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Frequency and spectrum of PIK3CA somatic mutations in breast cancer

Olga Martínez-Sáez1,2,3, Nuria Chic1,2,3, Tomás Pascual1,2,3

  • 1Department of Medical Oncology, Hospital Clinic of Barcelona, Villarroel 170, 08035, Barcelona, Spain.

Breast Cancer Research : BCR
|May 15, 2020
PubMed
Abstract

Insights

The therascreen assay misses about 20% of PIK3CA mutations in breast cancer (BC), including 95% of double mutations. This highlights the heterogeneity of PIK3CA mutations and the need for broader genomic testing for advanced BC.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • The therascreen PIK3CA mutation assay and alpelisib are FDA-approved for PIK3CA-mutated (PIK3CAmut) advanced breast cancer (BC).
  • Accurate detection of PIK3CA mutations is crucial for guiding alpelisib treatment decisions.

Purpose of the Study:

  • To evaluate the proportion and distribution of PIK3CA mutations in BC.
  • To assess the coverage of PIK3CA mutations by the therascreen assay.
  • To analyze PIK3CA mutation prevalence across BC subtypes and in circulating tumor DNA (ctDNA).

Main Methods:

  • Analysis of 6338 BC patient samples from 10 public studies.
  • In silico evaluation of therascreen panel's ability to detect PIK3CA mutations.
  • Assessment of PIK3CA mutation rates in hormone receptor-positive/HER2-negative (HR+/HER2-), HER2+, and triple-negative BC (TNBC).
  • Exploration of PIK3CA mutations in ctDNA using the Guardant B360 assay.

Main Results:

  • PIK3CA mutations were found in 35.7% of BC patients; five mutations (H1047R, E545K, E542K, N345K, H1047L) accounted for 73% of all mutations.
  • The therascreen panel captures 72% of all PIK3CA mutations and 80% of PIK3CAmut patients, but misses approximately 20% of known PIK3CA mutations and 95% of double PIK3CAmut tumors.
  • PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2- (42%) and HER2+ (31%) BC.
  • 28% of PIK3CA mutations detected in ctDNA were not on the therascreen panel.

Conclusions:

  • PIK3CA mutations in BC exhibit significant heterogeneity, with a substantial proportion not covered by the therascreen assay.
  • The therascreen panel may not fully capture the mutational landscape of PIK3CA in all BC patients, particularly those with double mutations.
  • Further investigation is needed into the clinical utility of PIK3CA mutations identified by broader sequencing assays beyond the therascreen companion diagnostic.
Keywords:
AlpelisibBreast cancerCompanion diagnosticHotspot mutationsMutationsPIK3CATherascreenctDNA

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