A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2– Metastatic Breast Cancer

Abstract

PIK3CA mutation frequency varies among breast cancer (BC) subtypes. Recent evidence suggests combination therapy with the PI3K inhibitor (PI3Ki) alpelisib and endocrine therapy (ET) improves response rates and progression-free survival (PFS) in PIK3CA-mutant, hormone receptor positive (HR+) BC versus ET alone; thus, better understanding the clinical and epidemiologic elements of these mutations is warranted. This systematic review characterizes the PIK3CA mutation epidemiology, type of testing approaches (e.g., liquid or tissue tumor biopsy), and stability/concordance (e.g., consistency in results by liquid versus solid tumor sample, by the same method over time) in patients with HR+/HER2– advanced (locally unresectable) or metastatic disease (HR+/HER2– mBC) and explores performance (e.g., pairwise concordance, sensitivity, specificity, or predictive value) of respective mutation findings. A comprehensive search of PubMed/MEDLINE, EMBASE, Cochrane Central, and select conference abstracts (i.e., AACR, ASCO, SABCS, ECCO, and ESMO conferences between 2014 and 2017) identified 39 studies of patients with HR+, HER2– mBC. The median prevalence of PIK3CA mutation was 36% (range: 13.3% to 61.5%); identified testing approaches more commonly used tissue over liquid biopsies and primarily utilized next-generation sequencing (NGS), polymerase chain reaction (PCR), or Sanger sequencing. There was concordance and stability between tissues (range: 70.4% to 94%) based on limited data. Given the clinical benefit of the PI3Ki alpelisib in patients with PIK3CA mutant HR+/HER2– mBC, determination of tumor PIK3CA mutation status is of importance in managing patients with HR+/HER2– mBC. Prevalence of this mutation and utility of test methodologies likely warrants PIK3CA mutation testing in all patients with this breast cancer subtype via definitive assessment of PIK3CA mutational status.

PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects

“…Therefore, PIK3CA is a target for cancer therapy [ 134 ]. Anderson EJ et al, reported 36% PIK3CA mutation in HR+/HER2- metastatic breast cancer [ 148 ].…”

PIK3CA Mutations as a Molecular Target for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer

“…Several other compounds with selective activity against different PI3K isoforms (α, β, γ, and δ) or acting as pan-PI3K inhibitors (on all class I isoforms) have also been investigated. However, their clinical value in terms of effectiveness and toxicity profile remains controversial (39). Of note are the mutations in the PI3K regulatory subunit 1 (PIK3R1), which inhibits the α subunit, that can be observed in ∼3% of patients with breast cancer (39,40).…”

“…Martínez-Sáez et al confirmed the clustering, reporting that the most common PIK3CA alterations (69% of the total identified) affect exon 20 (p.H1047R in 35% and p.H1047L in 4% of patients) and exon 9 (p.E545K in 17% and p.E542K in 11% of patients) ( 42 ). All these alterations respond to alpelisib ( 20 , 38 , 39 , 42 ). The fifth most frequently identified alteration was in exon 4 (p.N345K).…”

“…Liquid biopsy using blood components to assess PIK3CA mutations in circulating tumor DNA (ctDNA) of patients with breast cancer has been reported by different studies ( 39 ). Multiple technologies have been employed to assess breast cancer ctDNA with high sensitivity and specificity, leading to assays that have been useful in clinical trials and are entering clinical practice ( 63 ).…”

The frequency and spectrum of PIK3CA mutations in patients with estrogen receptor-positive HER2-negative advanced breast cancer residing in various regions of Russia

“…Ген PIK3CA кодирует каталитическую субъединицу p110-a киназы PI3K. Нарушения онкогенного сигнального каскада PI3K/Akt/mTOR встречаются практически при всех злокачественных новообразованиях человека, а соматические мутации PIK3CA выявляются примерно в 1/3 опухолей молочной железы [7][8][9]. Повреждения PIK3CA приводят к разнообразным функциональным последствиям, например, влияют на пролиферацию и выживаемость клеток, метаболические особенности, иммуногенность, предпочтительные зоны метастазирования и даже специфические паттерны роста опухоли, которые можно определить радиологически [10][11][12][13][14].…”