1. Aetna considers Herceptin (trastuzumab, Genentech, Inc.) medically necessary for use in members with breast cancer, advanced esophageal adenocarcinomas, gastric adenocarcinomas or gastroesophageal junction adenocarcinomas that over-express the HER2 (human epidermal growth factor receptor 2) protein (i.e., level 2 or 3 on the HercepTest) or where HER2 gene amplification is detected using a FISH technique (ratio greater than 2 on the PathVysion test).

   For individuals with breast cancer who are HER2 positive with no distant metastatic disease, up to 1 year of Herceptin treatment is considered medically necessary. A repeat course of Herceptin is considered medically necessary if these individuals have maintained remission for more than 1 year after finishing the prior course of Herceptin therapy.

   For persons with distant metastatic disease, Herceptin treatment is considered medically necessary unless disease progresses.

2. Aetna considers Herceptin (trastuzumab), alone or in combination with chemotherapy, experimental and investigational for the treatment of the following types of cancer (not an all inclusive list) and all other indications because trastuzumab has not been proven to be effective for these indications.

   • Bladder cancer
   • Dermal adnexal cancer
   • Endometrial cancer
   • Non-small cell lung cancer
   • Ovarian cancer
   • Pancreatic cancer
   • Prostate cancer
   • Salivary gland/duct cancer

   • Vulvar cancer.

Note: Dosing information is provided as an appendix to the background section.

The HER2 gene normally produces a small amount of protein called HER2 growth factor cell-surface receptor, which is responsible for growth and division of cells.  In 25 to 30% of women with breast cancer, there is a genetic alteration in the HER2 gene which results in increased amounts of this protein, and this protein over-expression is associated with more aggressive disease and shortened survival because it may be resistant to chemotherapy and other forms of treatment.

The HercepTest, manufactured by Dako, is a commercially available test that specifically identifies over-expression of HER2/neu (c-erbB-2) protein in patients with breast cancer, and has been approved by the FDA for selecting patients for treatment with trastuzumab.  It is an immunohistochemical antibody assay designed for the detection of HER2 over-expression of HER2/neu protein using specific antibodies, and localizes over-expressed protein in cells or tissues.  HER2 expression has been broken down into four levels: 0, 1, 2, 3. HER2/neu over-expression is defined as 2 or 3 circumferential membranous staining with an anti-HER2 antibody by immunohistochemistry (IHC) performed on a paraffin embedded tissue.  Clinical trastuzumab trials showed that patients with level 0-1 HER2 expression do not benefit from the drug; a few patients with level 2 expression do benefit from the drug; and many patients with level 3 expression also benefit.  The trastuzumab monoclonal antibody seeks out and binds to the specific HER2 or HER2/neu receptors on the surface of HER2 over-expressing breast cancer cells and directly inhibits tumor cell growth.

Trastuzumab is indicated for treatment of individuals with HER2 over-expressing breast cancer both as first line therapy in combination with paclitaxel (Taxol), and as a single agent in second and third line therapy.  Patients are given trastuzumab intravenously once a week.  The appropriate duration of therapy is unknown, although studies have reported patients that have been treated with trastuzumab for 9 weeks.

In a large, randomized controlled trial, trastuzumab improved response rates to chemotherapy by 53% in women with metastatic breast cancer that over-expressed HER2.  In this clinical trial, overall response rates were 43% with trastuzumab and chemotherapy, compared to only 28% in women treated with chemotherapy alone.  The greatest improvement in response rates was seen in patients who received trastuzumab plus the chemotherapeutic agent paclitaxel.  Thirty six percent of women treated with trastuzumab plus paclitaxel had a tumor response, compared to only 15% of women receiving paclitaxel alone.  Median duration of response, which is measured from the time the cancer responds to therapy to the time the cancer begins to spread or grow again, was seven months longer in women treated with trastuzumab and paclitaxel than it was in women treated with paclitaxel alone.

