Adjuvant Treatment Options
The luminal A and B subtypes are both characterized by HR expression, and 5 years of adjuvant anti-estrogen therapy became the standard of care based upon results from multiple trials. The addition of aromatase inhibitors in the adjuvant setting for postmenopausal women has improved disease-free survival compared with tamoxifen(Drug information on tamoxifen) alone. Aromatase inhibitors can be used as upfront continuous treatment for 5 years,[35,36] as sequential therapy after 2 to 3 years of tamoxifen,[37,38] or as extended adjuvant therapy after 5 years of tamoxifen.
Patients with HR-positive breast cancer continue to have relapse rates of 1% to 4% per year between 5 and 15 years from diagnosis, and the optimal duration of adjuvant hormonal therapy remains an important clinical question.[40,41] Long-term results of the
ATLAS trial (Adjuvant Tamoxifen: Longer Against Shorter) were recently presented, indicating that 10 years of adjuvant tamoxifen resulted in a further reduction in recurrence and mortality compared with 5 years of adjuvant tamoxifen, with continued benefit seen beyond 10 years of therapy. These results are most relevant for premenopausal patients, for whom extended adjuvant therapy with an aromatase inhibitor is not an alternative option. Molecular profiling will likely be important in determining which patients are at highest risk of late recurrence, and potentially derive benefit from extended adjuvant hormonal therapy. Patients with luminal B tumors, whose risk of recurrence is greatest in the first 5 years, may not benefit from hormonal therapy beyond 5 years.
Despite the marked success of endocrine agents in the treatment of early-stage, HR-positive breast cancers, many patients will relapse. These tumors have either intrinsic or acquired resistance to anti-estrogen therapy. The mechanisms underlying intrinsic and acquired resistance to endocrine agents are likely similar, and include activation of upstream and downstream pathways resulting in changes in co-regulators of the estrogen receptor.
The 21-gene RS can be used to determine the benefit of tamoxifen in node-negative, ER-positive breast cancers. Breast cancers with recurrence scores greater than 31 appear to derive little benefit from adjuvant tamoxifen compared with cancers that have recurrence scores of 30 or less. Concordance between luminal B and high-recurrence-score cancers has also been shown, suggesting that the poor prognosis seen in these cancers may be due in part to intrinsic resistance to endocrine therapy.
A better understanding of the differential expression of genes and proteins in luminal A and B cancers could shed significant light on the mechanisms underlying resistance to endocrine agents, which could in turn lead to novel therapeutic approaches to circumvent this resistance. There is increasing evidence to suggest that breast cancers that express both HRs and HER2 are somewhat intrinsically resistant to endocrine agents, and that these cancers are, in fact, driven by the HER2 pathway.[43,44] Support for this hypothesis comes from data on patients with metastatic HR-positive, HER2-positive breast cancers, in whom progression-free survival following treatment with single-agent anastrozole(Drug information on anastrozole) is extremely short at just over 2 months. However, there is some evidence to suggest the existence of a subset of HER2-positive cancers that express ER and PR, which may be driven more by ER than HER2. In fact, a subset of HER2-positive breast cancers that are ER-positive have been shown to have a good-prognosis signature based on assessment with the 70-gene signature.
Other growth factor pathways, including the epidermal growth factor receptor (EGFR), insulin growth factor receptor, and vascular endothelial growth factor (VEGF) receptor, have been demonstrated to play a role in resistance to endocrine agents.[44,47-49] Other agents such as the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor) may also play a role, based upon results showing improved response to everolimus in combination with endocrine therapy in the metastatic and neoadjuvant setting.[50-52] Going forward, it is essential that we identify novel therapies for patients with luminal B cancers, given their poor survival when treated using conventional therapies. The use of gene expression profiling can help to identify key genes that can then be exploited therapeutically.
When patients were stratified by breast tumor subtype and analyzed for time to distant metastasis and overall survival, those with the basal subtype had the worst clinical outcome. This likely reflects both the aggressive nature of basal-subtype breast tumors and the lack of targeted therapies, since these tumors do not express the ER and do not overexpress HER2. Conventional anthracycline- and taxane-based regimens are currently used to treat patients with the basal-like subtype of breast cancer.
