008 (May 20 suppl; abstr 2).
29. Varras MN, Sourvinos G, Diakomanolis E, et al. Detection and clinical correlations of ras gene mutations in human ovarian tumors. Oncology. 1999; 56(2):89-96.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Board of Genetic Counselors. Genetic Counselors' Scope of Practice. Available at: https://www.nsgc.org/p/cm/ld/fid=18#scope. Accessed on February 2, 2021.
2. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003; 21(12):2397-2406.
3. Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care. Can J Ophthalmol. 2009; 44 Suppl 2: S1-88. Available at: https://www.canadianjournalofophthalmology.ca/article/S0008-4182(09)80179-8/pdf. Accessed on February 2, 2021.
4. Casali PG, Abecassis N, Bauer S, et al. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29 Suppl 4: iv68-iv78.
5. Decker J, Neuhaus C, Macdonald F, et al. Clinical utility gene card for: von Hippel-Lindau (VHL). Eur J Hum Genet. 2014; 22(4).
6. Else T, Greenberg S, Fishbein L. Hereditary Paraganglioma-Pheochromocytoma Syndromes. 2008 May 21 [Updated 2018 Oct 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.
7. Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1):70-87.
8. Lohmann DR, Gallie BL. Retinoblastoma. 2000 Jul 18 [Updated 2018 Nov 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1452/. Accessed on February 2, 2021.
9. Miller DT, Lee K, Chung WK, et al.  ACMG Secondary Findings Working Group. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 23(8):1381-1390. Available at: https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/. Accessed on September 13, 2022.
10. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
    • B-Cell Lymphoma (V4.2022). Updated September 22, 2021.
    • Bone Cancer (V2.2022). Updated October 8, 2022
    • Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (V1.2023). Updated September 7, 2022. 
    • Hepatobiliary Cancer (V5.2021). Updated September 21, 2021.
    • Soft Tissue Sarcoma (V1.2021). Updated October 30, 2020.
11. Nelson HD, Pappas M, Cantor A, et al.  Assessment, genetic counseling, and genetic testing for brca1/2-related cancer in women: a systematic review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2019. Report No.: 19-05251-EF-1. Available at: https://www.ncbi.nlm.nih.gov/books/NBK545867/. Accessed on September 14, 2022.
12. Nielsen SM, Rhodes L, Blanco I, et al. von Hippel-Lindau Disease: genetics and role of genetic counseling in a multiple neoplasia syndrome. J Clin Oncol. 2016; (34)18: 2172-2181.
13. Raman G, Avendano EE, Chen M. Update on emerging genetic tests currently available for clinical use in common cancers. Evidence Report/Technology Assessment. No. (Prepared by the Tufts Evidence-based Practice Center under contract No. 290-2007-10055-I.). Rockville, MD: Agency for Healthcare Research and Quality (AHRQ). July 2013. Available at: https://www.ncbi.nlm.nih.gov/books/NBK285327/. Accessed on February 2, 2021.
14. Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, 2009: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2009; 59(1):27-41.
15. Sun F, Bruening W, Erinoff E, Schoelles KM. Addressing Challenges in Genetic Test Evaluation: Evaluation Frameworks and Assessment of Analytic Validity [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Report No.: 11-EHC048-EF. AHRQ Methods for Effective Health Care. Available at: https://www.ncbi.nlm.nih.gov/books/NBK56750/. Accessed on February 2, 2021.
16. U.S. Food and Drug Administration (FDA).
    • FDA-Approved Drugs: Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=210861. Accessed on February 2, 2021.
    • In Vitro Companion Diagnostic Devices - Guidance for Industry and Food and Drug Administration Staff. August 6, 2014. Available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf . Accessed on February 2, 2021.
    • Laboratory Developed Tests. Rockville, MD: FDA. September 27, 2018. Available at: https://www.fda.gov/medical-devices/vitro-diagnostics/laboratory-developed-tests. Accessed on February 2, 2021.
    • List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). Content current as of November 16, 2020. Available at: https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools. Accessed on February 2, 2021.
17. van Leeuwaarde RS, Ahmad S, Links TP, et al. Von Hippel-Lindau Syndrome. 2000 May 17 [Updated 2018 Sep 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Acute Lymphoblastic Leukemia

1. Hoelzer D, Bassan R, Dombret H, et al. ESMO Guidelines Committee. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016; 27(suppl 5): v69-v82.
2. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
   • Acute Lymphoblastic Leukemia (V4.2021) Updated January 7, 2022.