Trastuzumab can also induce responses in patients with HER2 over expressing metastatic breast cancers who have failed to respond to chemotherapy. In a trial of 222 women who had failed one or two prior chemotherapy regimens, 14% of women treated with trastuzumab alone had objective tumor responses with tumor shrinkage of 50% or more.

Two large randomized controlled clinical trials sponsored by the National Cancer Institute involving more than 3300 patients with early-stage HER2 positive invasive breast cancer found that those patients who received trastuzumab in combination with standard chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel) had a statistically significant 52% decrease in risk for breast cancer recurrence compared with patients who received chemotherapy alone (Romond, et al., 2005).  These studies included women with HER2 positive and node positive breast cancer with no distant metastatic disease.  One study also included persons with high risk node negative breast cancer: tumor greater than 2 cm, estrogen/progestin receptor negative, nuclear grade 2-3 or age less than 35 years.  In one study, Herceptin therapy was administered weekly for three months, then every 21 days for one year.  In another study, Herceptin therapy was administered weekly for one year.  Four years into the study, 85 percent of women with early-stage HER-2 positive breast cancer who received trastuzumab were free of recurrence, compared with 67 percent of women who did not receive the drug.  The data monitoring committees overseeing the combined analysis of these trials recommended that the results of a combined interim analysis be made public because the studies had met their primary endpoints of increasing disease-free survival and overall survival in patients receiving trastuzumab in combination with chemotherapy.  Most patients in these studies had lymph node-positive breast cancer, with only a minority having lymph node-negative disease.  The limited information in the node-negative group did not allow for a separate analysis of this group.  In these studies, the likelihood of congestive heart failure in women receiving standard combination chemotherapy and trastuzumab was increased by 3 percent to 4 percent.

An international, multicenter, randomized controlled clinical trial (Herceptin Adjuvant Trial (HERA)) found that one year treatment with trastuzumab after adjuvant chemotherapy significantly improved disease free survival among women with early stage HER2 positive breast cancer (Piccart-Gebhart, et al., 2005).  The study compared one or two years of trastuzumab given every three weeks with observation in women with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy (surgery with or without radiotherapy) and at least four cycles of neoadjuvant or adjuvant chemotherapy.  Eligible subjects had node positive disease (regardless of tumor size) or node-negative disease (if tumor size was greater than 1 cm) and no distant metastases.  Subjects in the HERA study were assigned to three groups: two years of treatment with trastuzumab, one year of trastuzumab, and observation.  The study by Piccart-Gebhart reported results only of the groups assigned to one year of trastuzumab treatment and observation.  At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second non-breast malignant disease, or death) were observed; 127 events in the trastuzumab group and 220 in the observation group.   The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval 0.43 to 0.67), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percent.  Overall survival in the two groups was not statistically significantly different (29 deaths with trastuzumab versus 37 with observation).  Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. 

Fluorescent in situ hybridization (FISH) assays have also been validated for use in the selection of candidates for trastuzumab therapy.  FISH assays contain a direct label DNA probe designed to bind to the HER2 gene, allowing direct visualization of the gene. Two FISH kits for HER2 are now available: PathVysion from Visis; and Inform, developed by Oncor and now marketed by Ventana.  Tumors that are candidates for trastuzumab therapy can be detected at the DNA level by FISH assays because there is a high correlation between over-expression of the HER2 protein and amplification of the gene that codes for it. Both the PathVysion and Inform FISH tests have been approved by the FDA for quantifying HER2/neu amplification.  However, only the PathVysion FISH test has been approved by the FDA for selecting patients with metastatic breast cancer for trastuzumab therapy.  FISH assays of HER2 gene amplification have been found to have a high correlation with immunochemical antibody assays for HER2 over-expression.  The American Society of Clinical Oncology recommends using either immunohistochemical antibody assays or FISH assays for selecting patients for trastuzumab therapy. ASCO's clinical practice guidelines for the use of tumor markers in breast and colorectal cancer (2001) states that, "[h]igh levels of c-erbB-2 [HER2/neu] expression or c-erbB-2 [HER2/neu] amplification can be used to identify patients for whom trastuzumab expression on a new or stored specimen of tumor tissue.  This assay may be of benefit for the treatment of metastatic, recurrent, or treatment-refractory unresectable locally advanced breast cancer."

