Correlative Biomarker Analysis of Intrinsic Subtypes and Efficacy Across the MONALEESA Phase III Studies

Abstract

Purpose: The prognostic and predictive value of intrinsic subtypes in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with endocrine therapy and ribociclib (RIB) is currently unknown. We evaluated the association of intrinsic subtypes with progression-free survival (PFS) in the MONALEESA trials.

Methods: A retrospective and exploratory PAM50-based analysis of tumor samples from the phase III MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials was undertaken. The prognostic relationship of PAM50-based subtypes with PFS and risk of disease progression by subtype and treatment were evaluated using a multivariable Cox proportional hazards model, adjusting for age, prior chemotherapy, performance status, visceral disease, bone-only metastases, histological grade, number of metastatic sites, prior endocrine therapy, and de novo metastatic disease.

Results: Overall, 1,160 tumors from the RIB (n = 672) and placebo (n = 488) cohorts were robustly profiled. Subtype distribution was luminal A (LumA), 46.7%; luminal B (LumB), 24.0%; normal-like, 14.0%; HER2-enriched (HER2E), 12.7%; and basal-like, 2.6% and was generally consistent across treatment arms and trials. The associations between subtypes and PFS were statistically significant in both arms (P < .001). The risks of disease progression for LumB, HER2E, and basal-like subtypes were 1.44, 2.31, and 3.96 times higher compared with those for LumA, respectively. All subtypes except basal-like demonstrated significant PFS benefit with RIB. HER2E (hazard ratio [HR], 0.39; P < .0001), LumB (HR, 0.52; P < .0001), LumA (HR, 0.63; P = .0007), and normal-like (HR, 0.47; P = .0005) subtypes derived benefit from RIB. Patients with basal-like subtype (n = 30) did not derive benefit from RIB (HR, 1.15; P = .77).

Conclusion: In this retrospective exploratory analysis of hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer, each intrinsic subtype exhibited a consistent PFS benefit with RIB, except for basal-like.

Trial registration: ClinicalTrials.gov NCT01958021 NCT02422615 NCT02278120.

FIG 1.

Intrinsic subtype distribution across the ML trials based on PAM50 analysis. (A) All patients pooled from the ML-2, ML-3, and ML-7 trials. (B) Patients with PAM50 performed in primary tumor samples. (C) Patients with PAM50 performed in metastatic tumor samples. HER2E, human epidermal growth factor receptor 2–enriched; ML, MONALEESA.

FIG 2.

PFS based on intrinsic subtype in the combined MONALEESA data set: (A) in the RIB arm and (B) in the PBO arm. Basal, basal-like; HER2, human epidermal growth factor receptor 2; HER2E, HER2-enriched; LumA, luminal A; LumB, luminal B; NA, not achieved; Normal, normal-like; PBO, placebo; PFS, progression-free survival; RIB, ribociclib.

FIG 3.

PFS based on treatment within each intrinsic subtype in the combined MONALEESA data set. (A) Within luminal A, (B) within luminal B, (C) within HER2E, (D) within basal-like, and (E) within normal-like. HER2E, human epidermal growth factor receptor 2–enriched; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; RIB, ribociclib.

FIG 4.

Gene expression differences across the intrinsic subtypes of breast cancer. (A) Unsupervised clustering using 152 genes across the prototypical PAM50 subtypes and the subtypes identified in the ML program. Sample and gene expression data from tumor samples of the same subtype have been combined into a single category. For each gene in a class, we calculated the standardized mean difference between the gene's expression in that class and its overall mean expression in the data set using a five-class Significance Analysis of Microarrays on the ML data set. Red represents relatively high gene expression, green represents relatively low gene expression, and black represents median gene expression. (B) Expression of selected breast cancer–related genes, obtained from the 152-gene list, across the prototypical PAM50 subtypes and the subtypes identified in the ML program. AR, androgen receptor; CCNE1, cyclin E1; CDKN2A, p16/cyclin-dependent kinase inhibitor 2A; EGFR, epidermal growth factor receptor; ESR1, estrogen receptor 1; FOXA1, forkhead box A1; HER2, human epidermal growth factor receptor 2; HER2E, HER2-enriched; LumA, luminal A; LumB, luminal B; ML, MONALEESA; PGR, progesterone receptor.