Acute Myeloid Leukemia

1. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021 Dec 30;138(26):2753-2767.
2. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
   • Acute Myeloid Leukemia (V1.2022). Updated December 2, 2021.
3. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018; 131(12):1275-1291

Acute Promyelocytic Leukemia

1. NCCN Clinical Practice Guidelines in Oncology^®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
   • Acute Myeloid Leukemia (V1.2022). December 2, 2021.
2. Pagnano KB, Rego EM, Rohr Set al. Guidelines on the diagnosis and treatment for acute promyelocytic leukemia: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associação Médica Brasileira - 2013. Rev Bras Hematol Hemoter. 2014;36(1):71-92.

BCR-ABL Mutation Analysis

1. American Cancer Society. Acute Lymphocytic Leukemia (ALL). 2022. Available at: http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/index. Accessed on September 21, 2022.
2. American Cancer Society. Chronic Myeloid Leukemia (CML). 2022. Available at: https://www.cancer.org/cancer/chronic-myeloid-leukemia.html. Accessed on September 21, 2022.
3. Baccarani M, Castagnetti F, Gugliotta G, Rosti G. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol. 2015; 94(Supplement 2):141-147.
4. National Cancer Institute. Acute Lymphoblastic Leukemia. Available at: https://www.cancer.gov/types/leukemia/hp. Accessed on December, 2021.
5. National Cancer Institute. Chronic Myelogenous Leukemia (PDQ^®). Last Modified on July 29, 2020. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/CML/HealthProfessional. Accessed on December 28, 2021.
6. NCCN Clinical Practice Guidelines in Oncology^®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 21, 2022.
   • Acute Lymphoblastic Leukemia (V.3.2021). Revised December 16, 2021.
   • Chronic Myeloid Leukemia (V.1.2023). Revised August 5, 2022.
7. Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am Soc Hematol Educ Program. 2005; 183-187

