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The prognostic and predictive value of intrinsic subtype across the MONALEESA-2, -3, and -7 studies

A pooled analysis of the MONALEESA-2, -3 and -7 studies in patients with HR+/HER2 advanced breast cancer confirms the prognostic and predictive value of the intrinsic PAM50-based subtype for overall survival. In these trials, the addition of ribociclib to endocrine therapy resulted in a consistent overall survival benefit across the luminal A, luminal B and HER2-enriched subtypes, but not for the basal-like subtype.

Ribociclib added to endocrine therapy (ET) demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) in the three phase III clinical trials MONALEESA-2, -3 and -7, in patients with HR+/HER2- advanced breast cancer. A prior pooled analysis of patients in these trials demonstrated a significant PFS benefit with ribociclib + ET compared to placebo + ET in the luminal A, luminal B and HER2- enriched subtypes. A novel retrospective exploratory analysis presented by Prof. Carey at SABCS 2021, now evaluated the association of intrinsic subtype with OS using tumour samples pooled from the MONALEESA-2,-3 and -7 trials.

Study design

Tumour samples (both primary and metastatic) underwent gene expression profiling using a customised NanoString nCounter GX 800-gene panel, including 36 out of 50 PAM50 genes. Intrinsic subtyping was performed using a 152-gene set that was selected based on the ability to accurately identify the PAM50 subtype in 48 independent tumours and the original PAM50 microarray training data set. The relationships between PAM50-based subtypes with OS were evaluated using univariable and multivariable Cox proportional hazard models. Multivariable models were adjusted for known clinical prognostic factors, including age, prior chemotherapy, prior ET, ECOG performance status, visceral disease (presence of liver/lung metastases), bone-only metastases, histological grade, number of metastatic sites, tumour type and de novo metastatic disease.


From the pooled patient population (N=2,066), 997 tumour samples (71% primary) from the ribociclib + ET (N=585) and placebo + ET (N=412) arms of the MONALEESA (ML) trials (ML-2, N=318; ML-3, N=414; ML-7, N=265) were profiled. Most samples (54.4%) were of luminal A subtype while luminal B, HER2-enriched and basal-like subtypes accounted for respectively 27.9%, 14.7% and 3.0% of samples. A similar OS benefit with ribociclib + ET compared to placebo + ET was observed in the ITT (HR [95%CI]: 0.76 [0.67-0.86]) and biomarker (HR [95%CI]: 0.75 [0.63-0.89]) populations.

In both univariable and multivariable analyses, intrinsic subtype was prognostic for OS in both the ribociclib and placebo arm (p<0.0001 for both). Patients with luminal A subtype had the best OS outcome in both arms, whereas patients with basal-like subtype had the worst OS prospect. In the univariable analysis, an OS benefit with ribociclib + ET was observed in patients with luminal A (HR: 0.75; p=0.021), luminal B (HR: 0.69; p=0.023) and HER2-enriched subtypes (HR: 0.60; p=0.018).  In contrast, patients with the basal-like subtype (N=30) did not obtain an OS benefit from ribociclib + ET (HR: 1.89; p=0.148). These results should however be interpreted with care given the small sample size (3% in each arm) and the exploratory nature of this analysis. The interaction test result between subtype and treatment arm was statistically significant (p=0.016). Also when adjusting for clinical covariates, the interaction test result remained statistically significant (p=0.0065). However, with the basal-like subtype removed, the interaction test result was no longer statistically significant in univariate (p= 0.47) nor in the multivariable models (p= 0.32).


In this pooled analysis of the MONALEESA-2, -3 and -7, a consistent OS benefit was observed with ribociclib plus endocrine therapy in the luminal A, luminal B and HER2-enriched breast cancer subtypes. There was no clear benefit in patients with a basal-like subtype, however the sample size of this subgroup was small. The prognostic value of the PAM50-based intrinsic subtype for OS in patients treated with ribociclib + ET and those treated with ET alone was confirmed. Finally, these results are consistent with those of the prior PFS analysis using the pooled MONALEESA data set.


Carey L, et al. Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer. Presented at SABCS 2021; abstract GS2-00.

Speaker Lisa Carey

Lisa Carey

Lisa Carey, MD, PhD, University of North Carolina, North Carolina, USA


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