The HER2/neu is over-expressed/amplified in a range of other tumor types including ovarian, bladder, pancreatic, salivary gland, endometrial and non-small-cell lung cancer (Scholl, et al., 2001). HER2 is implicated in disease initiation and progression, associated with poor prognosis, and may also predict the response to chemotherapy and hormonal therapy.  The prevalence of HER2 over-expression/amplification in various tumor types raises the possibility of using trastuzumab to antagonize the abnormal function of over-expressed HER2 receptors in HER2-positive tumors other than breast. Clinical trials are either planned or underway to assess the therapeutic role of trastuzumab in non-small cell lung cancer, bladder and ovarian cancer.

HER/2 neu gene amplification is uncommon in bladder cancer.  Evidence from breast cancer suggests that only tumors with HER2/neu gene amplification respond to trastuzumab. If this were true for bladder cancer, only  approximately 5% of muscle-invasive transitional cell carcinomas of the bladder would be suitable for treatment (Latif, et al., 2004; Kruger, et al., 2002).  Latif, et al. concluded that “[t[]e role of trastuzumab in these tumours remains untested at present.” 

HER2/neu gene amplification has also been rarely found in non-small cell lung cancer (Zinner, et al., 2004), and clinical studies to date have failed show a demonstrable advantage of trastuzumab in the majority of non-small cell lung cancer patients (Hirsch & Langer, 2004; Zinner, et al., 2004).  Langer, et al. (2004), reporting on the results of the Eastern Cooperative Oncology Group Phase II study of trastuzumab in non-small cell lung cancer, concluded that overall survival in patients treated with trastuzumab, carboplatin and paclitaxel is similar to historical data using carboplatin and paclitaxel alone. The investigators reported, however, that patients with 3+ HER2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of non-small cell lung cancer.  This finding needs to be confirmed by prospective clinical studies with internal controls.

In a multi-center, phase II clinical study, Clamon and colleagues (2005) determined whether trastuzumab would effect responses in patients with non-small cell lung carcinoma who had tumors that over-expressed HER2.  Patients were required to have Stage IIIB or Stage IV non-small cell lung carcinoma and tumors with 2+ or 3+ expression of HER2, as determined with immunohistochemistry, and they may have received up to 1 prior chemotherapy regimen.  Trastuzumab at a dose of 4 mg/kg was given intravenously on week 1; then, weekly doses of 2 mg/kg were given.  Response revaluation was performed every 8 weeks.  Among 209 screened patients, 24 patients (11 %) had tumors with 2+ or 3+ expression of HER2.  One patient achieved a partial response, and 1 patient experienced a treatment-related death due to pulmonary toxicity.  These investigators concluded that single-agent trastuzumab did not exhibit significant clinical activity against non-small cell lung carcinoma when HER2 expression levels were measured by immunohistochemistry.