BRAF Mutation Analysis

1. Bonis PA, Trikalinos TA, Chung M, et al. Hereditary Nonpolyposis Colorectal Cancer: Diagnostic Strategies and Their Implications. Evidence Report/Technology Assessment No. 150 (Prepared by Tufts-New England Medical Center Evidence-based Practice Center under Contract No. 290-02-0022). AHRQ Publication No. 07-E008. Rockville, MD: Agency for Healthcare Research and Quality. May 2007.
2. Diamond EL, Subbiah V, Lockhart AC, et al. FDA approval summary: Vemurafenib for the treatment of patients with Erdheim-Chester Disease with the BRAFV600 mutation. Oncologist. 2018; 23(12):1520-1524.
3. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. 2013; 15(7):517-527.
4. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1):35-41.
5. Garbe C, Peris K, Hauschild A, et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline--Update 2012. Eur J Cancer. 2012; 48(15):2375-2390.
6. Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2014; 80(2):197-220.
7. Hedge M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1):101-116.
8. Miller DT, Lee K, Chung WK, et al.  ACMG Secondary Findings Working Group. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021; 23(8):1381-1390. Available at: https://www.ncbi.nlm.nih.gov/clinvar/docs/acmg/. Accessed on September 13, 2022.
9. National Comprehensive Cancer Network^®. NCCN Drugs & Biologics Compendium^™ (electronic version). For additional information, visit the NCCN website: http://wwe.nccn.org. Accessed on July 17, 2020.
10. NCCN Clinical Practice Guidelines in Oncology^™. © 2021 National Comprehensive Cancer Network, Inc. For additional information visit NCCN website: http://www.nccn.org/index.asp. Accessed on December 16, 2020.
    • Colon Cancer (V3.2021). Revised June 15, 2020.
    • Central Nervous System Cancers (V3.2020). Revised September 10, 2021.
    • Cutaneous Melanoma (V1.2021). Revised November 25, 2020.
    • Genetic/Familial High-Risk: Colorectal (V1.2020). Revised July 21, 2020.
    • Hairy Cell Leukemia (V1.2022). Revised September 8, 2021.
    • Non-Small Cell Lung Cancer (V1.2022). Revised December 7, 2021.
    • Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer (V1.2020). Revised March 11, 2020.
    • Rectal Cancer (V6.2020). Revised June 25, 2020.
    • Soft Tissue Sarcoma (V1.2021). Revised October 30, 2020.
    • Thyroid Carcinoma (V2.2020). Revised July 15, 2020.
11. Odogwu L, Mathieu L, Blumenthal G, et al. FDA approval Summary: Dabrafenib and Trametinib for the treatment of metastatic non-small cell lung cancers harboring BRAF V600E mutations. Oncologist. 2018; 23(6):740-745.
12. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009; 11(1):42-65.
13. Planchard D, Mazieres J, Riely GJ, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. J Clin Oncol 31, 2013 (suppl; abstr 8009).
14. U.S. Food and Drug Administration. Label and approval information: Mekinist (trametinib). Updated June 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204114s016lbl.pdf. Accessed on January 12, 2022.
15. U.S. Food and Drug Administration. Label and approval information: Tafinlar (dabrafenib). Updated April 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202806s015lbl.pdf. Accessed on January 12, 2022.
16. U.S. Food and Drug Administration. Label and approval information: Welireg (belzutifan). Updated August 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf. Accessed on January 12, 2022.
17. U.S. Food and Drug Administration. Label and approval information: Zelboraf (vemurafenib) Tablet, 240mg. Updated May 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202429s019lbl.pdf. Accessed on January 12, 2022.
18. U.S. Food and Drug Administration. List of cleared or approved companion diagnostic devices (in vitro and imaging tools). Updated 11/16/2020. Available at: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm. Accessed on January 12, 2022.
19. United States Food and Drug Administration (FDA). Premarket approval letter (PMA). cobas^® 4800 BRAF V600 Mutation Test, PMA # P110020. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110020a.pdf. Accessed on January 12, 2022.
20. U.S. Food and Drug Administration. Premarket Notification Database. THxID^™ BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument Summary of Safety and Effectiveness. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120014b.pdf. Accessed on January 12, 2022.
21. U.S. Food and Drug Administration. Summary of Safety and Effectiveness Data (SEED). THxID^™ BRAF Kit for use on the ABI 7500 Fast Dx Real-Time PCR Instrument. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120014b.pdf. Accessed on January 12, 2022.

Chronic Lymphocytic Leukemia

1. Eichhorst B, Robak T, Montserrat E, et al. ESMO Guidelines Committee. Chronic lymphocytic leukaemia. ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32(1):23-33.
2. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018; 131(25):2745-2760.
3. Ladetto M, Buske C, Hutchings M, et al. ESMO Lymphoma Consensus Conference Panel Members. ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia. Ann Oncol. 2016; 27(12):2149-2160.
4. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
   • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (V1.2022). Updated September 8, 2021.

Chronic Myeloid Leukemia

1. American Cancer Society. Chronic myeloid leukemia causes, risk factors, and prevention. Last reviewed June 19, 2018. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/8685.00.pdf. Accessed on September 20, 2022. 
2. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 20, 2022.
   • Chronic Myeloid Leukemia (V1.2023). Updated August 5, 2022.
3. U.S. Food and Drug Administration (FDA). Bosulif package insert. FDA 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203341s020lbl.pdf Accessed on October 18, 2022.
4. U.S. Food and Drug Administration (FDA). Iclusig package insert. FDA 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/203469s035lbl.pdf. Accessed on October 18, 2022.
5. U.S. Food and Drug Administration (FDA). Scemblix package insert. FDA 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215358s000Orig1lbl.pdf. Accessed on October 18, 2022.
6. U.S. Food and Drug Administration (FDA). Sprycel package insert. FDA 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021986s025lbl.pdf . Accessed on October 18, 2022.
7. U.S. Food and Drug Administration (FDA). Tasigna package insert. FDA 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022068s035s036lbl.pdf . Accessed on October 18, 2022.

