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Breast Cancer Study Shows Number of Mutated PIK3CA Alleles Affects Tumor Aggressiveness

NEW YORK – Research by a team at University College London and elsewhere suggests that tumor features differ in breast cancers with one mutated copy of PIK3CA compared to those with two or more altered copies of the gene, which encodes PI3 kinase.

In particular, the researchers found that activating mutations affecting both copies of the gene coincide with more aggressive breast tumors with enhanced PI3K-alpha signaling activity and stem cell-related features, while heterozygous mutations affecting just one copy of the gene generally have more muted kinase activity, even compared to tumors with wild-type versions of the gene.

"Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a 'biphasic' relationship of mutant PIK3CA allele dosage with these scores," UCL researcher Ralitsa Madsen, the study's first and corresponding author, and her colleagues wrote in PLOS Genetics on Thursday, noting that "using information about a PIK3CA mutation alone to define patient groups for trials may miss important effects of mutation number."

In 2019, the US Food and Drug Administration approved a PI3K-alpha-specific inhibitor alpelisib (Novartis' Piqray) for treating certain advanced, hormone receptor-positive, PIK3CA-mutated breast cancers in combination with an estrogen receptor antagonist, following findings of the SOLAR-1 clinical trial.

That, in turn, prompted the investigators to look at the transcriptional consequences of PIK3CA mutations and the relationship between these mutations, the PI3K/AKT/mTOR pathway, and tumor "stemness" or having a stem cell-like state, which affects aggressiveness and treatment response.

The authors noted, for example, that "a substantial proportion of patients with PIK3CA-mutant tumors failed to improve on the combination therapy in the randomized [Phase 3] trial, highlighting the need for further refinement of current patient stratification strategies."

The team used machine learning and other computational methods to assess PI3K activity and stemness features in almost 3,000 breast cancer tumors — including 1,980 tumors profiled with array-based gene expression analyses for the "Molecular taxonomy of breast cancer international consortium" (METABRIC) study and 928 breast invasive carcinoma tumors tested by RNA sequencing for the Cancer Genome Atlas project.

The researchers saw higher-than-usual stemness scores or PI3K activity levels in aggressive breast cancer cases — features that coincided with other pro-proliferation tumor features and relatively poor breast cancer outcomes in these patient cohorts.

Likewise, tumors marked by cells with PIK3CA mutations affecting two or more copies of the gene appeared to have enhanced PI3K pathway activity and stem cell-like features, they reported.

Those features were not found, however, in tumors with alterations affecting just one copy of the PIK3CA gene. Instead, heterozygous PIK3CA mutations corresponded to diminished stemness scores and dialed-down PI3K activity.

Those patterns were backed up by the team's subsequent cell model and RNA-seq analyses on a breast epithelial cell line containing a hotspot mutation in PIK3CA. Again, the group saw stem cell features in cells where both copies of PIK3CA were affected by the mutation, but not in cells with just one mutated allele.

Since enhanced PI3K activity and stemness have been implicated in more aggressive breast cancer tumors with poorer outcomes, the authors explained, such results suggested that it may be beneficial to distinguish between heterozygous and homozygous mutations in PIK3CA and their effects when planning clinical trials focused on treatments targeting the PI3K pathway.

"[I]t will be of interest to evaluate the predictive power of a combined assessment of PIK3CA genotype and phenotypic PI3K/stemness scores in patient stratification for clinical trials with PI3K pathway inhibitors," they wrote, "and, given the well-established implication of PI3K signaling in therapeutic response and resistance, with other cancer therapies."