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Hollis RL, Churchman M, Grimes GR, Meynert AM, Gautier P, McMahon L, Sherwood K, Oswald AJ, Croy I, Ferguson M, Martin CW, McGoldrick T, McPhail N, Creedon H, Barrett JC, March R, Dougherty BA, Roxburgh P, Ewing A, Herrington CS, Semple CA, Gourley C. Somatic BRCA1/2 mutations are associated with a similar survival advantage to their germline counterparts in tubo-ovarian high grade serous carcinoma. Eur J Cancer 2025; 219:115299. [PMID: 39955805 DOI: 10.1016/j.ejca.2025.115299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/04/2025] [Accepted: 02/08/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND Half of high grade serous tubo-ovarian carcinomas (HGSOC) demonstrate homologous recombination repair (HRR) deficiency, most commonly through germline or somatic pathogenic variants in BRCA1/2 (gBRCA1/2 or sBRCA1/2). gBRCA1/2 is associated with favourable survival, greater response rate to platinum-based chemotherapy, and marked sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. sBRCA1/2 has been assumed to confer a similar clinical phenotype; however, few studies have specifically investigated sBRCA1/2 versus gBRCA1/2 to demonstrate their equivalence. METHODS We investigated the association of gBRCA1/2, sBRCA1/2 and non-BRCA HRR gene mutations with HGSOC patient survival using two patient cohorts (cohort 1, n = 174 matched FFPE tumour and normal with panel-based sequencing; cohort 2, n = 279 matched fresh tumour and normal with whole genome sequencing). TCGA-OV samples (n = 316) were used for external validation. RESULTS Patients with HRR-mutant tumours (BRCA1, BRCA2, non-BRCA HRR-mutant) demonstrated prolonged survival across both cohorts (cohort 1: multivariable hazard ratio [multiHR] 0.53 [0.32-0.87]; cohort 2: multiHR 0.36 [0.25-0.51]). gBRCA1/2 and sBRCA1/2 were associated with a similar survival benefit compared to the HRR-wildtype group in the combined cohort (cohort 1 +2) (gBRCA1/2: multiHR 0.50 [0.34-0.71]; sBRCA1/2: multiHR 0.41 [0.25-0.68]). These findings were recapitulated using the TCGA-OV dataset (gBRCA1/2: multiHR 0.56 [0.34-0.91]; sBRCA1/2: multiHR 0.48 [0.25-0.92]). Non-BRCA HRR mutations were associated with marked survival advantage (multiHR vs HRR-wildtype 0.22 [0.11-0.45]). The survival advantage in BRCA1-mutant cases (germline or somatic) was less marked (multiHR for non-BRCA HRR-mutant vs BRCA1-mutant 0.41 [0.19-0.90]). gBRCA1/2, sBRCA1/2 and non-BRCA HRR mutations were all associated with high HRDetect scores measuring HRR deficiency (median 1.00 versus 0.56 in HRR-wildtype, P < 0.01). CONCLUSION gBRCA1/2 and sBRCA1/2 are equivalent in their association with prolonged survival. Non-BRCA HRR gene mutations may be associated with markedly favourable survival in HGSOC.
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Affiliation(s)
- Robert L Hollis
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
| | - Michael Churchman
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Graeme R Grimes
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Alison M Meynert
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Philippe Gautier
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Lynn McMahon
- Precision Medicine Scotland (PMS-IC), Queen Elizabeth University Hospital, Glasgow, UK
| | - Kitty Sherwood
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Department of Oncology, University of Oxford, Oxford, UK; Edinburgh Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ailsa J Oswald
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Ian Croy
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | | | - Cameron W Martin
- The Simpson Centre for Reproductive Health, Royal Infirmary Edinburgh, Edinburgh, UK
| | | | - Neil McPhail
- Department of Oncology, Raigmore Hospital, NHS Highland, Inverness, UK
| | - Helen Creedon
- The Edinburgh Cancer Centre, Western General Hospital, NHS Lothian, Edinburgh, UK
| | - J Carl Barrett
- Translational Medicine, Oncology R&D, AstraZeneca, Waltham, MA, USA
| | - Ruth March
- Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, UK
| | | | - Patricia Roxburgh
- Cancer Research UK Scotland Centre, School of Cancer Sciences, Glasgow, UK; Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - Ailith Ewing
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Edinburgh Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - C Simon Herrington
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Colin A Semple
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Charlie Gourley
- The Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
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Duchon M, Naik R, Lecuru F, Ferron G, Cornou C, Madad Zadeh S, Pomel C. Management of Recurrence in Ovarian Cancer-The Role of Surgery and HIPEC with Relevance to BRCA Testing in a PARPi Landscape. Cancers (Basel) 2025; 17:646. [PMID: 40002241 PMCID: PMC11852647 DOI: 10.3390/cancers17040646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 01/22/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Background: The surgical and medical management of recurrent ovarian cancer is complex and requires a personalized approach based on several factors, including the timing of recurrence, the patient's performance status, previous treatment regimens, and the tumor's histology and molecular characteristics. Objectives: Five randomized trials-GOG-0213, DESKTOP III, SOC 1, HORSE, and CHIPOR-have been conducted and shed light on our practice. Results: Both the DESKTOP III and the SOC 1 trials support the benefit of secondary surgery. The GOG-0213 trial, however, did not show an overall survival benefit, confirming that surgery should not be offered to all patients with platinum-sensitive recurrent ovarian cancer and highlighting the importance of strict patient selection using evidence-based selection criteria including the AGO or iMODEL scores. In patients with a negative score, there may be a place for cytoreductive surgery plus HIPEC in BRCA-negative cases following a course of chemotherapy, although current evidence shows no additional benefit for HIPEC when cytoreductive surgery is performed as an adjuvant procedure. Conclusions: Secondary surgery is recommended for platinum-sensitive patients when respecting AGO or iModel criteria. In addition, surgery plus HIPEC can be considered in BRCA-negative patients with an initial negative AGO or iMODEL score who show sufficient response following a course of neoadjuvant chemotherapy to then be considered operable.