Circulating Tumor DNA

1. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018; 36(16):1631-1641.
2. National Cancer Institute. Definition of liquid biopsy - NCI dictionary of cancer terms. National Cancer Institute. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/liquid-biopsy. Accessed on January 22, 2022.

EGFR Mutation Analysis

1. Hanna N, Johnson D, Temin S, Masters G. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update summary. J Oncol Pract. 2017; 13(12):832-837.
2. Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011; 29(15):2121-2127.
3. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. J Mol Diagn. 2018; 20(2):129-159.
4. Masters GA, Temin S, Azzoli CG, et al.; American Society of Clinical Oncology Clinical Practice. Systemic therapy or stage IV non-small-cell lung Cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015; 33(30):3488-515.
5. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018; 36(16):1631-1641.
6. National Comprehensive Cancer Network (NCCN). ^© 2021 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on January 12, 2022.
   • Non-Small Cell Lung Cancer (V1.2022). Updated December 7, 2021.
7. Travis WD, Brambilla E, Nicholson AG, et al. On behalf of the WHO Panel. The 2015 World Health Organization classification of lung tumors. Impact of genetic, clinical, and radiologic advances since the 2004 classification. J Thorac Oncol. 2015; 10(9):1243-1260.
8. U.S. Food and Drug Administration (FDA). Vizimpro package insert. FDA 2018(a). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211288s000lbl.pdf. Accessed on January 12, 2022.
9. U.S. Food and Drug Administration (FDA). Gilotrif package insert. FDA 2018(b) Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf. Accessed on January 12, 2022.
10. U.S. Food and Drug Administration (FDA). Iressa package insert. FDA 2018(c). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206995s003lbl.pdf. Accessed on January 12, 2022.
11. U.S. Food and Drug Administration (FDA). Lytgobi package insert. FDA 2018(c). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214801Orig1s000lbledt.pdf. Accessed on October 18, 2022.
12. U.S. Food and Drug Administration (FDA). Tarceva package insert. (FDA, 2016(a). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021743s025lbl.pdf. Accessed on January 12, 2022.
13. U.S. Food and Drug Administration (FDA). Tagrisso package insert. FDA 2018(d). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208065s008lbl.pdf. Accessed on January 12, 2022.
14. U.S. Food and Drug Administration Premarket Approval Database. Cobas EGFR mutation test V2 summary of safety and effectiveness. P150047. Rockville, MD: FDA 2016(b). June 1, 2016. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf15/P150047B.pdf. Accessed on January 12, 2022.
15. U.S. Food and Drug Administration Premarket Approval Database. Cobas EGFR mutation test V2 summary of safety and effectiveness. P150044. Rockville, MD: FDA (2016c). February 2, 2021. Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150044b.pdf. Accessed on January 12, 2022.

Hairy Cell Leukemia

1. Grever MR, Abdel-Wahab O, Andritsos LA, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129(5):553-560.
2. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
   • Hairy Cell Leukemia (V1.2022) Updated September 8, 2021.
3. Parry-Jones N, Joshi A, Forconi F, et al. Guideline for diagnosis and management of hairy cell leukaemia (HCL) and hairy cell variant (HCL-V). Br J Haematol. 2020; 191(5):730-737.
4. Robak T, Matutes E, Catovsky D, et al. ESMO Guidelines Committee. Hairy cell leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v100-v1007.
5. Tiacci E, Pettirossi V, Schiavoni G, Falini B. Genomics of hairy cell leukemia. J Clin Oncol. 2017; 35(9):1002-1010.

