sábado, 11 de agosto de 2018

CLINICAL UTILITY OF PROSPECTIVE MOLECULAR CHARACTERIZATION IN ADVANCED ENDOMETRIAL CANCER. - PubMed - NCBI

2018 Aug 1. pii: clincanres.0412.2018. doi: 10.1158/1078-0432.CCR-18-0412. [Epub ahead of print]

CLINICAL UTILITY OF PROSPECTIVE MOLECULAR CHARACTERIZATION IN ADVANCED ENDOMETRIAL CANCER.

Soumerai TE1, Donoghue MTA2, Bandlamudi C3, Srinivasan P4, Chang MT1, Zamarin D5, Cadoo K5, Grisham R6, O'Cearbhaill RE7, Tew W8, Konner J9, Hensley ML6, Makker V10, Sabbatini PJ11, Spriggs DR12, Troso-Sandoval T5, Snyder Charen A1, Friedman CF13, Gorsky M1, Schweber SJ1, Middha S14, Murali R14, Chiang S14, Park KJ15, Soslow RA14, Ladanyi M4, Li BT1, Mueller JJ16, Weigelt B4, Zehir A14, Berger MF2, Abu-Rustum NR16, Aghajanian C5, DeLair D15, Solit DB17, Taylor BS17, Hyman DM18.

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Abstract

PURPOSE:

Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease revealed grade and histology-specific differences, facilitating enrollment onto clinical trials.

EXPERIMENTAL DESIGN:

We integrated prospective clinical sequencing and immunohistochemical data with clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering.

RESULTS:

Patients had advanced disease, high-grade histologies, and poor progression-free survival on first-line therapy (PFS1). Matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by The Cancer Genome Atlas (TCGA). Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein immunohistochemical staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared to other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months, p=0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials; 47% of these achieved clinical benefit.

CONCLUSIONS:

Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis aiding treatment decision-making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small proportion of all patients tested received investigational, genomically-matched therapy in clinical trials.