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Int J Cancer ; 146(7): 1851-1861, 2020 04 01.
Article in English | MEDLINE | ID: mdl-31603993

ABSTRACT

The goal of our study was to demonstrate the spectrum of genomic alterations present in the residual disease of patients with advanced high-grade serous ovarian cancer (HGSOC) after neoadjuvant chemotherapy (NAC), including matched pretreatment biopsies. During the study period between 2006 and 2017, we collected pre-NAC and post-NAC tumor tissue samples from patients with advanced HGSOC. We performed combined next-generation sequencing and immunohistochemistry to identify actionable targets and pathway activation in post-NAC residual tumors. We also examined whether post-NAC profiling of residual HGSOC identified targetable molecular lesions in the chemotherapy-resistant component of tumors. Among 102 post-NAC samples, 41 (40%) of patients had mutations in homologous recombination repair (HRR) genes (HRR deficiency). Patients with HRR mutations had higher tumor mutation burdens (p < 0.001) and higher alterations in the PI3K-AKT-mTOR pathway (p = 0.004) than patients without these HRR mutations. Nevertheless, we found no significant differences in progression-free survival (p = 0.662) and overall survival (OS; p = 0.828) between the two groups. Most patients (91%) had alterations in at least one of the targetable pathways, and those patients with cell cycle (p = 0.004) and PI3K-AKT-mTOR signaling (p = 0.005) pathway alterations had poorer OS (Bonferroni-corrected threshold = 0.0083, 0.05/6). We showed the genomic landscape of tumor cells remaining in advanced HGSOC after NAC. Once validated, these data can help inform biomarker-driven adjuvant studies in targeting residual tumors to improve the outcomes of patients with advanced HGSOC after NAC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cystadenocarcinoma, Serous/genetics , Ovarian Neoplasms/genetics , Ovary/pathology , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Cell Cycle/genetics , Cystadenocarcinoma, Serous/mortality , Cystadenocarcinoma, Serous/therapy , Cytoreduction Surgical Procedures/methods , Disease Progression , Drug Resistance, Neoplasm/genetics , Female , Genomics , Humans , Middle Aged , Mutation/drug effects , Neoadjuvant Therapy/methods , Neoplasm, Residual , Ovarian Neoplasms/mortality , Ovarian Neoplasms/therapy , Ovariectomy/methods , Ovary/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Progression-Free Survival , Proto-Oncogene Proteins c-akt/metabolism , Retrospective Studies , Signal Transduction/drug effects , Signal Transduction/genetics , Survival Analysis , TOR Serine-Threonine Kinases/metabolism
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