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

ABSTRACT: BACKGROUND:Neratinib 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. METHODS:Participants 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. RESULTS:Among 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). CONCLUSIONS:Although 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 REGISTRATION:ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

SUBMITTER: Chia SKL

PROVIDER: S-EPMC6417207 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Chia Stephen K L SKL Martin Miguel M Holmes Frankie A FA Ejlertsen Bent B Delaloge Suzette S Moy Beverly B Iwata Hiroji H von Minckwitz Gunter G Mansi Janine J Barrios Carlos H CH Gnant Michael M Tomašević Zorica Z Denduluri Neelima N Šeparović Robert R Kim Sung-Bae SB Jakobsen Erik Hugger EH Harvey Vernon V Robert Nicholas N Smith John J Harker Graydon G Zhang Bo B Eli Lisa D LD Ye Yining Y Lalani Alshad S AS Buyse Marc M Chan Arlene A

Breast cancer research : BCR 20190311 1

<h4>Background</h4>Neratinib 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.<h4>Methods</h4>Participants were wome ...[more]

PMID: 30867034

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

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

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