How to Treat Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Amplified Breast Cancer
Authors: Javier Cortes, José Baselga
Journal: Journal of Clinical Oncology (2009)

Breast cancer is a heterogeneous disease composed of different molecular subtypes on the basis of gene expression profiling; these subtypes are increasingly being used to estimate clinical outcomes and choose therapeutic options. The molecular subgroups are in great part defined by the expression status of hormone receptors (HRs) and human epidermal growth factor receptor 2 (HER2). However, HR and HER2 coexpression is not uncommon in breast cancer; approximately half of breast cancers with HER2 overexpression also coexpress HRs. How these tumors behave and, more importantly, how they respond to a variety of therapies are clinical questions that have been only partially addressed to date. Although HR positivity predicts efficacy of endocrine agents in breast cancer, preclinical and clinical data strongly suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment even in the presence of HRs. In addition, HER2 overexpression is an independent adverse prognostic factor for breast cancer regardless of the hormonal status of the tumor, suggesting that HR-positive/HER2-positive breast tumors may be too aggressive to derive benefit from single-agent hormonal therapy. These observations have provided a strong rationale for exploring combined anti-HR and anti-HER2 therapies in HR-positive/HER2-positive breast cancer. HER2-targeted strategies in preclinical models have shown therapeutic potential to subvert endocrine resistance in HRpositive/HER2-positive breast cancer. Although anti-HER2 therapies with chemotherapy have been the standard of care for patients with advanced HER2-positive breast cancer, an unanswered question is whether the subgroup of patients with HER2-positive and HRpositive breast tumors might also derive benefit from a combined anti-HER2 and hormonal therapy approach. If combined hormonal and anti-HER2 therapy were efficacious, this could become an option for patients with HR-positive/HER2-positive disease. In this issue of Journal of Clinical Oncology, the awaited results of two large randomized first-line clinical trials of the combination of aromatase inhibitors (AIs) with anti-HER2 therapies in patients with advanced HER2-positive breast cancer are published. In the first study—the TAnDEM (Trastuzumab and Anastrozole Directed Against Estrogen Receptor–Positive HER2-Positive Mammary Carcinoma) trial—Kaufman et al evaluated the benefit of adding trastuzumab to an AI (anastrozole). A total of 208 postmenopausal patients with HR-positive and HER2-positive advanced breast cancer were randomly selected to receive first-line treatment with anastrozole monotherapy (n 104) or anastrozole plus trastuzumab (n 103). The primary end point was progression-free survival (PFS). Median PFS was 4.8 months for the combination group versus 2.4 months for the anastrozole monotherapy group (P .0016), with a hazard ratio of 0.63 (P .0016; 95% CI, 0.47 to 0.84). In a planned subgroup analysis in patients with centrally confirmed HR-positive tumors, median PFS was longer in both arms (5.6 v 3.8 months; P .006). In the 147 evaluable patients with measurable disease, the overall response rate (RR) was significantly higher with the combination treatment compared with anastrozole alone (20.3% v 6.8%; P .018). The clinical benefit rate—defined as rate of complete response, partial response, and stable disease 6 months or longer in duration—was also significantly higher in patients in the combination arm compared with those in the anastrazole arm (42.7% v 27.9%; P .026). In terms of survival, median overall survival was prolonged by 4.6 months in patients receiving trastuzumab and anastrazole compared with patients receiving anastrozole monotherapy (28.5 v 23.9 months; P .325). This improvement in survival, albeit nonstatistically significant, was observed despite crossover of 73 patients (70%) from the anastrozole arm to the combination arm at disease progression. Treatment with the combination therapy was manageable and well tolerated. In the second trial, known as the EGF30008 study, Johnston et al assessed the efficacy of the combination of the anti-HER2 tyrosine kinase inhibitor lapatinib plus the AI letrozole compared with letrozole plus placebo in patients with HR-positive metastatic breast cancer. The primary end point of the study was PFS in patients with HR-positive and HER2-positive tumors. A total of 1,286 patients were included, 219 of whom also had HER2-positive tumors. In the HER2positive subgroup, the addition of lapatinib reduced risk of disease progression, with a hazard ratio of 0.71 (P .019; 95% CI, 0.53 to 0.96) and median PFS of 8.2 versus 3.0 months. The overall RR was also higher in the combination therapy group (28% v 15%; P .021). Clinical benefit was significantly greater for lapatinib plus letrozole (48% v 29%; odds ratio, 0.4; 95% CI, 0.2 to 0.8; P .003). Again, these benefits did not translate into an improvement in overall survival (33.3 v 32.3 months). In HER2-negative tumors, the combination of lapatinib and letrozole was not superior to letrozole alone in terms of PFS (hazard ratio, 0.90; P .188). However, a nonsignificant trend toward prolonged PFS from 3.1 to 8.3 months favoring the combination therapy was seen in patients who relapsed within 6 months of prior tamoxifen discontinuation, with an increase in median PFS (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P .117). From a safety viewpoint, both studies were safe and involved minimal adverse effects. As expected, patients who received lapatinib had higher frequency of diarrhea. Editorial