Title:
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Genomic heterogeneity and efficacy of PI3K pathway inhibitors in patients with gynaecological cancer
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Author:
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Rodriguez Freixinos, Victor; Ruiz Pace, Fiorella; Fariñas-Madrid, Lorena; Garrido-Castro, Ana Christina; Villacampa Javierre, Guillermo; Nuciforo, Paolo Giovanni; Vivancos Prellezo, Ana; Dienstmann, Rodrigo; Oaknin benzaquen, Ana Mazaltob
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Other authors:
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Institut Català de la Salut; [Rodriguez-Freixinos V, Fariñas-Madrid L, Oaknin A] Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Gynecological Malignancies Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Ruiz-Pace F, Villacampa G] Oncology Data Science - Prescreening Molecular, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Garrido-Castro AC] Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [Nuciforo P] Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Vivancos A] Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Dienstmann R] Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Oncology Data Science - Prescreening Molecular, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Hospital Universitari Vall d'Hebron |
Abstract:
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Malignitats ginecològiques; Fracció al·lel mutant; PI3K |
Abstract:
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Neoplasias ginecológicas; Fracción alélica mutante; PI3K |
Abstract:
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Gynecologic malignancies; Mutant allele fraction; PI3K |
Abstract:
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Objectives
Aberrant PI3K/AKT/mTOR activation is common in gynaecological malignancies. However, predictive biomarkers of response to PI3K pathway inhibitors (PAMi) have yet to be identified.
Methods
We analysed the outcomes of patients with advanced gynaecological cancer with available genomic data, treated with PAMi as single agents or in combination in phase I clinical trials. Clinical relevance of the PIK3CA mutant allele fraction (MAF) was investigated. MAF of each variant was normalised for tumour purity in the sample (adjMAFs) to infer clonality of PIK3CA mutations, defined as clonal (≥0.4) or subclonal (<0.4).
Results
A total of 50 patients with gynaecological cancer (24 ovarian; 15 endometrial; 11 cervical) with available targeted mutation profiling were selected. PAMi therapy was matched to PIK3CA/PTEN mutation in 30 patients (60%). The overall response rate, median time to progression (mTTP) and clinical benefit rate (CBR) of the entire population were 10% (N=5), 3.57 months (2.57–4.4) and 40% (N=18), respectively. Genotype-matched therapy did not lead to a favourable CBR (OR 0.91, p=1 (0.2–3.7)) or mTTP (3.57 months (2.6–4.4) vs 3.73 months (1.9–13.2); HR 1.41; p=0.29). We did not detect differences in mTTP according to therapy or PIK3CA codon mutation (HR 1.71, p=0.24). Overall, 41% of patients had a TTP ratio (TTP PAMi/TTP on immediately prior or subsequent palliative chemotherapy) ≥1.3, without statistically significant differences according to tumour type (p=0.39), molecular alteration status (p=0.13) or therapy (p=0.54). In univariate analysis, genotype-matched therapy in patients with PIK3CA clonal events was associated with improved mTTP (HR 3.6; p=0.03).
Conclusions
Our study demonstrates that patients with advanced gynaecological cancer, refractory to standard therapies, achieved meaningful clinical benefit from PAMi. The impact of PI3KCA clonality on response to selected PAMi in patients with gynaecological cancer deserves further investigation. |
Subject(s):
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-Inhibidors enzimàtics -Aparell genital femení - Càncer -DISEASES::Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Female -Other subheadings::Other subheadings::/therapy -CHEMICALS AND DRUGS::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Phosphatidylinositol 3-Kinases -ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales femeninos -Otros calificadores::Otros calificadores::/terapia -COMPUESTOS QUÍMICOS Y DROGAS::enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::fosfatidil inositol 3 cinasas |
Rights:
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Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
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Document type:
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Article Article - Published version |
Published by:
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BMJ
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