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

J Clin Oncol. 2021 May 1;39(13):1458-1467. doi: 10.1200/JCO.20.02977. Epub 2021 Mar 26.


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: NCT01958021 NCT02422615 NCT02278120.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / metabolism*
  • Bone Neoplasms / drug therapy
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism*
  • Retrospective Studies
  • Survival Rate


  • Biomarkers, Tumor
  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • Receptor, ErbB-2

Associated data