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| Breast cancer research : BCR. 2019 Mar 11. doi: 10.1186/s13058-019-1115-2. pii: 10.1186/s13058-019-1115-2 |
| PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial. |
| Chia SKL1, Martin M2, Holmes FA3, Ejlertsen B4, Delaloge S5, Moy B6, Iwata H7, von Minckwitz G8, Mansi J9, Barrios CH10, Gnant M11, Tomašević Z12, Denduluri N13, Šeparović R14, Kim SB15, Jakobsen EH16, Harvey V17, Robert N18, Smith J19, Harker G20, Zhang B21, Eli LD22, Ye Y23, Lalani AS24, Buyse M25, Chan A26 |
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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. |
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KEYWORDS: Breast cancer, Drug targets, Neratinib, PIK3CA, Predictive, Prognostic |
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Publikations ID: 30867034 Quelle: öffnen |
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