In a randomized controlled phase II clinical trial, Krug et al (2005) examined whether combined trastuzumab with weekly taxanes would improve outcomes over standard chemotherapy in patients with advanced non-small cell lung cancer.  The primary goal was to determine whether docetaxel plus trastuzumab or paclitaxel plus trastuzumab was the superior regimen based on response and toxicity, and to determine whether either regimen was appropriate for further testing in a randomized phase III clinical trial.  After stratification based on the results of HER2 immunohistochemistry, chemotherapy-naive patients were randomized to receive trastuzumab plus docetaxel or trastuzumab plus paclitaxel.  The study was designed so patients with or without HER2 over-expression would be distributed equally between the study arms.  Immunohistochemistry for HER2 protein expression was attempted for 182 pathologic samples from 169 patients.  Twenty-eight of the 179 evaluable samples (16 %) revealed 2+ or 3+ staining.  The objective response rate was 23 % (7 of 30 patients) in the patients treated with docetaxel plus trastuzumab and 32 % (11 of 34 patients) in the patients treated with paclitaxel plus trastuzumab (p = 0.76).  No difference was noted in the median survival (16 months versus 14 months) or 1-year survival (57 % versus 55 %) (p = 0.998).  Toxicities were mild in both treatment arms.  No difference with regard to response rates or survival was noted between HER2-positive (2+ or 3+) and HER2-negative (0-1+) patients.  These authors concluded that the expression of HER-2 protein in patients with advanced non-small cell lung cancer in this study was found to be similar to that reported in previous series.  The response rates and toxicities for patients treated with docetaxel and trastuzumab or paclitaxel and trastuzumab were not significantly different, though survival in both arms was better than expected.  HER2 expression status did not appear to affect outcomes for this uniform group of patients who were treated in a comparable fashion.  Because of the infrequency of HER2 over-expression, and the absence of improved outcomes in patients with non-small cell lung cancer who were treated with trastuzumab plus chemotherapy in other studies, neither regimen tested will be advanced to a Phase III clinical trial.

The value of trastuzumab in ovarian carcinoma is limited by the low frequency of HER2/neu over-expression and the low response rate of response to trastuzumab among patients with HER2/neu over-expression.  Bookman, et al. (2003) reported on the results of a Gynecology Oncology Group Phase II study of trastuzumab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+/3+ HER2 expression.  Only 11.4 percent of subjects screened for HER2 expression exhibited the requisite 2+ or 3+ HER2 expression level to be eligible for this study.  The investigators reported an overall response rate of 7.3 percent after a median treatment duration of 8 weeks, and the median progression-free interval was two months.  The investigators concluded that “the clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 over-expression and low rate of objective response among patients with HER2 over-expression.”  Iwamoto, et al. (2003) found HER2/neu over-expression in only one of 15 clear cell ovarian carcinoma cases that were immunostained for HER-2 /neu using HercepTest.  The investigators concluded that HER-2 /neu over-expression appeared to be uncommon in ovarian clear cell carcinomas. “Herceptin may thus target only a small proportion of ovarian clear cell carcinomas and be of limited clinical value for treatment of this carcinoma” (Iwamoto, et al., 2003).

Viani and colleagues (2007) performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting.  Survival, recurrence, brain metastases, cardiotoxicity and directions for future research were discussed.  Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria.  Pooled results from that five randomized trials of adjuvant trastuzumab showed a significant reduction of mortality (p < 0.00001), recurrence (p < 0.00001), metastases rates (p < 0.00001) and second tumors other than breast cancer (p = 0.007) as compared to no adjuvant trastuzumab patients.  There were more grade III or IV cardiac toxicity after trastuzumab (203/4555 = 4.5 %) versus no trastuzumab (86/4562 = 1.8 %).  The likelihood of cardiac toxicity was 2.45-fold higher (95 % CI 1.89 - 3.16) in trastuzumab arms, however that result was associated with heterogeneity.  The likelihood of brain metastases was 1.82-fold higher (95 % CI 1.16 - 2.85) in patients who received trastuzumab.  The authors concluded that the findings from this meta-analysis are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER2-positive early breast cancer based on the risk: benefit ratio demonstrated in these studies.

