Trastuzumab (Herceptin, Genentech, Inc., San Francisco, CA) is a humanized recombinant DNA monoclonal antibody that targets tumor cells that overexpress the Human Epidermal Growth Factor Receptor 2 (HER2) protein and/or amplification of the HER2 gene.

Medically Necessary:

1. Breast Cancer
   Trastuzumab is considered medically necessary for individuals with breast cancer who meet criteria (A) and (B) below and in addition, one or more of the indications listed in (C) below:
   
   1. Individuals whose breast tumors have HER2 protein overexpression documented by one of the following:
      1. Immunohistochemistry (IHC) is 3+; or
      2. Fluorescent in situ hybridization (FISH) HER2 gene copy is greater than 6; or
      3. FISH ratio of HER2 gene/chromosome 17 ratio is greater than 2.2;
         AND
   2. Baseline cardiac assessment (Multiple gated acquisition scan [MUGA] or echocardiogram) is performed prior to initiation of therapy;
      AND
   3. Individuals meet one or more of the following indications:
      1. For treatment of metastatic breast cancer, as a single agent or in combination with chemotherapy (any chemotherapy approved for use in breast cancer), either in treatment-naive individuals or individuals already receiving chemotherapy;
      2. As adjuvant therapy for treatment of breast cancer for completion of a 12-month course of trastuzumab;
      3. As neoadjuvant therapy for locally advanced breast cancer prior to surgical treatment;
      4. In combination therapy with lapatinib as a treatment of metastatic breast cancer when all of the following criteria are met:
         1. Individual has received or is receiving trastuzumab-based therapy; and
         2. Disease has progressed on or after this therapy; and
         3. Individual has received prior anthracycline- and taxane-based regimens in either the adjuvant or metastatic setting.
2. Gastric, Esophageal and Gastroesophageal Adenocarcinoma
   Trastuzumab is considered medically necessary for individuals with gastric, esophageal or gastroesophageal junction (GE) adenocarcinoma who meet criteria (A) and (B) below and in addition, both of the criteria listed in (C) below:
   
   1. Individuals whose tumors have HER2 protein overexpression documented by one of the following:
      1. Immunohistochemistry (IHC) 3+; or
      2. Fluorescent in situ hybridization (FISH) HER2 gene copy is greater than 6; or
      3. FISH ratio of HER2 gene/chromosome 17 ratio is greater than 2.2;
         AND
   2. Baseline cardiac assessment (MUGA or echocardiogram) is performed prior to initiation of therapy;
              AND
   3. Individuals meet the following criteria:
      1. Used in combination treatment; and
      2. Trastuzumab is used in only one line of therapy.

Investigational and Not Medically Necessary:

Trastuzumab is considered investigational and not medically necessary for individuals who do not meet the criteria listed above.

Concomitant use of trastuzumab with other targeted biologic agents not otherwise noted in the criteria above (including but not limited to erlotinib, cetuximab, panitumumab, and bevacizumab) is considered investigational and not medically necessary.

Breast Cancer 

Trastuzumab originally received approval in 1998 by the U.S. Food and Drug Administration (FDA) for the treatment of individuals with metastatic breast cancer whose tumors overexpressed HER2 (referred to as HER2+) and who had received one or more chemotherapy regimens for the metastatic disease. Additionally, trastuzumab in combination with paclitaxel as part of a first line regimen for metastatic disease was also approved. In 2006 and 2008, trastuzumab received additional FDA approval for use in the adjuvant setting in combination therapy for individuals with positive lymph nodes or node negative disease with high risk features, or as a single agent following multi-modality anthracycline based therapy. Although there are different FDA approved dosing recommendations, the maximum treatment period for adjuvant therapy is 52 weeks (Product Information, 2010).

These indications were based on the results of a variety of randomized controlled trials studying the role of trastuzumab as a treatment of metastatic breast disease, as neoadjuvant therapy or adjuvant therapy. These trials examined the use of trastuzumab as monotherapy or in combination with a variety of other therapies and all reported improved disease free survival. Specific review of each of these trials is beyond the scope of this review; a detailed discussion is provided in the guidelines of the National Comprehensive Cancer Network^® (NCCN^®, 2011).

