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PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial
- Source :
- Breast Cancer Research, Vol 21, Iss 1, Pp 1-9 (2019), Chia, S K L, Martin, M, Holmes, F A, Ejlertsen, B, Delaloge, S, Moy, B, Iwata, H, von Minckwitz, G, Mansi, J, Barrios, C H, Gnant, M, Tomašević, Z, Denduluri, N, Šeparović, R, Kim, S-B, Jakobsen, E H, Harvey, V, Robert, N, Smith, J, Harker, G, Zhang, B, Eli, L D, Ye, Y, Lalani, A S, Buyse, M & Chan, A 2019, ' PIK3CA alterations and benefit with neratinib : analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial ', Breast Cancer Research, vol. 21, 39 . https://doi.org/10.1186/s13058-019-1115-2, Breast Cancer Research : BCR
- Publication Year :
- 2019
- Publisher :
- BMC, 2019.
-
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.
- Subjects :
- Oncology
Drug targets
Receptor, ErbB-2
Neratinib
Predictive
0302 clinical medicine
Breast cancer
Trastuzumab
Clinical endpoint
Breast
Aged, 80 and over
education.field_of_study
Middle Aged
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Primary tumor
Chemotherapy, Adjuvant
030220 oncology & carcinogenesis
Quinolines
Female
Research Article
medicine.drug
Adult
medicine.medical_specialty
Class I Phosphatidylinositol 3-Kinases
Population
neratinib, breast cancer, PIK3CA alteration, predictive biomarker
Antineoplastic Agents
Breast Neoplasms
PIK3CA
Placebo
Prognostic
lcsh:RC254-282
Disease-Free Survival
03 medical and health sciences
Double-Blind Method
Internal medicine
Biomarkers, Tumor
medicine
Adjuvant therapy
Humans
education
neoplasms
Aged
business.industry
Patient Selection
medicine.disease
Mutation
business
Follow-Up Studies
Subjects
Details
- Language :
- English
- Volume :
- 21
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Breast Cancer Research
- Accession number :
- edsair.doi.dedup.....6eb1fd1b18b54e621eb1f47dbb2e863f