PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial

Abstract

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET.MethodsParticipants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models.ResultsAmong the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309).ConclusionsAlthough there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC.Trial registrationClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009.Electronic supplementary materialThe online version of this article (10.1186/s13058-019-1115-2) contains supplementary material, which is available to authorized users.

PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2+ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype

“…In our cohort, patients with PIK3CA mutation were more frequently postmenopausal and showed more frequently HR-positive disease. However, the association with hormone receptor-status is not consistent across studies (3,8,9). According to intrinsic subtype, in our study, Luminal A tumors showed the highest frequency of PIK3CA mutation, although the distribution of PIK3CA mutation across intrinsic subtypes was not statistically significant.…”

“…We did not find any prognostic impact of PIK3CA gene mutation in the overall study cohort. This result is concordant with data from other adjuvant trials showing no association between PIK3CA mutation and long-term outcome (7)(8)(9). Moreover, in the NSABP B-31 and FinHER studies, PIK3CA mutation was not predictive of reduced benefit from adjuvant trastuzumab (7,8).…”

“…Moreover, in the NSABP B-31 and FinHER studies, PIK3CA mutation was not predictive of reduced benefit from adjuvant trastuzumab (7,8). More recently, PIK3CA mutation did not result associated with differential benefit from adjuvant neratinib in the ExteNET trial (9). Two pooled analyses also confirmed no robust impact of PIK3CA mutation on long-term outcome.…”

Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer

“…Preclinically, neratinib inhibited proliferation in HER2 -amplified, PIK3CA -mutant tumor cell lines [73], and inhibited tumor growth in a HER2-positive, PIK3CA -mutant patient-derived xenograft model [119]. In the positive phase III ExteNET study, which compared 1 year of neratinib versus placebo given in the adjuvant setting after standard trastuzumab-based therapy, absolute risk reduction was associated with neratinib treatment of patients with PIK3CA -mutated or -amplified cancers, although this reduction was not statistically significant [120]. In the first 125 patients from the SUMMIT basket trial for HER2 -mutant, metastatic solid tumors who were treated with neratinib monotherapy, PIK3CA mutations were more prevalent in patients who were on treatment for <24 weeks than those who were on for ≥24 weeks, although this difference was not statistically significant [81].…”

The Predictive Role of PIK3CA Mutation Status on PI3K Inhibitors in HR+ Breast Cancer Therapy: A Systematic Review and Meta-Analysis

“…Therefore, circulating tumor DNA (ctDNA) analysis has been widely employed as a noninvasive approach to detect PIK3CA mutation status [28]. Comparing with archival tumor samples, ctDNA analysis is a more illustrative and less invasive technique to assess the mutational status and heterogenicity throughout the treatment [29]. In our methods, we collect the responsive and survival data according to the PIK3CA mutation status in ctDNA analysis, which is broadly applied to detect the gene mutation status in cancers.…”