It should be noted the majority of randomized studies of trastuzumab as adjuvant therapy enrolled individuals with breast cancer and positive axillary nodes, or individuals with negative nodes but with a primary tumor measuring greater than 1 cm in greatest dimension. The size limitation in individuals with negative nodes was based on the assumption that small tumors (less than 1 cm in diameter) were at low risk of recurrence such that trastuzumab would not be beneficial, particularly considering the cardiac side effects. However in 2008, data was presented at the San Antonio Breast Cancer Symposium that challenged this assumption. Gonzalez-Angulo and colleagues (2009) performed a retrospective review of 1390 individuals with early breast cancer no larger than 1 cm in any dimension and negative axillary nodes in the Breast Cancer Management Database at the University of Texas M.D. Anderson Cancer Center (MDACC). A total of 965 were eligible for the study. A second set of 350 individuals who met identical clinical criteria at two other institutions in Belgium and Austria were used to validate the MDACC results. Individuals were divided into three groups: triple negative (i.e. negative hormone receptors and negative HER2), HER 2+ (regardless of hormone status) and hormone receptor positive and HER2 negative. Individuals with HER2+ breast cancer had a significantly worse relapse free survival compared to individuals with hormone positive cancer or triple-negative breast cancer (P < .0001). The authors concluded that individuals with even small (less than 1 cm) HER2+ tumors have a significant risk of relapse and that adjuvant systemic therapy with trastuzumab should be considered. Therefore, adjuvant trastuzumab is considered in any individual with HER 2+ early breast cancer regardless of nodal status or size of primary tumor.

Blackwell and colleagues (2010) reported results from a phase three randomized study of lapatinib alone or in combination with trastuzumab for women with HER2 positive, trastuzumab-refractory metastatic breast cancer. Assessments were completed every 4 weeks through week 16, and then every 8 weeks thereafter. Participants were allowed to crossover to combination therapy if objective disease progression was noted after receiving a minimum of 4 weeks of monotherapy with lapatinib. A total of 286 participants were enrolled with random assignment of 148 participants per treatment arm. Median progression-free survival (PFS) of 12 weeks with combination therapy was significantly improved compared to 8.1 weeks PFS for monotherapy with lapatinib (HR of 0.73 [95% CI, 0.57 to 0.93; P = .008). The median overall survival (OS) data is not yet mature, however shows a trend to improved OS with combination therapy versus monotherapy. OS rates for 6- and 12- months were 80% and 45% for combination therapy and 70% and 36% for monotherapy, respectively. Adverse events had similar incidence rates of 94% in the combination cohort compared to 90% in the single-agent group. A significantly higher rate of diarrhea was noted in participants in the combination arm versus the monotherapy arm. The authors noted there are ongoing studies using the combination therapy in early stages of breast cancer and other lines of therapy.

Clinical indications combining trastuzumab with lapatinib are a category 2A offlabel recommendation in the NCCN practice guidelines (2010) for HER2 overexpressing breast cancer.

Gastric, Esophageal and Gastroesophageal Carcinoma

In October 2010, the FDA approved trastuzumab "in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of individuals with HER2 overexpressing metastatic gastric or gastroesophageal junction adenoarcinoma, who have not not received prior treatment for metastatic disease" (Product Information, 2010).

Bang (2010) and colleagues reported results from ToGA (trastuzumab for gastric cancer) a multicenter, phase III randomized trial investigating trastuzumab as first-line treatment of locally advanced, recurrent or metastatic gastric and gastroesophageal adenocarcinoma. A total of 3,807 individuals with gastric carcinoma were tested for HER2. Eligibility for inclusion in the study was HER2 positivity defined as IHC 3+ or FISH positive (defined as HER2: CEP17 ratio ≥ 2) (Bang, 2010). Of these, 594 individuals had HER2+ tumors and were randomized to a control group receiving either 5-fluorouracil or capecitabine and cisplatin with or without trastuzumab. At 17.1 months of follow-up, the median overall survival (OS) was 13.5 months in the trastuzumab arm, compared to 11.1 months in the control group (p = 0.0048). The overall response rate (ORR) was also significantly improved for the trastuzumab group compared to controls, 47.3% vs. 34.5%, respectively.

The NCCN practice guideline for gastric cancer (2011) lists the use of trastuzumab as a part of combination therapy for HER2-positive advanced gastric, esophageal and gastroesophageal adenocarcinoma. These recommendations were based on 2A category of evidence and uniform consensus.

In a Cochrane Review of chemotherapy for gastric cancer (Wagner, 2010), the authors recommended HER2 overexpression testing for all gastric cancers and use of trastuzumab in combination therapy with cisplatin and 5FU for HER2-positive gastric carcinomas.

