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

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