Multiple Endocrine Neoplasia Type 2 (MEN 2) and Thyroid Cancer

1. Moline J, Eng C. GeneReviews™. Multiple endocrine neoplasia type 2. Last updated June 25, 2015. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1257/. Accessed on October 4, 2021.
2. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
3. NCCN Clinical Practice Guidelines in Oncology^®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on September 26, 2022.
   • Neuroendocrine and Adrenal Tumors (V1.2022). Revised May 23, 2022.
   • Thyroid Carcinoma (V2.2021). Revised September 2021.
4. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology position statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010; 28(5):893-901.
5. Romei C, Cosci B, Renzini G, et al. RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC). Clin Endocrinol (Oxf). 2011; 74(2):241-247.
6. Romei C, Mariotti S, Fugazzola L, et al. ItaMEN network. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010; 163(2):301-308.
7. Szinnai G, Meier C, Komminoth P, Zumsteg UW. Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics. 2003; 111(2): E132-E139.
8. Wells S, Asa S, Dralle H, et al. Revised Medullary thyroid cancer: management guidelines of the American Thyroid Association. March 26, 2015. Available at: http://online.liebertpub.com/doi/pdf/10.1089/thy.2014.0335. Accessed on September 26, 2022.

Multiple Myeloma

1. Dimopoulos MA, Moreau P, Terpos Eet al. ESMO Guidelines Committee. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2021; 32(3):309-322.
2. Moreau P, San Miguel J, Sonneveld P, et al. ESMO Guidelines Committee. Multiple myeloma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017; 28(suppl_4):iv52-iv61.
3. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
   • Multiple Myeloma (V4.2022). Updated December 14, 2021.

Myelodysplastic Syndromes

1. Killick SB, Ingram W, Culligan D, et al. British Society for Haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol. 2021; 194(2):267-281.
2. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
   • Myelodysplastic Syndromes (V3.2022). Updated January 13, 2022.

Myeloproliferative Syndromes

1. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
   • Myeloproliferative Neoplasms (V2.2021). Updated August 18, 2021.

Non-small Cell Lung Cancer

1. NCCN Clinical Practice Guidelines in Oncology®. © 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
   • Non-Small Cell Lung Cancer V1.2022 Updated December 7, 2021

PIK3CA Mutation Analysis

1. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy? Genet Med. 2013; 15(7):517-527.
2. National Center for Biotechnology Information (NCBI). GTR: Genetic Testing Registry. PIK3CA Mutation by Sequencing. Last updated September 13, 2017. Available at: http://www.ncbi.nlm.nih.gov/gtr/tests/514565/performance-characteristics/. Accessed on February 2, 2021.
3. National Comprehensive Cancer Network (NCCN).^©  2021 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website at: http://www.nccn.org/index.asp. Accessed on December 16, 2020.
   • Breast Cancer (V2.2022). Revised December 20, 2021.
4. U.S. Food and Drug Administration Premarket Approval Database. Therascreen PIK3CA RGQ PCR kit. Summary of safety and effectiveness. P190001. Rockville, MD: FDA. 2019(a). Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190001B.pdf. Accessed February 2, 2021.
5. U.S. Food and Drug Administration Premarket Approval Database. Therascreen PIK3CA RGQ PCR kit. Summary of safety and effectiveness. P19004B. Rockville, MD: FDA. 2019(b). Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190004B.pdf. Accessed February 2, 2021.