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Affiliation(s)
- Mathilde Duchon
- Department of Surgical Oncology, Centre Jean-Perrin, 58, rue Montalembert, 63011 Clermont-Ferrand, France; (M.D.); (C.C.); (S.M.Z.)
| | - Raj Naik
- British Surgical Gynaecological Oncology Group (BSGOG), Newcastle upon Tyne NE2 4DJ, UK;
| | - Fabrice Lecuru
- Department of Surgical Oncology, Institut Curie, 26 Rue d’Ulm, 75005 Paris, France;
| | - Gwenaël Ferron
- Department of Surgical Oncology, IUCT Oncopole, Institut Universitaire du Cancer de Toulouse, 31100 Toulouse, France;
| | - Caroline Cornou
- Department of Surgical Oncology, Centre Jean-Perrin, 58, rue Montalembert, 63011 Clermont-Ferrand, France; (M.D.); (C.C.); (S.M.Z.)
| | - Sabrina Madad Zadeh
- Department of Surgical Oncology, Centre Jean-Perrin, 58, rue Montalembert, 63011 Clermont-Ferrand, France; (M.D.); (C.C.); (S.M.Z.)
| | - Christophe Pomel
- Department of Surgical Oncology, Centre Jean-Perrin, 58, rue Montalembert, 63011 Clermont-Ferrand, France; (M.D.); (C.C.); (S.M.Z.)
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Alexander S, Aleem U, Jacobs T, Frizziero M, Foy V, Hubner RA, McNamara MG. Antibody-Drug Conjugates and Their Potential in the Treatment of Patients with Biliary Tract Cancer. Cancers (Basel) 2024; 16:3345. [PMID: 39409965 PMCID: PMC11476249 DOI: 10.3390/cancers16193345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 09/16/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Biliary tract cancers (BTCs) are aggressive in nature, often presenting asymptomatically until they are diagnosed at an advanced stage. Surgical resection or liver transplantation are potential curative options. However, a large proportion of patients present with incurable locally advanced or metastatic disease and most of these patients are only eligible for palliative chemotherapy or best supportive care. More recently, targeted therapies have proven beneficial in a molecularly selected subgroup of patients with cholangiocarcinoma who have progressed on previous lines of systemic treatment. However, only a minority of patients with BTCs whose tumours harbour specific molecular alterations can access these therapies. Methods: In relation to ADCs, studies regarding use of antibody-drug conjugates in cancer, particularly in BTCs, were searched in Embase (1974 to 2024) and Ovid MEDLINE(R) (1946 to 2024) to obtain relevant articles. Examples of current clinical trials utilising ADC treatment in BTCs were extracted from the ClinicalTrials.gov trial registry. Conclusions: Overall, this review has highlighted that ADCs have shown encouraging outcomes in cancer therapy, and this should lead to further research including in BTCs, where treatment options are often limited. The promising results observed with ADCs in various cancers underscore their potential as a transformative approach in oncology, warranting continued exploration and development and the need for education on the management of their specific toxicities. By addressing current challenges and optimising ADC design and application, future studies could potentially improve treatment outcomes for patients with BTCs and beyond, potentially in both early and advanced stage settings.
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Affiliation(s)
- Shaun Alexander
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (U.A.); (M.F.); (V.F.); (R.A.H.)
| | - Umair Aleem
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (U.A.); (M.F.); (V.F.); (R.A.H.)
| | - Timothy Jacobs
- The Library, The Christie NHS Foundation Trust, Manchester M20 4BX, UK;
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (U.A.); (M.F.); (V.F.); (R.A.H.)
| | - Victoria Foy
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (U.A.); (M.F.); (V.F.); (R.A.H.)
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK; (U.A.); (M.F.); (V.F.); (R.A.H.)
| | - Mairéad G. McNamara
- Division of Cancer Sciences, School of Medical Sciences, University of Manchester, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
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Valerio M, Inno A, Zambelli A, Cortesi L, Lorusso D, Viassolo V, Verzè M, Nicolis F, Gori S. Deep Neural Network Integrated into Network-Based Stratification (D3NS): A Method to Uncover Cancer Subtypes from Somatic Mutations. Cancers (Basel) 2024; 16:2845. [PMID: 39199616 PMCID: PMC11352240 DOI: 10.3390/cancers16162845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 08/06/2024] [Accepted: 08/12/2024] [Indexed: 09/01/2024] Open
Abstract
(1) Background: The identification of tumor subtypes is fundamental in precision medicine for accurate diagnoses and personalized therapies. Cancer development is often driven by the accumulation of somatic mutations that can cause alterations in tissue functions and morphologies. In this work, a method based on a deep neural network integrated into a network-based stratification framework (D3NS) is proposed to stratify tumors according to somatic mutations. (2) Methods: This approach leverages the power of deep neural networks to detect hidden information in the data by combining the knowledge contained in a network of gene interactions, as typical of network-based stratification methods. D3NS was applied using real-world data from The Cancer Genome Atlas for bladder, ovarian, and kidney cancers. (3) Results: This technique allows for the identification of tumor subtypes characterized by different survival rates and significant associations with several clinical outcomes (tumor stage, grade or response to therapy). (4) Conclusion: D3NS can provide a base model in cancer research and could be considered as a useful tool for tumor stratification, offering potential support in clinical settings.
