Related Experiment Video
Updated: Apr 14, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Genomic determinants of response to alpelisib plus fulvestrant in the SOLAR-1 trial
Background:
Approximately 40% of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of PIK3CA-mutated, HR-positive, HER2-negative ABC, based on the results of the SOLAR-1 trial (NCT02437318). Aside from PIK3CA, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population.
Patients And Methods:
In this retrospective analysis, we carried out tissue-based next-generation sequencing of 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was carried out in the PIK3CA-altered cohort.
Results:
PIK3CA-altered and PIK3CA-wild type tumors had distinct genomic profiles. In the PIK3CA-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (P = 0.0004). Patients in the lowest tumor mutational burden quartile as well as those with FGFR1 or FGFR2 alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant [18.5 versus 3.22 months: hazard ratio (HR) 0.38, 95% confidence interval (CI) 0.21-0.68; FGFR1 12.71 versus 3.75 months: HR 0.38, 95% CI 0.17-0.81, P = 0.32; FGFR2 9.63 versus 2.78 months: HR 0.31, 95% CI 0.1-0.94, P = 0.29]; patients with MYC or RAD21 alterations derived limited PFS benefit. Cox and multitask machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and PTEN or TP53 alterations among the most deleterious factors for PFS in the PIK3CA-altered cohort.
Conclusions:
Alpelisib plus fulvestrant provides clinical benefit for patients with PIK3CA-altered, HR-positive, HER2-negative ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models can identify factors including gene mutations that influenced PFS.
Insights
Alpelisib plus fulvestrant benefits patients with PIK3CA-altered advanced breast cancer (ABC). Genomic profiling revealed distinct tumor profiles and identified factors influencing progression-free survival (PFS).
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Approximately 40% of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients harbor PIK3CA alterations, contributing to endocrine therapy resistance.
- Alpelisib combined with fulvestrant is an approved treatment for PIK3CA-mutated, HR+, HER2- ABC, demonstrating efficacy in the SOLAR-1 trial.
- Beyond PIK3CA, other genetic alterations in this patient population are linked to poorer prognosis and reduced treatment response.
Purpose of the Study:
- To investigate the genomic profiles of PIK3CA-altered versus PIK3CA-wild type tumors in advanced breast cancer.
- To analyze progression-free survival (PFS) benefits of alpelisib plus fulvestrant in the PIK3CA-altered cohort.
- To identify genomic and clinical factors influencing PFS in patients treated with alpelisib plus fulvestrant.
Main Methods:
- Retrospective analysis of tissue-based next-generation sequencing data from 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from the SOLAR-1 trial.
- Correlative analysis of progression-free survival (PFS) in the PIK3CA-altered cohort.
- Application of Cox and multi-task machine learning models to identify factors impacting PFS.
Main Results:
- PIK3CA-altered and PIK3CA-wild type tumors exhibited distinct genomic landscapes.
- Patients with PIK3CA-altered tumors receiving alpelisib plus fulvestrant achieved a median PFS of 11.01 months compared to 5.55 months with placebo plus fulvestrant (P=0.0004).
- Greater PFS benefit was observed in patients with low tumor mutational burden or FGFR1/FGFR2 alterations; however, MYC or RAD21 alterations showed limited benefit. Lower ECOG performance status, prior CDK4/6 inhibitor treatment, and PTEN/TP53 alterations were associated with poorer PFS.
Conclusions:
- Alpelisib plus fulvestrant demonstrates clinical benefit in PIK3CA-altered HR+, HER2- ABC patients, irrespective of certain concomitant alterations.
- The combination therapy remains effective even in the presence of genetic alterations previously linked to resistance to endocrine therapy or CDK4/6 inhibitors.
- Machine learning models successfully identified key genomic and clinical factors that significantly influenced PFS in this patient cohort.
More Related Videos
10:27Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
07:48Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
Related Concept Videos
01:29Pharmacogenomics: Identification of New Drug Targets
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:56Treatment Resistent Cancers
02:56Treatment Resistant Cancers
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...