bims-ovdlit 2023-02-26 papers

bims-ovdlit

Biomed News

on Ovarian cancer: early diagnosis, liquid biopsy and therapy

Issue of 2023–02–26
nine papers selected by
Lara Paracchini, Humanitas Research

Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics.
Functional homologous recombination assay on FFPE specimens of advanced high-grade serous ovarian cancer predicts clinical outcomes.
Liquid biopsy accelerates precision medicine.
Opportunistic Salpingectomy for the Primary Prevention of Ovarian Cancer.
The Psychosocial Impact of the Decision to Undergo Risk-Reducing Salpingo-Oophorectomy Surgery in BRCA Mutation Carriers and the Role of Physician-Patient Communication.
High-Grade Serous Carcinoma at Risk-Reducing Salpingo-Oophorectomy in Asymptomatic Carriers of BRCA1/2 Pathogenic Variants: Prevalence and Clinical Factors.
Prophylactic Radical Fimbriectomy with Delayed Oophorectomy in Women with a High Risk of Developing an Ovarian Carcinoma: Results of a Prospective National Pilot Study.
The repertoire of copy number alteration signatures in human cancer.
Glucose-Regulated Protein 78 Is a Potential Serum and Imaging Marker for Early Detection of Ovarian Cancer.

Nat Commun. 2023 Feb 22. 14(1): 982

Reconstructing clonal tree for phylo-phenotypic characterization of cancer using single-cell transcriptomics.

Seong-Hwan Jun, Hosein Toosi, Jeff Mold, Camilla Engblom, Xinsong Chen, Ciara O'Flanagan, Michael Hagemann-Jensen, Rickard Sandberg, Samuel Aparicio, Johan Hartman, Andrew Roth, Jens Lagergren.

Functional characterization of the cancer clones can shed light on the evolutionary mechanisms driving cancer's proliferation and relapse mechanisms. Single-cell RNA sequencing data provide grounds for understanding the functional state of cancer as a whole; however, much research remains to identify and reconstruct clonal relationships toward characterizing the changes in functions of individual clones. We present PhylEx that integrates bulk genomics data with co-occurrences of mutations from single-cell RNA sequencing data to reconstruct high-fidelity clonal trees. We evaluate PhylEx on synthetic and well-characterized high-grade serous ovarian cancer cell line datasets. PhylEx outperforms the state-of-the-art methods both when comparing capacity for clonal tree reconstruction and for identifying clones. We analyze high-grade serous ovarian cancer and breast cancer data to show that PhylEx exploits clonal expression profiles beyond what is possible with expression-based clustering methods and clear the way for accurate inference of clonal trees and robust phylo-phenotypic analysis of cancer.

DOI: https://doi.org/10.1038/s41467-023-36202-y
Clin Cancer Res. 2023 Feb 20. pii: CCR-22-3156. [Epub ahead of print]

Functional homologous recombination assay on FFPE specimens of advanced high-grade serous ovarian cancer predicts clinical outcomes.

Sanna Pikkusaari, Manuela Tumiati, Anni Virtanen, Jaana Oikkonen, Yilin Li, Fernando Perez-Villatoro, Taru Muranen, Matilda Salko, Kaisa Huhtinen, Anna Kanerva, Heidi Koskela, Johanna Tapper, Riitta Koivisto-Korander, Titta Joutsiniemi, Ulla-Maija Haltia, Heini Lassus, Sampsa Hautaniemi, Anniina Farkkila, Johanna Hynninen, Sakari Hietanen, Olli Carpén, Liisa Kauppi.

PURPOSE: Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD, and/or require high tumor cell content which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes.
EXPERIMENTAL DESIGN: We quantified RAD51, a key HR protein, in immunostained FFPE tumor samples obtained from both chemotherapy-naïve and neoadjuvant chemotherapy (NACT) treated HGSC patients. We defined cut-offs for functional HRD separately for these sample types, classified the patients accordingly as HR-deficient or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures and genomic scars) were also determined, and compared with functional HR status.
RESULTS: Functional HR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS p<0.0001; OS p<0.0001) as well as NACT-treated (PFS p<0.0001; OS p=0.0033) tumor specimens. The functional HR test also identified as HRD those PARPi-at-recurrence -treated patients with longer OS (p=0.0188).
CONCLUSIONS: We developed a functional HR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3156
Ann Oncol. 2023 Feb 15. pii: S0923-7534(23)00074-1. [Epub ahead of print]

Liquid biopsy accelerates precision medicine.