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Affiliation(s)
- Matteo Valerio
- Medical Oncology, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Verona, Italy
| | - Alessandro Inno
- Medical Oncology, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Verona, Italy
| | - Alberto Zambelli
- Medical Oncology Unit, IRCCS Istituto Clinico Humanitas and Department of Biomedical Sciences, Humanitas University, 20089 Rozzano, Milan, Italy;
| | - Laura Cortesi
- Oncology, Hematology, and Respiratory Diseases, Azienda Ospedaliera-Universitaria, Policlinico di Modena, 41124 Modena, Italy
| | - Domenica Lorusso
- Gynecologic Oncology Unit, Humanitas San Pio X, Milan and Humanitas University, Pieve Emanuele, 20090 Milan, Italy
| | - Valeria Viassolo
- Medical Genetics, Medical Direction, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Verona, Italy;
| | - Matteo Verzè
- Medical Direction, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Verona, Italy; (M.V.)
| | - Fabrizio Nicolis
- Medical Direction, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Verona, Italy; (M.V.)
| | - Stefania Gori
- Medical Oncology, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Verona, Italy
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Fusegi A, Nomura H, Ueki A, Abe A, Kamata M, Misaka S, Aoki Y, Tanigawa T, Yunokawa M, Kanao H. Ovarian surveillance including endometrial cytology for patients with hereditary breast and ovarian cancer before risk-reducing salpingo-oophorectomy: A retrospective analysis. J Obstet Gynaecol Res 2024; 50:1002-1009. [PMID: 38528763 DOI: 10.1111/jog.15935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 03/17/2024] [Indexed: 03/27/2024]
Abstract
AIM Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology. METHODS We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer. RESULTS Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence. CONCLUSIONS The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality.
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Affiliation(s)
- Atsushi Fusegi
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hidetaka Nomura
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Arisa Ueki
- Department of Clinical Genetic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akiko Abe
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mayumi Kamata
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoki Misaka
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yoichi Aoki
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Terumi Tanigawa
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Mayu Yunokawa
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hiroyuki Kanao
- Department of Gynecologic Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
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Nasimi Shad A, Moghbeli M. Integrins as the pivotal regulators of cisplatin response in tumor cells. Cell Commun Signal 2024; 22:265. [PMID: 38741195 DOI: 10.1186/s12964-024-01648-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 05/04/2024] [Indexed: 05/16/2024] Open
Abstract
Cisplatin (CDDP) is a widely used first-line chemotherapeutic drug in various cancers. However, CDDP resistance is frequently observed in cancer patients. Therefore, it is required to evaluate the molecular mechanisms associated with CDDP resistance to improve prognosis among cancer patients. Integrins are critical factors involved in tumor metastasis that regulate cell-matrix and cell-cell interactions. They modulate several cellular mechanisms including proliferation, invasion, angiogenesis, polarity, and chemo resistance. Modification of integrin expression levels can be associated with both tumor progression and inhibition. Integrins are also involved in drug resistance of various solid tumors through modulation of the tumor cell interactions with interstitial matrix and extracellular matrix (ECM). Therefore, in the present review we discussed the role of integrin protein family in regulation of CDDP response in tumor cells. It has been reported that integrins mainly promoted the CDDP resistance through interaction with PI3K/AKT, MAPK, and WNT signaling pathways. They also regulated the CDDP mediated apoptosis in tumor cells. This review paves the way to suggest the integrins as the reliable therapeutic targets to improve CDDP response in tumor cells.
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Affiliation(s)
- Arya Nasimi Shad
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zouzoulas D, Tsolakidis D, Tzitzis P, Chatzistamatiou K, Theodoulidis V, Sofianou I, Grimbizis G, Timotheadou E. CA-125 KELIM as an Alternative Predictive Tool to Identify Which Patients Can Benefit from PARPi in High-Grade Serous Advanced Ovarian Cancer: A Retrospective Pilot Diagnostic Accuracy Study. Int J Mol Sci 2024; 25:5230. [PMID: 38791269 PMCID: PMC11121425 DOI: 10.3390/ijms25105230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/02/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
BRCA mutation and homologous recombination deficiency (HRD) are the criteria for the administration of PARP inhibitor (PARPi) maintenance therapy. It is known that PARPi efficacy is related to platinum sensitivity and that the latter can be demonstrated from the CA-125 elimination rate constant (KELIM). This study aims to investigate if KELIM can be another tool in the identification of patients that could be benefit from PARPi therapy. Retrospective analysis of patients with high-grade serous advanced ovarian cancer that underwent cytoreduction and was further tested for HRD status. The HRD status was tested either by myChoice HRD CDx assay or by RediScore assay. KELIM score was measured in both neoadjuvant and adjuvant settings with the online tool biomarker-kinetics.org. A total of 39 patients had available data for estimating both HRD status and KELIM score. When assuming KELIM as a binary index test with the value 1 as the cut-off point, the sensitivity was 0.86, 95% CI (0.64-0.97) and the specificity was 0.83, 95% CI (0.59-0.96). On the other hand, when assuming KELIM as a continuous index test, the area under the curve (AUC) was 81% and the optimal threshold, using the Youden index, was identified as 1.03 with a sensitivity of 85.7% and a specificity of 83.3%. KELIM score seems to be a new, cheaper, and faster tool to identify patients that can benefit from PARPi maintenance therapy.
