bims-ovdlit 2023-04-23 papers

Issue of 2023–04–23
five papers selected by
Lara Paracchini, Humanitas Research

Ann Transl Med. 2023 Mar 31. 11(6): 275

Discussing maintenance therapy for ovarian, peritoneal, and fallopian tube cancers.

Keywords: Ovarian cancer; Taxens; maintenance therapy

DOI: https://doi.org/10.21037/atm-22-6521

Clin Cancer Res. 2023 Apr 17. pii: CCR-22-3328. [Epub ahead of print]

Clinical relevance of BRCA1 promoter methylation testing in ovarian cancer patients.

Félix Blanc-Durand, Roseline Tang, Margaux Pommier, Marzieh Nashvi, Sophie Cotteret, Catherine Genestie, Audrey Le Formal, Patricia Pautier, Judith Michels, Maria Kfoury, Robert Hervé, Sylvie Mengue, Estelle Wafo, Antoine Elies, Gregoire Miailhe, Jennifer Uzan, Etienne Rouleau, Alexandra Leary.

PURPOSE: Homologous-recombination deficiency (HRD) is closely related to PARPi benefit in ovarian cancer (OC). The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade OC to HRD status and clinical behavior to assess its clinical relevance.
DESIGN: This is a retrospective monocentric analysis of patients centrally tested for genomic-instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative ddPCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing.
RESULTS: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score≥42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA-wild-type OC had high BRCA1 methylation levels. All of the highly methylated tumors were classified HRD achieving a positive predictive value of 100%. We detected 14% (11/79) low methylated tumors (1-69%) and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth and 33.3 for BRCAwt unmethylated (P<0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum.
CONCLUSIONS: OC patients with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be relevant to other tumor types for HRD prediction.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3328

J Clin Pathol. 2023 Apr 18. pii: jcp-2023-208852. [Epub ahead of print]

In-house homologous recombination deficiency testing in ovarian cancer: a multi-institutional Italian pilot study.

AIMS: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPIs) represent a standard of care for the clinical management of high-grade serous ovarian cancer (HGSOC). The recognition of homologous recombination deficiency (HRD) has emerged as a predictive biomarker of response for first-line PARPIs treatment in patients with HGOSC. On the other hand, this test is extremely complex and therefore it is often externalised. Regrettably, the reliability of outsourced HRD testing can be troubled by inconclusive results and high rejection rates. In this methodological study, we assessed the technical feasibility, interassay and interlaboratory reproducibility of in-house HRD testing using three different commercially available next-generation sequencing assays.
METHODS: A total of n=20 epithelial ovarian cancer samples previously analysed with MyChoice CDx were subjected to HRD retesting using three different platforms in three different major pathology laboratories, that is, SOPHiA DDM HRD Solution, HRD focus and Oncomine homologous recombination repair pathway predesigned panel. Concordance was calculated by Cohen's (dual) and Fleiss (triple) κ coefficients.
RESULTS: In-house BRCA1/2 molecular testing yielded a concordance rate >90.0% among all participating centres. HRD scores were successfully calculated by each institution with a concordance rate of 76.5%. Concerning the external gold standard test, the overall percentage of agreement ranged from 80.0% to 90.0% with a positive percentage agreement ranging from 75.0% to 80.0% and a negative percentage agreement ranging from 80.0% to 100%.
CONCLUSIONS: In-house testing for HRD can be reliably performed with commercially available next-generation sequencing assays.

Keywords: ovarian neoplasms; pathology, molecular; point-of-care testing

DOI: https://doi.org/10.1136/jcp-2023-208852

Nat Cancer. 2023 Apr 20.

Inferring early genetic progression in cancers with unobtainable premalignant disease.

Ignaty Leshchiner, Edmund A Mroz, Justin Cha, Daniel Rosebrock, Oliver Spiro, Juliana Bonilla-Velez, William C Faquin, Armida Lefranc-Torres, Derrick T Lin, William A Michaud, Gad Getz, James W Rocco.

Analysis of premalignant tissue has identified the typical order of somatic events leading to invasive tumors in several cancer types. For other cancers, premalignant tissue is unobtainable, leaving genetic progression unknown. Here, we demonstrate how to infer progression from exome sequencing of primary tumors. Our computational method, PhylogicNDT, recapitulated the previous experimentally determined genetic progression of human papillomavirus-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). We then evaluated HPV+ HNSCC, which lacks premalignant tissue, and uncovered its previously unknown progression, identifying early drivers. We converted relative timing estimates of driver mutations and HPV integration to years before diagnosis based on a clock-like mutational signature. We associated the timing of transitions to aneuploidy with increased intratumor genetic heterogeneity and shorter overall survival. Our approach can establish previously unknown early genetic progression of cancers with unobtainable premalignant tissue, supporting development of experimental models and methods for early detection, interception and prognostication.

DOI: https://doi.org/10.1038/s43018-023-00533-y