Targeted Combinations for Hormone Receptor–Positive Advanced Breast Cancer: Who Benefits?

Abstract

Although endocrine therapy is an effective strategy for patients with hormone receptor–positive (HR-positive) locally advanced, metastatic breast cancer (MBC), not all patients respond to first-line treatment because of primary, de novo resistance; those who do respond subsequently progress with secondary, acquired resistance. Significant progress has been made in understanding the molecular signaling pathways that account for endocrine resistance, and in recent years, this has led to various targeted combination strategies aimed at reversing or preventing endocrine resistance. One of the key signaling pathways in HR-positive breast cancer is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and indeed, good evidence suggests that this pathway becomes activated during secondary endocrine resistance in HRpositive breast cancer. As such, the BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) study in endocrine-resistant MBC demonstrated a significant improvement in progression-free survival (PFS) for mTOR antagonist everolimus in combination with steroidal aromatase inactivator exemestane compared with exemestane alone in 724 postmenopausal women with HR-positive MBC after progression on a nonsteroidal aromatase inhibitor (median PFS, 7.8 versus 3.2 months; hazard ratio, 0.45; log-rank P , .001). This clinically relevant improvement in PFSwas sufficient for regulatory approval to be granted in 2012 for this targeted combination to become a new standard of care for the treatment of endocrine-resistant postmenopausal breast cancer. The key questions when considering targeted combination treatment for HR-positive MBC are who benefits most from this approach and what the best setting is in which to use this strategy. For example, would a combination of an mTOR inhibitor with endocrine therapy only be effective in the second-line setting for endocrine-resistant MBC, or could this option delay or prevent endocrine resistance from developing in the first-line endocrinesensitive setting? The HORIZON (Letrozole Plus Oral Temsirolimus as First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer) trial of the oral mTOR antagonist temsirolimus in combination with letrozole in the first-line setting showed no benefit compared with letrozole plus placebo in 1,112 patients with HR-positive MBC, 60% of whom were endocrine therapy naive. One explanation for this result, which contrasts with BOLERO-2, could be that the PI3K/Akt/mTOR cell survival pathway is not operative in all endocrine-sensitive estrogen receptor (ER) –positive breast cancer cells, only becoming switched on during the development of acquired secondary resistance. Therefore, at the present time, clinical data only support a role for mTOR therapy for endocrine-pretreated HR-positive MBC. Identifying biomarkers that might help to predict which patients will derive the greatest clinical benefit from costly and potentially more toxic targeted therapies in HR-positive MBC is an important research priority. The lesson from the success of trastuzumab in HER2-positive MBC was the reliable identification of the oncogenic driver in this disease subset, namely HER2 gene amplification. To date, a similar goal has proven elusive for targeted combination strategies in a more heterogenous population of patients with HR-positive MBC. In the article accompanying this editorial, Hortobagyi et al report the first HER2 correlative analysis of genomic alterations, as determined by next-generation sequencing, with clinical efficacy for the targeted combination of everolimus and exemestane from a subset of representative patients with HRpositive MBC treated within the randomized, placebo-controlled BOLERO-2 study. The authors tested a reasonable mechanistic hypothesis that tumors addicted to a hyperactive PI3K/mTOR pathway might derive greater benefit from everolimus. Although this retrospective analysis was conducted predominantly on archival primary, rather than real-time, metastatic tumors, the premise was that key activating mutations within the original primary tumor may have primed the disease for relapse on endocrine therapy and that these mutations represent a reasonable target for therapy in the endocrine-resistant second-line setting. The results showed, perhaps disappointingly, that mutations in PIK3CA or the PI3K/Akt/mTOR pathway as a whole were not associated with everolimus efficacy, although subgroup analysis did suggest a greater PFS benefit from everolimus in patients with exon 9 compared with exon 20 mutations, a finding first reported in a neoadjuvant study of everolimus with letrozole. This specific finding could relate to different activating mutations of PIK3CA regulating Akt-mediated tumor cell survival and differential responses to mTOR antagonism. Whether PIK3CA mutations, which represent the most common genomic alteration in HR-positive breast cancer, will be any more predictive for benefit from specific PI3K inhibitors remains to be determined. Several pan-isoform inhibitors that target the PI3K/Akt pathway upstream of mTOR, including buparlisib (BKM-120) and pictilisib (GDC-0941), are currently being tested in endocrine-resistant MBC in similarly designed studies to BOLERO-2, both with prospective stratification/selection for PIK3CA mutation status. Although preliminary results for pictilisib in the phase II FERGI (Fulvestrant in