Although women who carry BRCA1 mutations are predisposed to developing breast cancers of the basal-like subtype, expression levels of BRCA1 have not been well characterized in sporadic triple-negative tumors.[3,53] BRCA1 mediates the cellular response to DNA damage by sensing damage, preventing apoptosis, and participating in DNA repair.[54,55] The loss of BRCA1 expression in basal-like tumors may lead to selective sensitivity to DNA cross-linking chemotherapeutic agents, such as platinum analogues. Cisplatin(Drug information on cisplatin), a platinum analogue, has demonstrated single-agent activity as neoadjuvant treatment for triple-negative breast cancers. There are multiple ongoing clinical trials investigating the addition of cisplatin or carboplatin(Drug information on carboplatin) to neoadjuvant chemotherapy; however, most of these have enrolled patients with triple-negative breast cancer, not just the basal subtype. Genomic profiling could potentially aid in identifying tumors among BRCA-negative patients with a “BRCA-like” profile for whom platinums or other agents targeting DNA repair, such as poly(ADP-ribose) polymerase (PARP) inhibitors, may be more effective.
Other potential targets for basal-like breast cancer have been identified using genomic profiling. The EGFR is part of the basal cluster, and EGFR-targeting agents have been investigated in the metastatic setting, demonstrating modest clinical activity. In a study combining carboplatin and cetuximab(Drug information on cetuximab) (Erbitux), a monoclonal antibody against EGFR, clinical benefit was seen among patients with EGFR pathway inactivation. Anti-angiogenic agents targeting VEGF have also shown promise in the metastatic setting, and studies in the adjuvant setting are ongoing. Bevacizumab(Drug information on bevacizumab) (Avastin), a monoclonal antibody against VEGF, showed improved disease-free survival in the first-line[57,58] and second-line setting, but it did not show an overall survival advantage. Benefit from the addition of bevacizumab was similar among patients with HR-positive vs HR-negative breast cancer, suggesting that intrinsic subtyping might not predict anti-angiogenic benefit.
Additional gene expression analysis of triple-negative breast cancers from multiple data sets has further defined this group of cancers. Cluster analysis identified a second “basal-like” subtype in addition to immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen receptor subtype. Triple-negative breast cancer cell lines corresponding to these subtypes responded differently to therapies such as cisplatin, mTOR inhibitors, Src inhibitors, and an androgen receptor antagonist. This would suggest that gene expression profiling of triple-negative breast cancers should play an important role in future trial design of novel, targeted therapies.
The HER2-enriched subtype is characterized by high expression of HER2, most commonly due to amplification of the HER2 gene. Genes such as GRB7 and TOP2A, which are located in close proximity to the HER2 gene on chromosome 17, are often co-amplified. Multiple studies have been performed to correlate TOP2A gene status, topo2a expression levels, and response to anthracyclines.[62-67] The role of TOP2A amplification was examined in the Breast Cancer International Research Group (BCIRG) 006 trial in which early-stage, HER2-positive patients were randomized between three arms: standard anthracycline- and taxane-based chemotherapy with or without trastuzumab(Drug information on trastuzumab), and a third non–anthracycline-containing regimen of docetaxel(Drug information on docetaxel), carboplatin, and trastuzumab. Patients without co-amplification derived greater benefit from the addition of trastuzumab. In patients with co-amplification of TOP2A and HER2, minimal incremental benefit was seen with the addition of trastuzumab; however, the long-term toxicity profile favored the non–anthracycline-containing regimen.
For ER-positive, early-stage breast cancer, genomic profiling using the 21-gene RS and the 70-gene signature has already impacted clinical decision-making. These tests have aided treating oncologists by differentiating patients with low- vs high-risk ER-positive tumors for whom chemotherapy is indicated. Ongoing clinical trials such as MINDACT and TAILORx have focused primarily on how to best apply these tests in the adjuvant setting, using our current standard treatments. Additional insight into the biology of ER-positive breast cancers, particularly the higher risk luminal B cancers, may also be gained from genomic profiling, and potentially could aid in identifying potential targets and new, effective therapies.
Genomic profiling of triple-negative breast cancers has revealed that this is a heterogeneous group of cancers. Although the majority of triple-negative breast cancers are the “basal-like” subtype, significant proportions are in other subtypes. Incorporation of genomic profiling into future clinical trials will have implications for drug development, where the ability to identify aberrant gene expression will help to inform one’s choice of targeted therapies. Ultimately it is hoped that the ability to better define an individual patient’s breast cancer biology will lead to improvements in therapy selection, discovery of new drug targets, and better long-term outcomes for patients.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.