O Amato, P Aftimos, M Ignatiadis.

The concept of liquid biopsies based on circulating tumoral DNA (ctDNA) has gained space in precision oncology in the last few years. Indeed, molecular alterations can be detected in ctDNA fragments released by cancer cells in the bloodstream. This technique can then be used for tumor genotyping, to study tumor evolution as genomic alterations are acquired under therapy pressure, for the evaluation of anti-tumor response during follow-up, and for the detection of minimal residual disease1. In this Issue of Annals of Oncology, Bayle et al. present results from the STING study2 in the context of the PRISM French initiative, involving the comprehensive molecular profiling of ctDNA in 1,772 patients with advanced solid tumors to guide matched targeted therapy, representing the largest exclusively ctDNA-based molecular profiling program across multiple advanced cancers reporting results to date.

DOI: https://doi.org/10.1016/j.annonc.2023.02.004
Dtsch Arztebl Int. 2022 Dec 09. pii: arztebl.m2022.0232. [Epub ahead of print]119(49): 846-847

Opportunistic Salpingectomy for the Primary Prevention of Ovarian Cancer.

Ingo B Runnebaum, Angela Kather, Jalid Sehouli.

DOI: https://doi.org/10.3238/arztebl.m2022.0232
Curr Oncol. 2023 Feb 17. 30(2): 2429-2440

The Psychosocial Impact of the Decision to Undergo Risk-Reducing Salpingo-Oophorectomy Surgery in BRCA Mutation Carriers and the Role of Physician-Patient Communication.

Ana C Alves-Nogueira, Daniela Melo, Carlos Carona, Margarida Figueiredo-Dias.

  Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective prophylactic surgery provided to premenopausal women carrying BRCA1 or BRCA2 mutations and presenting an increased risk of developing breast or ovarian cancer. This procedure is related to physiological, sexual, and psychosocial distress, which altogether increase uncertainty and complexity in the clinical decision-making process and post-surgery adaptation. Physician-patient communication (PPC) has been pointed out as a determinant factor in the decision-making to undergo RRSO, and the subsequent adjustment of women. However, studies examining the psychosocial impact of the decision-making process have been scarce and often lack clear theoretical frameworks. While the role of PPC in such processes has been highlighted in a few qualitative studies, there is a paucity of quantitative research addressing this question. Therefore, this narrative review, conducted using a multidisciplinary approach, was planned to: (1) present an updated medical background for RRSO; (2) analyze the psychosocial impact of the decision-making process within a theoretical framework of the Health Belief Model; and (3) discuss the role of PPC in such a decision-making process and in post-surgery. The collected research also enabled the recommendation of some additions to the existing clinical guidelines and the outlining of future research directions.

Keywords:  BRCA mutation; breast cancer; ovarian cancer; physician-patient communication (PPC); psychosocial adjustment; risk-reducing salpingo-oophorectomy (RRSO); shared decision-making

DOI:  https://doi.org/10.3390/curroncol30020185
J Clin Oncol. 2023 Feb 21. JCO2201237

High-Grade Serous Carcinoma at Risk-Reducing Salpingo-Oophorectomy in Asymptomatic Carriers of BRCA1/2 Pathogenic Variants: Prevalence and Clinical Factors.

HEBON Investigators

PURPOSE: To investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic variant (PV) carriers.
PATIENTS AND METHODS: We included BRCA1/2-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO.
RESULTS: Of the 2,557 included women, 1,624 had BRCA1, 930 had BRCA2, and three had both BRCA1/2-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for BRCA1-PV and 46.8 years (27.6-77.9) for BRCA2-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%) BRCA1-PV and 6 (0.6%) BRCA2-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among BRCA1/2-PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective.
CONCLUSION: We detected HGSC in 1.5% (BRCA1-PV) and 0.6% (BRCA2-PV) of RRSO specimens from asymptomatic BRCA1/2-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP.

DOI: https://doi.org/10.1200/JCO.22.01237
Cancers (Basel). 2023 Feb 10. pii: 1141. [Epub ahead of print]15(4):

Prophylactic Radical Fimbriectomy with Delayed Oophorectomy in Women with a High Risk of Developing an Ovarian Carcinoma: Results of a Prospective National Pilot Study.