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Affiliation(s)
- Dimitrios Zouzoulas
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Dimitrios Tsolakidis
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Panagiotis Tzitzis
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Kimon Chatzistamatiou
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Vasilis Theodoulidis
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Iliana Sofianou
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Grigoris Grimbizis
- 1st Department of Obstetrics & Gynecology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
| | - Eleni Timotheadou
- Department of Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, 56403 Thessaloniki, Greece
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Boursi B, Wileyto EP, Mamtani R, Domchek SM, Golan T, Hood R, Reiss KA. Analysis of BRCA1- and BRCA2-Related Pancreatic Cancer and Survival. JAMA Netw Open 2023; 6:e2345013. [PMID: 38010655 PMCID: PMC10682833 DOI: 10.1001/jamanetworkopen.2023.45013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 10/15/2023] [Indexed: 11/29/2023] Open
Abstract
This cohort study compares the outcomes of patients with BRCA1 and BRCA-related pancreatic cancers using 2 large data sets.
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Affiliation(s)
- Ben Boursi
- Department of Oncology, Sheba Medical Center, Tel HaShomer, Israel
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia
| | - E. Paul Wileyto
- Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Ronac Mamtani
- Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Susan M. Domchek
- Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Talia Golan
- Department of Oncology, Sheba Medical Center, Tel HaShomer, Israel
| | - Ryan Hood
- Abramson Cancer Center, University of Pennsylvania, Philadelphia
| | - Kim A. Reiss
- Abramson Cancer Center, University of Pennsylvania, Philadelphia
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Liu Y, Lawson BC, Huang X, Broom BM, Weinstein JN. Prediction of Ovarian Cancer Response to Therapy Based on Deep Learning Analysis of Histopathology Images. Cancers (Basel) 2023; 15:4044. [PMID: 37627071 PMCID: PMC10452505 DOI: 10.3390/cancers15164044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/06/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Ovarian cancer remains the leading gynecological cause of cancer mortality. Predicting the sensitivity of ovarian cancer to chemotherapy at the time of pathological diagnosis is a goal of precision medicine research that we have addressed in this study using a novel deep-learning neural network framework to analyze the histopathological images. METHODS We have developed a method based on the Inception V3 deep learning algorithm that complements other methods for predicting response to standard platinum-based therapy of the disease. For the study, we used histopathological H&E images (pre-treatment) of high-grade serous carcinoma from The Cancer Genome Atlas (TCGA) Genomic Data Commons portal to train the Inception V3 convolutional neural network system to predict whether cancers had independently been labeled as sensitive or resistant to subsequent platinum-based chemotherapy. The trained model was then tested using data from patients left out of the training process. We used receiver operating characteristic (ROC) and confusion matrix analyses to evaluate model performance and Kaplan-Meier survival analysis to correlate the predicted probability of resistance with patient outcome. Finally, occlusion sensitivity analysis was piloted as a start toward correlating histopathological features with a response. RESULTS The study dataset consisted of 248 patients with stage 2 to 4 serous ovarian cancer. For a held-out test set of forty patients, the trained deep learning network model distinguished sensitive from resistant cancers with an area under the curve (AUC) of 0.846 ± 0.009 (SE). The probability of resistance calculated from the deep-learning network was also significantly correlated with patient survival and progression-free survival. In confusion matrix analysis, the network classifier achieved an overall predictive accuracy of 85% with a sensitivity of 73% and specificity of 90% for this cohort based on the Youden-J cut-off. Stage, grade, and patient age were not statistically significant for this cohort size. Occlusion sensitivity analysis suggested histopathological features learned by the network that may be associated with sensitivity or resistance to the chemotherapy, but multiple marker studies will be necessary to follow up on those preliminary results. CONCLUSIONS This type of analysis has the potential, if further developed, to improve the prediction of response to therapy of high-grade serous ovarian cancer and perhaps be useful as a factor in deciding between platinum-based and other therapies. More broadly, it may increase our understanding of the histopathological variables that predict response and may be adaptable to other cancer types and imaging modalities.
