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The 2010 San Antonio Breast Cancer Symposium (SABCS; December 8–12, 2010) highlighted targeted therapy strategies in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the optimization of endocrine therapy in metastatic breast cancer, and the tempering of enthusiasm for bisphosphonates in adjuvant therapy for early-stage breast cancer. Key presentations are summarized below; for more information, readers are encouraged to visit the SABCS website.
Trastuzumab and lapatinib have been available for treating HER2-positive metastatic breast cancer for several years and are highly effective. Yet, some patients who receive these agents develop recurrent or progressive metastatic disease. In efforts to improve the overall efficacy of anti-HER2 therapies, novel agents and combinations have been assessed in the preoperative setting.
In the GeparQuinto trial (Abstract S3-1), researchers evaluated lapatinib versus trastuzumab administered concurrently with neoadjuvant chemotherapy (epirubicin and cyclophosphamide followed by docetaxel) in patients with primary breast cancer. The primary endpoint was pathologic complete remission (pCR) in the breast and axillary lymph nodes; pCR rates were 31.3% in the trastuzumab group versus 21.7% in the lapatinib group. More patients who received lapatinib experienced grade 3/4 diarrhea resulting in therapy discontinuation or dose reduction.
Investigators presented the first results of the NeoALTTO trial (Abstract S3-3), a randomized, open-label, phase III trial of neoadjuvant lapatinib, trastuzumab, or both agents plus paclitaxel. Rates of pCR were similar in women who received lapatinib or trastuzumab (29.5% and 24.7%, respectively) and substantially higher in women who received both trastuzumab and lapatinib (51.3%). As in the GeparQuinto trial, regimens containing lapatinib (alone or in combination with trastuzumab) were associated with higher rates of grade 3/4 diarrhea. A large international trial of similar design in the adjuvant setting is under way.
Pertuzumab is an antibody that binds to a site distinct from the trastuzumab binding site, thereby preventing HER2–HER3 heterodimerization. The NeoSphere trial (Abstract S3-2) is a randomized phase II study with four neoadjuvant treatment arms: (1) docetaxel and trastuzumab; (2) docetaxel, trastuzumab, and pertuzumab; (3) trastuzumab and pertuzumab; and (4) docetaxel and pertuzumab. Patients who received docetaxel plus both anti-HER2 antibodies had significantly higher pCR rates than did those who received either antibody plus docetaxel or the combination of both anti-HER2 agents without chemotherapy. Patients with estrogen receptor (ER)-negative tumors had much higher response rates than did patients with ER-positive tumors (a finding that was also reported in the NeoALTTO trial). Of note, about 16% of patients who received only pertuzumab plus trastuzumab attained pCRs, raising the possibility that biomarker studies might help identify future patients who can avoid chemotherapy.
Collectively, these results suggest that certain anti-HER2 agents, whether alone or in combination with other anti-HER2 agents, can enhance response rates; however, whether higher pCR rates necessarily translate into improved overall outcomes remains unknown. As additional data about these agents (as well as the novel antibody–drug conjugate, trastuzumab-DM1) become available, an optimal treatment strategy might come to light.
Pharmacogenomics has emerged as a potential means to explain why some patients benefit more than others from tamoxifen therapy. The CYP2D6 enzyme converts tamoxifen into its most active metabolite, endoxifen. Many CYP2D6 polymorphisms have been identified that metabolize tamoxifen extensively, moderately, poorly, or not at all. Previous data have indicated that poor metabolizers receive less benefit from tamoxifen than do extensive metabolizers, an observation that has led some to suggest that CYP2D6 testing should be considered before initiating tamoxifen. In two studies (Abstract S1-7 and Abstract S1-8), researchers evaluated large datasets from the ATAC and BIG 1-98 trials, respectively, to determine whether categorization of patients based on CYP2D6 polymorphisms could define groups more or less likely to benefit from tamoxifen. Results from both studies failed to show a difference in outcomes between extensive metabolizers and poor metabolizers. Thus, the recommendation of CYP2D6 genotype testing currently has little support.
In the FIRST trial (Abstract S1-3), researchers evaluated high-dose fulvestrant (500 mg) versus anastrozole as first-line treatment for ER-positive, metastatic breast cancer. Median time to progression was 23.4 months in the fulvestrant group versus 13.1 months in the anastrozole group, translating to a 35% reduction in risk for progression (P=0.01). Clinical benefit rate was 72.5% for patients who received fulvestrant versus 67% for patients who received anastrozole, corresponding to a 30% increase in odds of clinical benefit that did not reach statistical significance. These results lend further support to the recent FDA recommendation that fulvestrant be administered at a dose of 500 mg monthly rather than at the initially approved dose of 250 mg monthly.
Results of the AZURE study (Abstract S4-5) have been awaited since publication of the ABSCG 12 trial, in which investigators showed that adding zoledronic acid to adjuvant endocrine therapy substantially improved outcomes in premenopausal women with early-stage breast cancer (N Engl J Med 2009; 360:679). The AZURE study is based on a clinical trial involving 3360 patients with stage 2/3 disease who were randomized to standard adjuvant therapy (chemotherapy, endocrine therapy, or both), with or without zoledronic acid. Adverse effects were similar between groups except that 26 cases of osteonecrosis of the jaw occurred in patients who received zoledronic acid. Disease-free survival, overall survival, and recurrence type (local, regional, or distant) did not differ between groups. Subgroup analysis suggested that zoledronic acid conferred benefit in postmenopausal women who have low estrogen concentrations within bone, but the data are not sufficiently compelling to support routine use of zoledronic acid in adjuvant therapy.