Eric Leblanc, Fabrice Narducci, Gwenaël Ferron, Audrey Mailliez, Jean-Yves Charvolin, Houssein El Hajj, Frédéric Guyon, Virginie Fourchotte, Eric Lambaudie, Agathe Crouzet, Yves Fouche, Sébastien Gouy, Pierre Collinet, Frédéric Caquant, Christophe Pomel, François Golfier, Véronique Vaini-Cowen, Isabelle Fournier, Michel Salzet, Emmanuelle Tresch, Alicia Probst, Anne-Sophie Lemaire, Marie-Cécile Le Deley, Delphine Hudry.

  Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.

Keywords:  delayed oophorectomy; early menopause; high risk of breast and ovarian cancer; ovarian cancer prevention; radical fimbriectomy; risk-reducing surgery

DOI:  https://doi.org/10.3390/cancers15041141
Brief Bioinform. 2023 Feb 20. pii: bbad053. [Epub ahead of print]

The repertoire of copy number alteration signatures in human cancer.

Ziyu Tao, Shixiang Wang, Chenxu Wu, Tao Wu, Xiangyu Zhao, Wei Ning, Guangshuai Wang, Jinyu Wang, Jing Chen, Kaixuan Diao, Fuxiang Chen, Xue-Song Liu.

  Copy number alterations (CNAs) are a predominant source of genetic alterations in human cancer and play an important role in cancer progression. However comprehensive understanding of the mutational processes and signatures of CNA is still lacking. Here we developed a mechanism-agnostic method to categorize CNA based on various fragment properties, which reflect the consequences of mutagenic processes and can be extracted from different types of data, including whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) array. The 14 signatures of CNA have been extracted from 2778 pan-cancer analysis of whole genomes WGS samples, and further validated with 10 851 the cancer genome atlas SNP array dataset. Novel patterns of CNA have been revealed through this study. The activities of some CNA signatures consistently predict cancer patients' prognosis. This study provides a repertoire for understanding the signatures of CNA in cancer, with potential implications for cancer prognosis, evolution and etiology.

Keywords:  cancer genome; cancer prognosis; copy number alteration; copy number signature; mutational signature

DOI:  https://doi.org/10.1093/bib/bbad053
Cancers (Basel). 2023 Feb 10. pii: 1140. [Epub ahead of print]15(4):

Glucose-Regulated Protein 78 Is a Potential Serum and Imaging Marker for Early Detection of Ovarian Cancer.

Elizabeth A Paris, Janice M Bahr, Jacques S Abramowicz, Sanjib Basu, Animesh Barua.

   BACKGROUND: Understanding malignant transformation associated with ovarian cancer (OVCA) is important to establish early detection tests. This study examined whether expression of glucose-regulated protein 78 (GRP78, marker of cellular stress) increases during OVCA development, and whether GRP78 can be detected by targeted-transvaginal ultrasound (TVUS) imaging.
METHODS: Normal ovaries (n = 10), benign (n = 10) and malignant ovarian tumors at early (n = 8) and late stages (n = 16), hens with and without ovarian tumors at early and late stages (n = 10, each) were examined for GRP78 expression during OVCA development by immunohistochemistry, immunoblotting, gene expression and immunoassay. Feasibility of GRP78-targeted TVUS imaging in detecting early OVCA was examined.
RESULTS: Compared with normal ovaries and benign tumors, intensity of GRP78 expression was higher (p < 0.0001) in OVCA patients. Compared with normal (9007.76 ± 816.54 pg/mL), serum GRP78 levels were significantly higher (p < 0.05) in patients with early (12,730.59 ± 817.35 pg/mL) and late-stage OVCA (13,930.12 ± 202.35) (p < 0.01). Compared with normal (222.62 ± 181.69 pg/mL), serum GRP78 levels increased (p < 0.05) in hens with early (590.19 ± 198.18 pg/mL) and late-stage OVCA (1261.38 ± 372.85) (p < 0.01). Compared with non-targeted, GRP78-targeted imaging enhanced signal intensity of TVUS (p < 0.0001).
CONCLUSIONS: Tissue and serum levels of GRP78 increase in association with OVCA. GRP78 offers a potential serum and imaging marker for early OVCA detection.

Keywords:  chronic inflammation; early detection; glucose-regulated protein 78; laying hen; ovarian cancer; oxidative stress; targeted-imaging agents; transvaginal ultrasound imaging

DOI:  https://doi.org/10.3390/cancers15041140