Breast Cancer and HER2
Approximately 30% of malignant breast cancers demonstrate overamplification of the human epidermal receptor type 2 (HER2) gene, resulting in an overexpression of the HER2 receptor, a transmembrane tyrosine kinase receptor within the epidermal growth factor receptor (EGFR) family. Activation of this class of cellular receptors is known to result in increased activity of a variety of molecular pathways associated with tumor growth and progression. Extensive published pre-clinical and clinical data have demonstrated that patients whose cancers overexpress HER2 have a relatively poor prognosis independent of other clinical features (eg, age, stage, tumor grade).1
Clinical Implications of the Genetic Mutation
Trastuzumab (Herceptin), a humanized recombinant monoclonal antibody specifically directed against the HER2 receptor, has been shown to be biologically active and of considerable clinical utility in breast cancer patients with documented HER2 amplification. Trastuzumab mediates antibody-dependent cellular cytotoxicity against cells that overproduce HER2, and lacks effect on cells not overexpressing HER2.
Clinical trials have shown that the addition of trastuzumab to a combination chemotherapy regimen in the adjuvant and the metastatic settings significantly improves outcomes and survival measures.2,3 In a phase III trial of 469 women with chemo-naïve, HER2-positive, metastatic breast cancer, patients randomized to trastuzumab plus chemotherapy (doxorubicin or epirubicin + cyclophosphamide or paclitaxel) demonstrated a significantly higher rate of overall response (50% vs. 32%, P < 0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P < 0.001), a longer time to treatment failure (median, 6.9 vs. 4.5 months; P < 0.001), and a significantly lower rate of death (22% vs. 33%; P = 0.008) compared with those randomized to chemotherapy alone. Overall survival was significantly different between the groups(25.1 months vs. 20.3 months; P = 0.046), and trastuzumab reduced the relative risk of death by 18% to 20% at a median follow-up of 30 months.2 It should be noted that the overall survival results in the chemotherapy alone arm included patients who received open-label trastuzumab after progression on this protocol. Therefore, use of the agent in this setting may have favorably impacted the ultimate survival outcome in this population.
In the adjuvant setting, results from two phase III trials comparing trastuzumab + chemotherapy (doxorubicin + cyclophosphamide followed by paclitaxel) vs. chemotherapy alone were combined for analysis. Patients in both trials had surgically removed, HER2-positive breast cancers that were node-positive or that were node-negative but considered at high risk for progression due to size (ie, > 2 cm in diameter) or hormone receptor status (ie, both estrogen and progesterone negative). Data from the 3351 patients who had at least one follow-up evaluation demonstrated a significant improvement in disease-free survival (85.3% vs. 67.1% at four years; P < 0.0001) as well as a significant improvement in overall survival (91.4% vs. 86.6% at four years; P = 0.015) in the trastuzumab group vs. chemotherapy alone.3
Lapatinib (Tykerb), a 4-anililoquinazoline kinase that inhibits intracellular tyrosine kinase domains of EGFR (ErbB1) and HER2 (ErbB2), has also been shown to improve time to progression when combined with chemotherapy in the management of advanced breast cancer.4 In a phase III trial, 324 patients with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomized to lapatinib plus capecitabine or capecitabine alone. Patients randomized to lapatinib + capecitabine demonstrated significant improvements in both median time to progression (8.4 months vs. 4.4 months; P < 0.001) and median progression-free survival (8.4 months vs. 4.1 months; P < 0.001).4
Based on data from these and other randomized phase III clinical trials, in the absence of a medical contraindication, high-risk, HER2-positive breast cancers should be treated with a HER2 inhibitor (eg, trastuzumab, lapatinib) in addition to cytotoxic chemotherapy.
NCCN Clinical Practice Guidelines recommend adjuvant use of this class of agents in combination with chemotherapy for patients with node-positive, HER2-positive breast cancers > 1 cm, and suggest consideration of its use in patients with HER2-positive, node-negative breast cancers between 0.6 and 1.0 cm.5
In patients with HER2-positive, metastatic breast cancer, the Guidelines recommend the use of trastuzumab or lapatinib in combination with chemotherapy or as a single agent in the first line as well as continuation of trastuzumab in patients whose cancers progress despite treatment with a trastuzumab-containing regimen in the adjuvant setting.5
Testing for the Genetic Mutation
The goal of laboratory-based analysis for HER2 is to document the presence of HER2 gene amplification or receptor overexpression within the malignant cell population.
It is critical that any laboratory providing clinical testing for HER2 have considerable experience with the measurement of this molecular marker. Two types of tests are generally available: immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).6 IHC is a semi-quantitative method that measures overexpression of the HER2 receptor, with the degree of staining graded on a scale from 0 to 3+. Patients with breast cancers with intensive staining (3+) should definitely receive anti-HER2 therapy; the clinical relevance of 2+ staining is uncertain.
FISH is a far more quantitative and reproducible method, as it directly measures the number of copies of the HER2 gene. However, FISH testing is associated with greater cost and takes more time than an analysis employing IHC.
More information about breast cancer, HER2, and targeted treatments for HER2-overexpressing breast cancer can be found in Medscape’s Breast Cancer Resource Center and the Cancer: Biologic Therapies Resource Center as well as in the eMedicine article on Breast Cancer.