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Affiliation(s)
- Yuexin Liu
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Barrett C. Lawson
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Xuelin Huang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Bradley M. Broom
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - John N. Weinstein
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Osman K, Ahmet K, Hilmi T, İlker N, Ercan Ö, Devrim Ç, Murat S, Emre Ç, İlhan H, Mustafa G, Yüksel Ü, Bahiddin Y, Cihan E, Mehmet Ali NŞ, Emrah E, Umut D, Zeynep O, Mehmet Ali K, Ali G, İvo G, Erkan Ö, Muhammet B, Bülent E, Selma D, Sernaz U, Mahmut G, Hakan G, İrfan Ç. BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers. Balkan J Med Genet 2023; 25:5-14. [PMID: 37265975 PMCID: PMC10230841 DOI: 10.2478/bjmg-2022-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023] Open
Abstract
The demographic and clinical characteristics of patients who have BRCA 1/BRCA 2 pathogenic/likely pathogenic variants may differ from their relatives who had BRCA-related cancer. In this study, we aimed to demonstrate the clinical and demographic findings of patients who had BRCA-related cancer and to assess the differences comparing their relatives who had BRCA-related cancer with breast, genital tract, prostate, and pancreas cancers as well. The results of sequencing analysis of 200 cancer patients (190 women, 10 men) who have been directed to genetic counseling with an indication of BRCA1/BRCA2 testing from different regions across 9 medical oncology centers were retrospectively analyzed. A total of 200 consecutive cancer patients who harbored the BRCA1/BRCA2 pathogenic/likely pathogenic variant (130 (65%) patients harbored BRCA 1 pathogenic/likely pathogenic variant, and 70 harbored BRCA 2 pathogenic/likely pathogenic variant) were included. Of these, 64.0% had breast cancer (43.8% of them had the triple-negative disease, and about 2.3% had only the HER-2 mutant), 31.5% had genital cancers (92.1% of them had ovarian cancer, 3.2% had endometrium, and 1.6% had peritoneum cancer as the primary site and mostly serous adenocarcinoma was the most common histopathology and 14.3% of the patients had endometrioid adenocarcinoma), 3.5% had prostate (median time from metastasis to castration-resistant status was 28 months) and 1.0% had pancreas cancer. Newly diagnosed cancer (breast and ovary) patients who had BRCA 1/BRCA 2 pathogenic/ likely pathogenic variant were younger than their previous cancer diagnosed (breast, ovary, and pancreas) parents who harbored BRCA pathogenic/likely pathogenic variant. We suggest that the genetic screening of BRCA 1/ BRCA 2 pathogenic/likely pathogenic variant is needed as a routine screening for those with a personal or family history of breast, ovarian, tubal, or peritoneal cancer. In addition, once BRCA 1 or BRCA 2 germline pathogenic variant has been identified in a family, testing of at-risk next-generation relatives earlier can identify those family members who also have the familial pathogenic variant, and thus need increased surveillance.
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Affiliation(s)
- K. Osman
- Marmara University, School of Medicine, Department of Medical Oncology, İstanbul, Turkey
| | - K. Ahmet
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - T. Hilmi
- Namık Kemal University, Department of Medical Genetic, Tekirdag, Turkey
| | - N.O. İlker
- Medeniyet University, Department of Medical Oncology, İstanbul, Turkey
| | - Ö. Ercan
- Kocaeli University, Department of Medical Oncology, Kocaeli, Turkey
| | - Ç. Devrim
- Kocaeli University, Department of Medical Oncology, Kocaeli, Turkey
| | - S. Murat
- Marmara University, School of Medicine, Department of Medical Oncology, İstanbul, Turkey
| | - Ç. Emre
- Sakarya University, Department of Medical Oncology, Sakarya, Turkey
| | - H. İlhan
- Sakarya University, Department of Medical Oncology, Sakarya, Turkey
| | - G. Mustafa
- Ankara university, Department of Medical Oncology, Ankara, Turkey
| | - Ü. Yüksel
- Ankara university, Department of Medical Oncology, Ankara, Turkey
| | - Y. Bahiddin
- Ondokuz Mayıs University, Department of Medical Oncology, Samsun, Turkey
| | - E. Cihan
- Ankara City Hospital, Yildirim Beyazit University, Department of Medical Oncology, Ankara, Turkey
| | - N. Ş. Mehmet Ali
- Ankara City Hospital, Yildirim Beyazit University, Department of Medical Oncology, Ankara, Turkey
| | - E. Emrah
- University of Health Sciences, Dr. A.Y Ankara Oncology Research and Education Hospital, Oncology Department, Ankara, Turkey
| | - D. Umut
- University of Health Sciences, Dr. A.Y Ankara Oncology Research and Education Hospital, Oncology Department, Ankara, Turkey
| | - O. Zeynep
- Dicle University, Department of Medical Oncology, Diyarbakır, Turkey
| | - K. Mehmet Ali
- Trakya University, Department of Medical Genetic, Edirne, Turkey
| | - G. Ali
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - G. İvo
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - Ö. Erkan
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - B.H. Muhammet
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - E. Bülent
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - D. Selma
- Trakya University, Department of Medical Genetic, Edirne, Turkey
| | - U. Sernaz
- Trakya University, Department of Medical Oncology, Edirne, Turkey
| | - G. Mahmut
- Medeniyet University, Department of Medical Oncology, İstanbul, Turkey
| | - G. Hakan
- Trakya University, Department of Medical Genetic, Edirne, Turkey
| | - Ç. İrfan
- Trakya University, Department of Medical Oncology, Edirne, Turkey
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Sharma T, Nisar S, Masoodi T, Macha MA, Uddin S, Akil AAS, Pandita TK, Singh M, Bhat AA. Current and emerging biomarkers in ovarian cancer diagnosis; CA125 and beyond. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2023; 133:85-114. [PMID: 36707207 DOI: 10.1016/bs.apcsb.2022.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Ovarian cancer (OC) is one of the most common causes of cancer-related death in women worldwide. Its five-year survival rates are worse than the two most common gynecological cancers, cervical and endometrial. This is because it is asymptomatic in the early stages and usually detected in the advanced metastasized stage. Thus, survival is increasingly dependent on timely diagnosis. The delay in detection is contributed partly by the occurrence of non-specific clinical symptoms in the early stages and the lack of effective biomarkers and detection approaches. This underlines the need for biomarker identification and clinical validation, enabling earlier diagnosis, effective prognosis, and response to therapy. Apart from the traditional diagnostic biomarkers for OC, several new biomarkers have been delineated using advanced high-throughput molecular approaches in recent years. They are currently being clinically evaluated for their true diagnostic potential. In this chapter, we document the commonly utilized traditional screening markers and recently identified emerging biomarkers in OC diagnosis, focusing on secretory and protein biomarkers. We also briefly reviewed the recent advances and prospects in OC diagnosis.