In January 2008, the FDA rendered trastuzumab the additional indication of adjuvant monotherapy for early-stage HER2-positive breast cancer.  The FDA decision was predicated on 1-year data from the HERA (HERceptin Adjuvant) trial.  It found a significant 46 % reduction in recurrence among women who took trastuzumab for 52 weeks following multi-modality anthracycline-based therapy compared with controls.  The HERA trial also reported a significant increase in disease-free survival among women who received adjuvant therapy with trastuzumab.  Trastuzumab was, however, associated with a higher rate of congestive heart failure -- 2 % versus 0.3 % in the control group.  Serious infusion reactions including fatal infusion reactions as well as pulmonary toxicity have been reported with trastuzumab.  In most cases symptoms occurred during infusion or within 24 hours of infusion.  Trastuzumab infusion should be interrupted for patients with dyspnea or clinically significant hypotension.  Patients should be monitored until signs and symptoms completely resolve.  Trastuzumab should be discontinued for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Advanced gastric cancer is an incurable disease; several authorities have stated that new and less toxic treatments are needed. HER2 overexpression has been reported in 6% to 35% of stomach and gastroesophageal tumors. Gravalos and Jimeno (2008) noted that gastric cancer is the second leading cause of cancer mortality in the world and its management, especially in advanced stages, has evolved relatively little.  In particular, no targeted modality has so far been incorporated to its treatment armamentarium.  HER2 over-expression is increasingly recognized as a frequent molecular abnormality, driven as in breast cancer by gene amplification.  There is mounting evidence of the role of HER2 over-expression in patients with gastric cancer, and it has been solidly correlated to poor outcomes and a more aggressive disease.  Additionally, pre-clinical data are showing significant anti-tumor efficacy of anti-HER2 therapies (particularly monoclonal antibodies directed towards the protein) in in-vitro as well as in-vivo models of gastric cancer.  As a result, several clinical trials are exploring in different settings and with diverse designs the potential of anti-HER2 therapies in gastric cancer patients. 

A randomized trial investigating anti-HER2 therapy in advanced gastric cancer showed that trastuzumab plus chemotherapy was superior to chemotherapy alone (van Custem, et al., 2009). The ToGA study is the first randomized, prospective, multicenter, phase III trial to study the efficacy and safety of trastuzumab in HER2- positive gastric cancer. Patients with HER2-positive gastroesophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were randomized to receive trastuzumab plus chemotherapy (5-fluorouracil or capecitabine and cisplatin) every three weeks for 6 cycles or chemotherapy alone. Trastuzumab was given until disease progression. The primary end point was overall survival (OS); secondary end points included overall response rate (ORR), progression-free survival, time to progression, duration of response, and safety. An interim analysis was planned at 75% of deaths and the Independent Data Monitoring Committee recommended releasing the data as the pre-specified boundary was exceeded and median follow-up of patients was 17.1 months. Tumors from 3,807 patients were centrally tested for HER2 status: 22.1% were HER2 positive; 594 pts were randomized 1:1 at sites in Europe, Latin America, and Asia. The investigators reported that baseline characteristics were well balanced across arms. Median OS was significantly improved with trastuzumab plus chemotherapy compared to chemotherapy alone: 13.5 versus 11.1 months, respectively (p = 0.0048; hazard ratio 0.74; 95% confidence interval 0.60 to 0.91). ORR was 47.3% in the trastuzumab plus chemotherapy arm and 34.5% in the chemotherapy arm (p = 0.0017). Safety profiles were similar with no unexpected adverse events in the trastuzumab plus chemotherapy arm. There was no difference in symptomatic congestive heart failure between arms. Asymptomatic left ventricular ejection fraction decreases were reported in 4.6% of patients in the trastuzumab plus chemotherapy arm and 1.1% in the chemotherapy arm. The investigators conclude that this randomized trial investigating anti-HER2 therapy in advanced gastric cancer showed that herceptin plus chemotherapy is superior to chemotherapy alone.