HER2 overexpression 

The key selection criterion for trastuzumab is HER2 overexpression. In the pivotal breast cancer clinical trials, HER2 overexpression was determined by scores of 2+ or 3+ resulting from the immunohistochemistry Clinical Trial Assay (CTA), which is utilized in research settings. Individuals with scores of 0 or 1+ were not included in the trials. Subsequently, the FDA has approved commercially available immunohistochemistry (IHC) tests to determine HER2 overexpression, which include Herceptest^® (Dako Corp., Glostrup, Denmark) and Pathway™ (Ventana Medical Systems, Tucson, AZ). In addition, FDA approved tests which measure fluorescent in situ hybridization (FISH) of the HER2/neu protein including PathVysion™ (Abott-Vysis Inc, Downers Grove, IL) and INFORM (Ventana medical Systems, Tucson, AZ).

However, studies have shown that HER2 positivity may vary from laboratory to laboratory and according to whether immunohistochemistry or FISH methodology is used. In response, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) developed joint guideline recommendations (Wolff, 2007) for HER2 testing for breast cancer in 2007. The guidelines were established to promote complete and standardized reporting of malignant pathology. IHC results of 3+ cell surface protein expression (defined as uniform intense membrane staining of greater than 30% of invasive tumor cells) are defined as a positive HER2 test. A positive FISH test result includes amplified gene copies (average of greater than six gene copies/nucleus test systems without internal control probe) or HER2/CEP 17 ratio of more than 2.2. FISH testing is recommended in individuals with an equivocal (2+) expression by IHC. ASCO/CAP guidelines recommended increased cell counting in the sample and/or repeat sample testing for equivocal FISH results and note that individuals with equivocal HER2 test results "constitute a poorly studied subgroup with uncertain association of test scores to benefit from HER2-directed therapy (Wolff, 2007)." Additionally, NCCN recommends IHC 2+ (equivocal) HER2 overexpressing tumors to be examined by FISH or other methods (2011).

Specific IHC scoring criteria were developed for gastric carcinoma based on the identification of basolateral membrane staining of gastric tumor specimens obtained surgically or via biopsy. Staining of surgical specimens with "strong complete, basolateral or lateral membranous reactivity in ≥10% of tumor cells" was deemed IHC 3+ and HER2 positive (Bang, 2010). Staining of biopsy specimens with "tumor cell cluster with a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of tumor cells stained" were deemed IHC 3+ and HER2 positive (Bang, 2010). Equivocal results were categorized as IHC 2+ with staining of surgical specimens "weak to moderate complete, basolateral or lateral membranous reactivity in ≥10% of tumor cells" (Bang, 2010). Equivocal HER2 was determined if staining on biopsy specimens included "cancer cell cluster with a weak to moderate complete, basolateral, or lateral membranous reactivity irrespective of percentage of cancer cells" was HER2 equivocal (Bang, 2010).

Cardiac Function

Trastuzumab is associated with a risk of cardiac dysfunction. The practice guidelines from the NCCN recommend baseline cardiac monitoring and intermittent cardiac function testing during the course of therapy. Additionally, the product label states treatment with trastuzumab should only start or continue if the left ventricular ejection fraction (LVEF) is above the institutional lower limit of normal. Jones and colleagues (2009) noted "patients with metastatic disease have a very different oncology risk profile to those receiving adjuvant treatment; the monitoring strategy and thresholds for treatment discontinuation should thus be individualized in consultation with the oncologist and cardiologist when appropriate."

Other Uses 

As a result of clinical trials demonstrating the effectiveness of trastuzumab with chemotherapy, additional clinical trials are studying the efficacy of adding trastuzumab to specific targeted biologic agents. However, at this time, there is no evidence to support the safety and efficacy of combining trastuzumab with other biologic agents not discussed above.

Additionally, investigators continue to study the prevalence and role of HER2 in other malignancies. However, there have been no large randomized controlled trials demonstrating the safety and efficacy of trastuzumab versus current standard therapies for malignancies other than breast, gastric, esophageal and gastroesophageal cancers.

The human epidermal growth factor receptor 2 gene ERBB2 is commonly referred to as HER2. Other names for this gene include NEU, Her-2, HER-2/neu and c-erb B2. Initially the HER2 gene was detected in frozen breast tumor samples. Amplification of the HER2 gene was later correlated to overexpression of protein levels in samples of breast cancer. The HER2 overexpression is present in approximately 18% - 25% of all early breast cancers (Baselga, 2006; Robert, 2006; Wolff, 2007) and is associated with aggressive disease, shortened disease-free survival (DFS) and overall survival (OS) (Robert, 2006; Wolff, 2007).

