bims-tumhet 2021-12-05 papers

Issue of 2021–12–05
five papers selected by
Sergio Marchini, Humanitas Research

Ann Oncol. 2021 Nov 30. pii: S0923-7534(21)04828-6. [Epub ahead of print]

European Experts Consensus: BRCA/Homologous Recombination Deficiency Testing in First-Line Ovarian Cancer.

European experts consensus group

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. Homologous recombination repair deficiency (HRR deficiency) is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition.
DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (N=14) and contributors (N=84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the PRISMA guidelines.
RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive.
CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.

Keywords: BRCA1/2, homologous recombination deficiency; Ovarian cancer; PARP inhibition; genetic counselling; mainstream genetic testing

DOI: https://doi.org/10.1016/j.annonc.2021.11.013

Adv Genet. 2021 ;pii: S0065-2660(21)00013-4. [Epub ahead of print]108 35-80

PARP inhibitors in hereditary breast and ovarian cancer and other cancers: A review.

Prashant Mehta, Sneha J Bothra.

There has been a paradigm shift in the management of cancer, with the immense progress in cancer genomics. More and more targeted therapies are becoming available by the day and personalized medicine is becoming popular with specific drugs being designed for selected subgroups of patients. One such new class of targeted drugs in the armamentarium is Poly ADP Ribose Polymerase (PARP) inhibitors (PARPi), which inhibit the enzyme PARP, thus interfering with DNA repair. This strategy utilizes a pre-existing genomic lesion in tumors with homologous recombination repair defects (including BRCA mutations), weakening tumor cells further by blocking the alternate pathway of DNA repair. In this review, we discuss in detail, the evolution, genetics, mechanism of action, mechanism of resistance, indications of use of PARP inhibitors, as well as combination with other agents and future directions.

Keywords: BRCA mutation; Breast cancer; DNA repair defect; Ovarian cancer; PARP inhibitors

DOI: https://doi.org/10.1016/bs.adgen.2021.08.002

Semin Diagn Pathol. 2021 Nov 20. pii: S0740-2570(21)00082-4. [Epub ahead of print]

High-grade endometrial carcinomas: Morphologic spectrum and molecular classification.

Cunxian Zhang, Wenxin Zheng.

High-grade endometrial carcinoma (HGEC) is a heterogeneous group of tumors with various morphologic, genetic, and clinical characteristics. Morphologically, HGEC includes high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, undifferentiated/dedifferentiated carcinoma, and carcinosarcoma. The morphologic classification has been used for prognostication and treatment decisions. However, patient management based on morphologic classification is limited by suboptimal interobserver reproducibility, variable clinical outcomes observed within the same histotype, and frequent discordant histotyping/grading between biopsy and hysterectomy specimens. Recent studies from The Cancer Genome Atlas (TCGA) Research Network established four distinct molecular subtypes: POLE-ultramutated, microsatellite unstable, copy number high, and copy number low groups. Compared to histotyping, the TCGA molecular classification appears superior in risk stratification. The best prognosis is seen in the POLE-ultramutated group and the worst in copy number high group, while the prognosis in the microsatellite unstable and copy number low groups is in between. The TCGA subtyping is more reproducible and shows a better concordance between endometrial biopsy and resection specimens. It has now become apparent that the molecular classification can supplement histotyping in patient management. This article provides an overview of the pathologic diagnosis/differential diagnosis of HGEC and the TCGA classification of endometrial cancers, with the clinical significance and applications of TCGA classification briefly discussed when appropriate.

Keywords: Endometrial cancer; High-grade endometrial carcinoma; Molecular classification; Morphologic classification; TCGA

DOI: https://doi.org/10.1053/j.semdp.2021.11.002

Reprod Biol Endocrinol. 2021 Dec 03. 19(1): 178

Circulating tumor DNA: a noninvasive biomarker for tracking ovarian cancer.

Fang Yang, Jun Tang, Zihao Zhao, Chunling Zhao, Yuancai Xiang.

Ovarian cancer is the fifth leading cause of cancer-related mortality in women worldwide. Despite the development of technologies over decades to improve the diagnosis and treatment of patients with ovarian cancer, the survival rate remains dismal, mainly because most patients are diagnosed at a late stage. Traditional treatment methods and biomarkers such as cancer antigen-125 as a cancer screening tool lack specificity and cannot offer personalized combinatorial therapy schemes. Circulating tumor DNA (ctDNA) is a promising biomarker for ovarian cancer and can be detected using a noninvasive liquid biopsy. A wide variety of ctDNA applications are being elucidated in multiple studies for tracking ovarian carcinoma during diagnostic and prognostic evaluations of patients and are being integrated into clinical trials to evaluate the disease. Furthermore, ctDNA analysis may be used in combination with multiple "omic" techniques to analyze proteins, epigenetics, RNA, nucleosomes, exosomes, and associated immune markers to promote early detection. However, several technical and biological hurdles impede the application of ctDNA analysis. Certain intrinsic features of ctDNA that may enhance its utility as a biomarker are problematic for its detection, including ctDNA lengths, copy number variations, and methylation. Before the development of ctDNA assays for integration in the clinic, such issues are required to be resolved since these assays have substantial potential as a test for cancer screening. This review focuses on studies concerning the potential clinical applications of ctDNA in ovarian cancer diagnosis and discusses our perspective on the clinical research aimed to treat this daunting form of cancer.

Keywords: Ovarian cancer; biomarker; cancer early detection; circulating tumor DNA; liquid biopsy

DOI: https://doi.org/10.1186/s12958-021-00860-8

Gene. 2021 Nov 29. pii: S0378-1119(21)00678-8. [Epub ahead of print] 146083

Altered cervicovaginal microbiota in premenopausal ovarian cancer patients.

Asuka Morikawa, Ayako Kawabata, Katsuhiko Shirahige, Tetsu Akiyama, Aikou Okamoto, Takashi Sutani.

Nearly three hundred thousand female patients are diagnosed with ovarian cancer in the world annually, and this number shows an increasing trend. However, characteristic symptoms caused by ovarian cancer are so few that early diagnosis remains challenging, and an effective screening method has not yet been established. Here, we conducted a case-control study in Japan to analyze the association between cervicovaginal microbiome and ovarian cancer, using 16S rRNA amplicon sequencing. Analysis of DNA extracted from cervical smear samples revealed Lactobacillus-dominant and Lactobacillus-deficient, highly-diversified bacterial communities in premenopausal and postmenopausal healthy controls, respectively, as reported for vaginal microbiota previously. We found that cervicovaginal microbiota in ovarian cancer patients, regardless of their menopausal status, were frequently a diversified community and similar to those in healthy subjects at postmenopausal ages. The diverse microbiota was associated with the major histotypes of epithelial ovarian cancer, including serous ovarian cancer and ovarian clear cell cancer. The present study implies the potential of a cervicovaginal microbiome biomarker in screening ovarian cancer in premenopausal women.

Keywords: 16S rRNA gene sequencing; Human microbiome; biomarker; vaginal microbiome

DOI: https://doi.org/10.1016/j.gene.2021.146083