NCCN guidelines (2010) recommend the use of herceptin in combination with systemic chemotherapy for persons with advanced, HER2 positive esophageal or gastroesophageal adenocarcinoma. Homs and colleagues (2009) evaluated current treatment strategies and new developments including targeted therapy for esophageal cancer.  Published clinical trials as well as abstracts were selected regarding chemo-radiation or targeted therapy for esophageal cancer.  Preoperative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive.  For pre-operative chemo-radiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more phase III trials and, consequently, meta-analyses are needed.  Until now, for palliative chemotherapy, no survival benefit has been shown.  This is largely due to a lack of studies and difficulties in performing randomized trials.  The application of targeted therapy is widespread and reported for several tumor types.  For esophageal cancer, most studies have been performed with EGFR inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab.  Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors.  As yet, targeted therapies are proven to be safe often in combination with chemo-radiation, but modestly effective for esophageal cancer.  Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.

In a review on systemic therapies for recurrent and/or metastatic salivary gland cancers, Vattemi and colleagues (2008) noted that salivary gland carcinomas are rare cancers, comprising 1 to 5 % of head and neck cancers.  They represent a morphologically and clinically diverse group of tumors.  The most commonly histopathological types are muco-epidermoid cancer, adenoid cystic cancer and adenocarcinomas.  Malignant salivary gland tumors generally present as painless, slow-growing tumors that are indistinguishable from benign tumors.  Surgery is the principal treatment and is curative in early stage.  Radiation therapy should be considered in most patients after surgical resection.  Chemotherapy is reserved for palliative treatment of metastatic disease but results are disappointing.  Recent studies have investigated the role of targeted therapies in a palliative setting.  Multi-center co-operative group clinical trials are required to assess novel therapies to maximize patient resources in this uncommon tumor.

Fleming et al (2010) evaluated the effectiveness of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification.  Eligible patients had measurable stage III, IV, or recurrent EC.  There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2).  Tumors were required to have HER2 over-expression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio greater than 2.0).  Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression.  The primary end point was tumor response.  Of the 286 tumors centrally screened by LabCorp, 33 (11.5 %) were HER2-amplified.  Three of 8 clear (38 %) cell carcinomas and 7 of 25 serous carcinomas (28 %) screened exhibited HER2 amplification compared with 7 % (2/29) of endometrioid adenocarcinomas.  Over-expression of HER2 was correlated with amplification of HER2 (r = 0.459; p < 0.0001).  A total of 34 women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification.  No major tumor responses were observed.  Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response.  Neither HER2 over-expression nor HER2 amplification appeared to be associated with progression-free survival or OS.  The authors concluded that trastuzumab as a single agent did not exhibit activity against endometrial carcinomas with HER2 over-expression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment.  Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

Nash and colleagues (2007) reported the case of a 44-year-old man was referred for a right chest nodule of 3-month duration.  A "benign" nodule had been excised from this location 8 years prior.  On examination, palpable nodes were noted in the right axilla.  Radiographical studies were significant only for right axillary lymphadenopathy.  Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor.  Features of a clear cell hidradenoma were noted focally.  Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu.  Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2.  A wide local excision and axillary node dissection was performed.  Metastatic tumor involved 9 of 28 nodes.  Inter-phase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis.  The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic.  The authors believed this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor.  In analogy to breast carcinoma, these findings suggested the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.  The role of trastuzumab, if any, for the treatment of dermal adnexal carcinoma needs to be validated by well-designed studies.

Appendix

Trastuzumab Dosing

According to the FDA approved labeling of Herceptin for breast cancer, the usual dose of trastuzumab is a 4 mg/kg loading dose, followed by 2 mg/kg every week (Genentech, 2006). An alternative every 3 weeks dosing schedule for breast cancer, used in the Herceptin Adjuvant (HERA) trial, is an 8 mg/kg loading dose of trastuzumab, followed by 6 mg/kg every 3 weeks (Piccart-Gebhart et al, 2005; Smith et al, 2007).

For gastric cancer, Herceptin should be administered at an initial dose of 8 mg/kg as a 90-min intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 mins every 3 weeks until disease progression.