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Affiliation(s)
- Tarang Sharma
- Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Sabah Nisar
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tariq Masoodi
- Laboratory of Cancer immunology and genetics, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Jammu and Kashmir, India
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ammira Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar
| | - Tej K Pandita
- Center for Genomics and Precision Medicine, Texas A&M College of Medicine, Houston, TX, United States
| | - Mayank Singh
- Department of Medical Oncology, Dr. B.R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Program, Sidra Medicine, Doha, Qatar.
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DiSilvestro P, Banerjee S, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, McNamara J, Lowe ES, Ah-See ML, Moore KN. Overall Survival With Maintenance Olaparib at a 7-Year Follow-Up in Patients With Newly Diagnosed Advanced Ovarian Cancer and a BRCA Mutation: The SOLO1/GOG 3004 Trial. J Clin Oncol 2023; 41:609-617. [PMID: 36082969 PMCID: PMC9870219 DOI: 10.1200/jco.22.01549] [Citation(s) in RCA: 219] [Impact Index Per Article: 109.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
PURPOSE In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting. METHODS This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up. RESULTS The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups. CONCLUSION Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.
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Affiliation(s)
- Paul DiSilvestro
- Program in Women's Oncology, Women & Infants Hospital, Providence, RI
- Paul DiSilvestro, MD, Women & Infants Hospital, 101 Dudley St, Providence, RI 02905; e-mail:
| | - Susana Banerjee
- The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, United Kingdom
| | - Nicoletta Colombo
- University of Milan-Bicocca and Istituto Europeo di Oncologia IRCCS, Milan, Italy
| | - Giovanni Scambia
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Byoung-Gie Kim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ana Oaknin
- Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Michael Friedlander
- University of New South Wales Clinical School, Prince of Wales Hospital, Randwick, New South Wales, Australia
| | | | - Anne Floquet
- Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France
- Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France
| | - Alexandra Leary
- Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens, Paris, France
- Institut Gustave-Roussy, Villejuif, France
| | - Gabe S. Sonke
- The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Charlie Gourley
- Cancer Research UK Scotland Center, University of Edinburgh, Edinburgh, United Kingdom
| | - Amit Oza
- Princess Margaret Cancer Center, Toronto, ON, Canada
| | - Antonio González-Martín
- Clínica Universidad de Navarra, Madrid, Spain
- Program In Solid Tumours, CIMA, Pamplona, Spain
| | | | - William Bradley
- Froedtert and the Medical College of Wisconsin, Milwaukee, WI
| | - Cara Mathews
- Program in Women's Oncology, Women & Infants Hospital, Providence, RI
| | - Joyce Liu
- Dana-Farber Cancer Institute, Boston, MA
| | - John McNamara
- Biostatistics, Oncology Biometrics, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
| | - Elizabeth S. Lowe
- Global Medicines Development, Oncology, AstraZeneca, Gaithersburg, MD
| | - Mei-Lin Ah-See
- Oncology R&D, Late-stage Development, AstraZeneca, Cambridge, United Kingdom
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Hu Q, Shen G, Li Y, Xie Y, Ma X, Jiang L, Lv Q. Lymphocyte-to-monocyte ratio after primary surgery is an independent prognostic factor for patients with epithelial ovarian cancer: A propensity score matching analysis. Front Oncol 2023; 13:1139929. [PMID: 37035193 PMCID: PMC10075326 DOI: 10.3389/fonc.2023.1139929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Accepted: 02/27/2023] [Indexed: 04/11/2023] Open
Abstract
Background The aim of this study was to elucidate the prognostic value of preoperative lymphocyte-to-monocyte ratio (LMR) after primary surgery in epithelial ovarian cancer (EOC) patients using a propensity score matching (PSM) analysis. Methods We retrospectively reviewed consecutive EOC patients who underwent primary surgery between January 2008 and December 2019. Patients were divided into two groups according to the optimal cutoff value of preoperative LMR. PSM (1:1) was conducted to eliminate confounding factors. A Cox proportional hazards model and the Kaplan-Meier estimator were employed to investigate the potential prognostic factors. Results A total of 368 EOC patients were included in this study. The optimal cutoff value of LMR was identified as 4.65. Low preoperative LMR was significantly correlated with low albumin, high CA125 level, more blood loss, a high likelihood of ascites, advanced FIGO stage, and poor differentiation (all p < 0.05). After matching, Kaplan-Meier curves showed that the group with LMR < 4.65 experienced significantly shorter OS (p = 0.015). Multivariate Cox analysis revealed that low LMR (HR = 1.49, p = 0.041), advanced FIGO stage (HR = 5.25, p < 0.001), and undefined residual disease (HR = 3.77, p = 0.002) were independent factors in predicting poor OS. A forest plot revealed that LMR had better prognostic value in younger EOC patients, patients with BMI ≥ 25 kg/m2 and albumin ≥ 35 g/L, CA125 ≥ 35 U/L, patients who had undergone optimal surgery, and those who had completed chemotherapy. Additionally, low-LMR patients who had undergone incomplete chemotherapy had a shorter median OS compared with those who completed chemotherapy treatment (48.5 vs. 105.9 months, p = 0.026). Conclusions LMR could be used as an independent prognostic factor for EOC patients after primary surgery; a noticeable negative effect of LMR was observed among EOC patients with age < 65, good preoperative nutritional status, and more aggressive tumor biology, and among those who underwent optimal surgery. Completing adjuvant chemotherapy is essential to improve survival outcomes among EOC patients with LMR < 4.65 after surgery.
