Everolimus plus exemestane for hormone receptor-positive advanced breast cancer: A PAM50 intrinsic subtype analysis of BOLERO-2 Journal Article


Authors: Prat, A.; Brase, J. C.; Cheng, Y.; Nuciforo, P.; Paré, L.; Pascual, T.; Martínez, D.; Galván, P.; Vidal, M.; Adamo, B.; Hortobagyi, G. N.; Baselga, J.; Ciruelos, E.
Article Title: Everolimus plus exemestane for hormone receptor-positive advanced breast cancer: A PAM50 intrinsic subtype analysis of BOLERO-2
Abstract: Background: The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]-enriched and basal-like) subtypes within advanced hormone receptor-positive (HR+) breast cancer is currently unknown. Materials and Methods: This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO-2 study; BOLERO-2 randomized 724 patients with advanced HR+/HER2-negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression-free survival (PFS) were evaluated. Results: Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2-enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal-like (n = 37), and 1.9% basal-like (n = 5); HER2-enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p =.038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47–0.94; p =.020) and HER2-enriched and non-HER2-enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07–2.19; p =.019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2-enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26–0.90; p =.034); however, the association between HER2-enriched tumors and everolimus benefit was nonsignificant (p =.433). Conclusion: The HER2-enriched subtype was identified in a substantial proportion of advanced HR+/HER2-negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2-enriched tumors in the advanced HR+/HER2-negative breast cancer setting. Implications for Practice: Using 261 tumor samples from the BOLERO-2 phase III clinical trial, this study shows that a substantial proportion (20%–30%) of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2-negative breast cancer. © AlphaMed Press 2019
Keywords: exemestane; mammalian target of rapamycin; everolimus; advanced breast cancer; intrinsic subtype
Journal Title: The Oncologist
Volume: 24
Issue: 7
ISSN: 1083-7159
Publisher: Oxford University Press  
Date Published: 2019-07-01
Start Page: 893
End Page: 900
Language: English
DOI: 10.1634/theoncologist.2018-0407
PROVIDER: scopus
PMCID: PMC6656445
PUBMED: 30679318
DOI/URL:
Notes: Source: Scopus
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  1. Jose T Baselga
    484 Baselga