According to the National Cancer Institute (NCI, 2010) approximately 10% to 20% of all new gastric cancer cases are diagnosed at an early stage of disease. The remaining individuals are diagnosed with regional or distant metastatic disease. A review by Gravalos (2008) noted HER2 overexpression in gastric cancer ranged from 9% - 38% in reported series. 

Adverse Events and Warnings:
Trastuzumab has the following Black Box warnings (Product Information Label, 2010):

Cardiomyopathy

Herceptin administration can result in sub-clinical and clinical cardiac failure. The incidence and severity was highest in patients receiving Herceptin with anthracycline containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and withhold Herceptin in patients with metastatic disease for clinically significant decrease in left ventricular function.

Infusion Reactions; Pulmonary Toxicity

Herceptin administration can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of Herceptin administration. Interrupt Herceptin infusion for dyspnea or clinically significant hypotension. Monitor patients until signs and symptoms completely resolve. Discontinue Herceptin for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Embryo-fetal Toxicity

Exposure to Herceptin during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death (Product Information Label, 2010).

Other serious adverse reactions caused by trastuzumab include diarrhea, exacerbation of chemotherapy-induced neutropenia and infection.

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure; may include chemotherapy, radiation, hormone or biological therapy.

Disease free survival (DFS): The interval between a complete disappearance of the cancer (complete response) and the time of relapse.

First-line of therapy: The first or primary treatment for the diagnosis; may include surgery, chemotherapy, radiation therapy or a combination of these therapies.

Metastatic: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Monoclonal Antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Neoadjuvant therapy: Treatment given before the primary treatment which may include chemotherapy, radiation therapy, or hormone therapy.

Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.

Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

The following codes for treatments and procedures applicable to this document 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 Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, and for all other diagnoses not listed

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Bang YJ, Van Cutsem E, Feyereislova A, et al.; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomized controlled trial. Lancet. 2010; 376(9742):687-697.
2. Baselga J, Perez E, Pienkowski T, Bell R. Adjuvant trastuzumab: A milestone in the treatment of HER-2-positive early breast cancer. Oncologist. 2006; 11 Suppl 1:4-12.
3. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010; 28(7):1124-1130.
4. Dowsett M, Procter M, McCaskill-Stevens W, et al. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol. 2009; 27(18):2962-2969.
5. Gonzalez-Angulo AM, Litton JK, Broglio KR, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009; 27(34):5700-5706.
6. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol. 2008; 19(9):1523-1529.
7. Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer. 2009; 100(5):684-692.
8. Perez EA, Roche PC, Jenkins RB, et al. HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin Proc. 2002; 77(2):148-154.
9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al.; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353(16):1659-1672.
10. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353(16):1673-1684.
11. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369(9555):29-36.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS^®). AHFS Drug Information 2011^®_. Bethesda, MD: American Society of Health-System Pharmacists, 2011.
2. Herceptin Trastuzumab [Product Information], San Francisco, CA. Genentech, October 29, 2010. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5256lbl.pdf. Accessed on January 21, 2011.
3. NCCN Clinical Practice Guidelines in Oncology™. © 2011 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org. Accessed on April 4, 2011.
   • Breast Cancer (V.2.2011). Revised March 25, 2011.
   • Esophageal and Esophagogastric Junction Cancers (V.2.2011). Revised May 13, 2011.
   • Gastric Cancer (V.1.2011). Revised March 4, 2011.
4. NCCN Drugs & Biologic Compendium^{™ ©} 2011 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org. Accessed on March 9, 2011.
5. Trastuzumab (systemic). In: DrugPoints System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Updated December 13, 2010. Available at: http://www.thomsonhc.com. Accessed on March 9, 2011.
6. Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane Database of Systematic Reviews. 2010, Issue 3. Art No.3: CD004064.
7. Wolff A, Hammond MEH, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007; 25(1):118-145.

1. American Cancer Society. Available at: http://www.orgsites.com/ga/acs/. Accessed on January 21, 2011.
2. National Cancer Institute. Breast Cancer Treatment PDQ^®. February 14, 2011. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/breast/healthprofessional. Accessed on April 4, 2011.
3. National Cancer Institute. Gastric Cancer Treatment PDQ. March 25, 2011. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/gastric/healthprofessional/allpages. Accessed on April 4, 2011.

HER2; Her2-neu
Herceptin
Monoclonal antibody
Trastuzumab

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.