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Affiliation(s)
- Qian Hu
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Guihua Shen
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ye Li
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Ya Xie
- Gynecology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiao Ma
- Department of Obstetrics and Gynecology, Beijing Pinggu Hospital, Beijing, China
| | - Lijuan Jiang
- Department of Obstetrics and Gynecology, Shunyi Maternal and Children’s Hospital of Beijing Children’s Hospital, Beijing, China
| | - Qiubo Lv
- Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Qiubo Lv,
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14
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Implementation of Comprehensive Genomic Profiling in Ovarian Cancer Patients: A Retrospective Analysis. Cancers (Basel) 2022; 15:cancers15010218. [PMID: 36612212 PMCID: PMC9818378 DOI: 10.3390/cancers15010218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/17/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted.
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15
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Philpott S, Raikou M, Manchanda R, Lockley M, Singh N, Scott M, Evans DG, Adlard J, Ahmed M, Edmondson R, Woodward ER, Lamnisos A, Balega J, Brady AF, Sharma A, Izatt L, Kulkarni A, Tripathi V, Solomons JS, Hayes K, Hanson H, Snape K, Side L, Skates S, McGuire A, Rosenthal AN. The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants in BRCA1and BRCA2. J Med Genet 2022; 60:440-449. [PMID: 36319079 PMCID: PMC10176325 DOI: 10.1136/jmg-2022-108741] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/17/2022] [Indexed: 11/22/2022]
Abstract
BackgroundOur study aimed to establish ‘real-world’ performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germlineBRCA1/2variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).MethodsOur study recruited 875 femaleBRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation.ResultsOur study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9–100), 75% (34.9–96.8) and 99.9% (99.9–100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY.ConclusionOC surveillance for women deferring RRSO in a ‘real-world’ setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for femaleBRCA-heterozygotes who are deferring such surgery.
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Affiliation(s)
- Sue Philpott
- North Central London Cancer Alliance, University College London Hospitals NHS Foundation Trust, London, UK
| | - Maria Raikou
- Department of Economics, University of Piraeus, Athens, Greece
- Health Economics, The London School of Economics and Political Science, London, UK
| | - Ranjit Manchanda
- Department of Gynaecological Oncology, Barts Health NHS Trust, London, UK
- London School of Hygiene and Tropical Medicine, London, UK
- Wolfsen Institue of Population Health Medicine, Barts CRUK Cancer Centre, Queen Mary University of London, London, UK
| | - Michelle Lockley
- Centre for Cancer genomics and Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, London, UK
| | - Naveena Singh
- Department of Cellular Pathology, Barts Health NHS Trust, London, London, UK
| | - Malcolm Scott
- Familial Cancer Clinic, Department of Gynaecology, University College London Hospitals NHS Foundation Trust, London, London, UK
| | - D Gareth Evans
- Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, Manchester, UK
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Julian Adlard
- Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, West Yorkshire, UK
| | - Munaza Ahmed
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, London, UK
| | - Richard Edmondson
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, St Mary's Hospital, University of Manchester, Manchester, UK, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Emma Roisin Woodward
- Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, Manchester, UK
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | | | - Janos Balega
- Birmingham City Hospital, Birmingham, Birmingham, UK
| | - Angela F Brady
- North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Harrow, London, UK
| | - Aarti Sharma
- University Hospital of Wales Healthcare NHS Trust, Heath Park, Cardiff, UK
| | - Louise Izatt
- Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, London, UK
- Medical and Molecular Genetics, King's College London Faculty of Life Sciences and Medicine, London, UK
| | - Anjana Kulkarni
- Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, London, UK
| | - Vishakha Tripathi
- Department of Clinical Genetics, Guy's and St Thomas' Hospitals NHS Trust, London, London, UK
| | - Joyce S Solomons
- Oxford Centre for Genomic Medicine (OXGeM), Oxford University Hospitals NHS Trust, Oxford, UK
| | - Kevin Hayes
- St George's University Hospitals NHS Foundation Trust, London, London, UK
| | - Helen Hanson
- 23 Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Katie Snape
- Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK
- IMBE, University of London St George's, London, UK
| | - Lucy Side
- 25, Wesses Clinical Genetics Service, University Hospitals Southampton, Southampton, Southampton, UK
| | - Steve Skates
- Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alistair McGuire
- Health Economics, The London School of Economics and Political Science, London, London, UK
| | - Adam N Rosenthal
- Familial Cancer Clinic, Department of Gynaecology, University College London Hospitals NHS Foundation Trust, London, London, UK
- Gynaecological Oncology, University College London EGA Institute for Women's Health Department of Women's Cancer, London, London, UK
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Heemskerk-Gerritsen BAM, Hollestelle A, van Asperen CJ, van den Beek I, van Driel WJ, van Engelen K, Gómez Garcia EB, de Hullu JA, Koudijs MJ, Mourits MJE, Hooning MJ, Boere IA. Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: A matched cohort study. PLoS One 2022; 17:e0275015. [PMID: 36137114 PMCID: PMC9498928 DOI: 10.1371/journal.pone.0275015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 09/08/2022] [Indexed: 11/19/2022] Open
Abstract
Introduction
Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking.