RAS Mutation Analysis

1. Allegra CJ, Rumble RB, Hamilton SR, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J Clin Oncol. 2016; 34(2):179-185.
2. Cetuximab (systemic). In: DrugPoints^® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 6, 2019. Available at: http://www.micromedexsolutions.com. Accessed on April 13, 2020.
3. Elta GH, Enestvedt BK, Sauer BG, Lennon AM. ACG Clinical Guideline: Diagnosis and management of pancreatic cysts. Am J Gastroenterol. 2018; 113(4):464-479.
4. Erbitux (cetuximab) [Product Information]. Branchburg, NJ. ImClone Systems Incorporated. Revised June 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125084s269lbl.pdf. Accessed on April 13, 2020.
5. Kalemkerian GP, Narula N, Kennedy EB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update. J Clin Oncol. 2018; 36(9):911-919.
6. Khalid, A, Brugge, W. ACG practice guidelines for the diagnosis and management of neoplastic pancreatic cysts. Am J Gastroenterol. 2007; 102(10):2339-2349.
7. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018; 142(3):321-346.
8. Lorenzen S, Langer R, Rothling N, et al. Absence of mutations of the K-ras gene in squamous cell carcinoma of the esophagus: Analysis from the randomized oesotux phase II study (cetuximab and cisplatin/5-FU versus cisplatin/5-FU alone). ASCO. 2009; Suppl Abstract No.38
9. NCCN Clinical Practice Guidelines in Oncology™. ^© 2020 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed April 13, 2020.
   • Anal Carcinoma (V1.2020). Revised November 19, 2019.
   • Colon Cancer (V2.2020). Revised March 3, 2020.
   • Non-Small Cell Lung Cancer (V3.2020). Revised February 11, 2020.
   • Pancreatic Adenocarcinoma (V1.2020). Revised July 2, 2019.
   • Rectal Cancer (V2.2020). Revised March 3, 2020.
10. Panitumumab (systemic). In: DrugPoints^® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated December 6, 2019. Available at: http://www.micromedexsolutions.com. Accessed on April 13, 2020.
11. Sepulveda AR, Hamilton SR, Allegra CJ. Et al. Molecular biomarkers for the evaluation of colorectal cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017; 35(13):1453-1486.
12. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology. 2006; 6(1-2):17-32.
13. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016; 27(8):1386-422.
14. Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3:iii1-9.
15. Vectibix (Panitumumab) [Product Information], Thousand Oaks, CA. Amgen. Revised June 2017. Available at: https://pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/vectibix/vectibix_pi.pdf. Accessed on February 2, 2021.

Systemic Mastocytosis

1. NCCN Clinical Practice Guidelines in Oncology^®. ^© 2022 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: visit the NCCN website: http://www.nccn.org/index.asp. Accessed on February 7, 2022.
   • Systemic Mastocytosis V3 2021. Updated July 9, 2021.
2. Valent P, Akin C, Hartmann K, et al. Updated diagnostic criteria and classification of mast cell disorders: A consensus proposal. Hemasphere. 2021; 5(11):e646. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659997/. Accessed on February 7, 2022.

1. American Cancer Society. Key statistics for acute myeloid leukemia (AML). Last revised January 12, 2022. Available at: https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed on February 5, 2022.
2. American Cancer Society. What Is targeted cancer therapy? Last revised January 29, 2021. Available at: https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/targeted-therapy/what-is.html. Accessed on February 2, 2021.
3. National Library of Medicine (NLM). Genetics Home Reference. Published August 31, 2020. Available at: http://ghr.nlm.nih.gov/. Accessed on February 2, 2021.
4. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
5. Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010; 28(5):893-901.

BRAF Mutation Analysis

1. Genetics Home Reference:
   • BRAF. Reviewed August 1, 2018. Available at: http://ghr.nlm.nih.gov/gene/BRAF. Accessed on February 2, 2021.
   • Erdheim-Chester Disease. Reviewed April 1, 2017. Available at: https://ghr.nlm.nih.gov/condition/erdheim-chester-disease. Accessed on February 2, 2021.
2. National Institutes of Health. Genetic and Rare Diseases Information Center. Langerhans cell histiocytosis. Available at: https://rarediseases.info.nih.gov/diseases/6858/langerhans-cell-histiocytosis. Accessed on February 2, 2021.

Circulating Tumor DNA

1. American Cancer Society. Liquid biopsies: Past, Present, and Future. February 12, 2018. Available at: https://www.cancer.org/latest-news/liquid-biopsies-past-present-future.html. Accessed on September 30, 2020.
2. National Cancer Institute. Liquid biopsy: using DNA in blood to detect, track, and treat cancer. November 8, 2017. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/liquid-biopsy-detects-treats-cancer. Accessed on September 30, 2020
3. National Cancer Institute. What is circulating tumor DNA and how is it used to diagnose and manage cancer? Published September 21, 2020. Available at: https://ghr.nlm.nih.gov/primer/testing/circulatingtumordna . Accessed on February 2, 2021.

Epidermal Growth Factor Receptor (EGFR) Mutation Analysis

1. American Cancer Association. Lung Cancer - Non-small cell. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/index. Accessed on February 2, 2021.
2. National Cancer Institute. Non-small cell cancer tTreatment (PDQ^®). Available at: http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/HealthProfessional/page2. Accessed on February 2, 2021.
3. National Library of Medicine. Medical Encyclopedia: Non-small cell lung cancer. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/007194.htm. Accessed on February 2, 2021.

