Click below for educational background on intrinsic subtypes
Intrinsic subtypes and patient outcomes
Intrinsic subtypes in HR+/HER2- aBC are associated with different outcomes for patients
While it is known that breast cancer is a heterogeneous disease, advancements in gene-expression profiling have uncovered that even within the classically defined HR+/HER2– subgroup, heterogeneity continues to exist. This diversity is driven by intrinsic subtypes, and may lead to different prognoses and response to treatment in patients with HR+/HER2– aBC.1,2
Intrinsic subtypes provide clinically relevant information beyond current pathology-based classifications to help clinicians better understand prognoses and guide treatment selection.1,2
How does tumor biology impact outcomes for patients?
These 4 main subtypes vary in their prevalence and impact on patients’ survival and response to treatment in HR+/HER2– aBC.
Intrinsic subtypes and overall survival
Intrinsic subtype is prognostic for overall survival
Pooled exploratory analysis of tumor samples from patients in the placebo arms of the MONALEESA trials11
OVERALL SURVIVAL | PLACEBO + ET11
- Median OS differed by subtype, with luminal cancers seeing better outcomes and HER2E cancers seeing worse outcomes11
Pooled MONALEESA exploratory analysis study design
Intrinsic subtypes across the MONALEESA clinical trial program
Analysis background:
The MONALEESA clinical trial program in HR+/HER2− aBC includes 3 phase III trials studying KISQALI in combination with various ET partners and in different lines of therapy and patient populations, including:
- KISQALI + AI in 1L postmenopausal patients (MONALEESA-2)12
- KISQALI + ET in 1L premenopausal patients (MONALEESA-7)13
- KISQALI + fulvestrant in 1L/2L postmenopausal patients (MONALEESA-3)14
A pooled exploratory analysis of these 3 trials (N=2066) was conducted to analyze the correlation between intrinsic subtype and OS.11
- 997 tumor samples (71% primary) from patients enrolled in the MONALEESA-2 (n=318), MONALEESA-3 (n=414), and MONALEESA-7 (n=265) trials underwent subtyping11
- Subtype distribution was consistent across treatment arms (KISQALI arm, n=585; placebo arm, n=412)4,11
SUBTYPE DISTRIBUTION IN THE POOLED MONALEESA DATASET11
The OS benefit achieved with KISQALI + ET included patients with HER2E-classified tumor subtypes11
- The greatest relative reduction in risk of death was observed in the HER2E subtype, which is commonly associated with endocrine resistance and a very poor prognosis compared with luminal disease4
- Intrinsic subtype was prognostic for and predictive of OS outcomes in both the KISQALI and placebo arms4
OVERALL SURVIVAL BY INTRINSIC SUBTYPE | KISQALI + ET4
Data from the univariable analysis.
- The only subtype in which an OS benefit was not observed was the basal-like subtype
- The investigators warned the results should be interpreted with caution due to small sample size (3% in each arm)11
- From a clinical and biological perspective, the basal-like subtype is more similar to triple-negative breast cancer than to HR+/HER2– breast cancer, including its association with poor outcomes5
The most common intrinsic subtypes in HR+/HER2– aBC are luminal A, luminal B, and HER2E.1
Aleix Prat, MD, PhD
Barcelona, Spain
Dr Aleix Prat discusses results from the latest OS data from the whole MONALEESA program, analyzed by intrinsic subtypes as presented at SABCS 2021, and how these results may differentiate ribociclib from other CDK4/inhibitors.
Wolfgang Janni, MD, PhD
Ulm, Germany
Dr Wolfgang Janni speaks about how the latest OS data by intrinsic subtypes from KISQALI® (ribociclib) provides molecular rationale for KISQALI’s consistent OS across three phase 3 trials.
Click below for information on the ongoing HARMONIA trial
HARMONIA trial in patients classified as HER2E
The HARMONIA trial will test whether KISQALI can uniquely change tumor biology from HER2E to luminal subtypes in HR+/HER2- aBC15,16
- HARMONIA will evaluate whether KISQALI may improve the course of disease for patients with HR+/HER2– aBC by positively altering tumor biology, inducing a switch from HER2E to luminal subtypes, enabling a better response to ET15,16
- The HARMONIA trial is an international, randomized, phase III, multicenter, open-label, head-to-head study of KISQALI vs palbociclib, both in combination with ET, and in patients with the HER2E intrinsic subtype15
- The HER2E subtype is commonly associated with endocrine resistance and a very poor prognosis compared with luminal disease4
- The HARMONIA trial is the first trial to directly compare 2 CDK4/6 inhibitors in patients with HR+/HER2– aBC15
- HARMONIA is the first prospective phase III trial to enroll patients selected by RNA-based molecular subtyping of their tumors15
- HARMONIA is expected to be complete January 1, 2026
- The HARMONIA trial is an international, randomized, phase III, multicenter, open-label, head-to-head study of KISQALI vs palbociclib, both in combination with ET, and in patients with the HER2E intrinsic subtype15