Multiple Endocrine Neoplasia Type 2 (MEN 2) and Thyroid Cancer

1. American Society of Clinical Oncology. Multiple endocrine neoplasia type 2. Last reviewed May 2019. Available at: http://www.cancer.net/cancer-types/multiple-endocrine-neoplasia-type-2. Accessed on September 27, 2022.
2.  National Cancer Institute. Genetics of endocrine and neuroendocrine neoplasias–for health professionals (PDQ^®). Last updated July 1, 2022. Available at: http://www.cancer.gov/types/thyroid/hp/medullary-thyroid-genetics-pdq. Accessed on September 27, 2022.
3. National Library of Medicine (NLM). Genetics Home Reference: Multiple endocrine neoplasia. Updated August 18, 2020. Available at: http://ghr.nlm.nih.gov/condition/multiple-endocrine-neoplasia. Accessed on October 4, 2021.
4. SEER Stat Fact Sheets: Thyroid. National Cancer Institute. Available at: http://seer.cancer.gov/statfacts/html/thyro.html. Accessed on October 4, 2021.

PIK3CA Mutation Analysis

1. National Center for Biotechnology Information (NCBI). Genetic Testing Registry (GTR). Genetic tests for PIK3CA. Available at: https://www.ncbi.nlm.nih.gov/gtr/tests/514565.1/. Last updated: May 26, 2015. Accessed on February 2, 2021.

RAS Mutation Analysis

1. National Library of Medicine. Genetics Home Reference. HRAS. Last updated: August 18, 2020. Available at: https://ghr.nlm.nih.gov/gene/HRAS. Accessed on February 2, 2021.
2. National Library of Medicine. Genetics Home Reference. KRAS. Last updated August 18, 2020. Available at: http://ghr.nlm.nih.gov/gene/KRAS. Accessed on February 2, 2021.
3. National Library of Medicine. Genetics Home Reference. NRAS. Last updated: August 18, 2020. Available at: https://ghr.nlm.nih.gov/gene/NRAS. Accessed on February 2, 2021.

Systemic Mastocytosis

1. National Comprehensive Cancer Networks. NCCN guidelines for patients. Systemic mastocytosis 2022. Available at: https://www.nccn.org/patients/guidelines/content/PDF/systemic-mastocytosis-patient-guideline.pdf. Accessed on February 7, 2022. 

Acute lymphoblastic leukemia (ALL)
Acute myeloid leukemia (AML)
Acute promyelocytic leukemia (APL)
Afatinib
lpelisib (PIQRAY)
Anaplastic thyroid cancer
BRAF Mutation Analysis
Cancer susceptibility
Catalytic subunit alpha polypeptide gene (PIK3CA)
Central nervous system tumor
Chronic lymphocytic leukemia (CLL)
Chronic myeloid leukemia (CML)
Circulating tumor DNA
cobas Mutation Test V2
Cobas^® 4800 BRAF V600 Mutation Test
Colorectal Cancer
Colvera test
Dacomitinib
EGFR
Endocrine gland cancer
Epidermal Growth Factor Receptor
Erdheim-Chester Disease
Erlotinib
Gefitinib
Gilotrif
Hairy-cell leukemia
Iressa
KRAS
Langerhans cell histiocytosis
Liquid biopsy
Lynch Syndrome
Medullary thyroid cancer
Mekinist (trametinib)
Melanoma
MEN2
Multiple endocrine neoplasia (MEN)
Myelodysplastic syndrome (MDS)
Myeloproliferative neoplasm (MPN)
Non-small cell lung cancer
NRAS
OncoBEAM^™ Lung1: EGFR
PI3K
PI3K-alpha
PI3KCA
PI3-kinase p110 subunit alpha
PIK3CA
RET gene
RET proto-oncogene
Systemic mastocytosis
Tafinlar (dabrafenib)
Tarceva
Targeted therapy
Therascreen EGFR
THxID BRAF assay
Tyrosine Kinase
Vizimpro
Zelboraf^® (vemurafenib)

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.