Methods
We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage (< = IIA/> = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls.
Results
The median follow-up was 4.4 years (range 0.1–30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74–1.04) and BRCA2 (HR 0.58, 95% CI 0.41–0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58–0.84) and BRCA2 (HR 0.41, 95% CI 0.29–0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients.
Conclusion
For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis.
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Affiliation(s)
| | | | - Christi J. van Asperen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Irma van den Beek
- Department of Human Genetics, Amsterdam University Medical Center (University of Amsterdam), Amsterdam, the Netherlands
| | | | - Klaartje van Engelen
- Department of Clinical Genetics, Amsterdam University Medical Center (VUmc), Amsterdam, the Netherlands
| | - Encarna B. Gómez Garcia
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Joanne A. de Hullu
- Department of Obstetrics & Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Marco J. Koudijs
- Department of Biomedical Genetics, Utrecht University Medical Center, Utrecht, the Netherlands
| | - Marian J. E. Mourits
- Department of Gynecologic Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | - Maartje J. Hooning
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Ingrid A. Boere
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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Moore G, Majumdar R, Powell SN, Khan AJ, Weinhold N, Yin S, Higginson DS. Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer. Mol Cancer Res 2022; 20:1061-1070. [PMID: 35385581 PMCID: PMC9372910 DOI: 10.1158/1541-7786.mcr-21-1012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/14/2022] [Accepted: 04/01/2022] [Indexed: 01/09/2023]
Abstract
Cancer cells defective in homologous recombination (HR) are responsive to DNA-crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta (Pol θ), a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic biallelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single-base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we used what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor Pol θ to design and test novel signatures of polymerase theta-mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions (TINS). We find that TINS consistent with TMEJ repair are highly specific to tumors with pathogenic biallelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. In addition, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared with current state-of-the-art signatures. IMPLICATIONS Small, templated insertions indicative of theta-mediated end-joining likely can be used in conjunction with other HRD mutational signatures as a prognostic tool for patient response to therapies targeting HR deficiency.
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Affiliation(s)
- Grace Moore
- Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065
| | - Rahul Majumdar
- Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065
| | - Simon N. Powell
- Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065
| | - Atif J. Khan
- Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065
| | - Nils Weinhold
- Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065
| | - Shen Yin
- Epidemiology & Biostatistics, Memorial Sloan Kettering
Cancer Center, New York, NY 10065
| | - Daniel S. Higginson
- Department of Radiation Oncology, Memorial Sloan Kettering
Cancer Center, New York, NY 10065.,Corresponding author: Daniel S.
Higginson, Department of Radiation Oncology, Memorial Sloan Kettering Cancer
Center, 1275 York Ave Box #22, New York, NY 10065; Phone: (646) 888-3567;
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18
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Tinker AV, Altman AD, Bernardini MQ, Ghatage P, Gien LT, Provencher D, Salvador S, Doucette S, Oza AM. A Pan-Canadian Consensus Statement on First-Line PARP Inhibitor Maintenance for Advanced, High-Grade Serous and Endometrioid Tubal, Ovarian, and Primary Peritoneal Cancers. Curr Oncol 2022; 29:4354-4369. [PMID: 35735457 PMCID: PMC9221681 DOI: 10.3390/curroncol29060348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 11/16/2022] Open
Abstract
The majority of patients with advanced, high-grade epithelial-tubo ovarian cancer (EOC) respond well to initial treatment with platinum-based chemotherapy; however, up to 80% of patients will experience a recurrence. Poly(ADP-ribose) Polymerase (PARP) inhibitors have been established as a standard of care maintenance therapy to prolong remission and prevent relapse following a response to first-line platinum-chemotherapy. Olaparib and niraparib are the PARP inhibitors currently approved for use in the first-line maintenance setting in Canada. Selection of maintenance therapy requires consideration of patient and tumour factors, presence of germline and somatic mutations, expected drug toxicity profile, and treatment access. This paper discusses the current clinical evidence for first-line PARP inhibitor maintenance therapy in patients with advanced, high-grade EOC and presents consensus statements and a treatment algorithm to aid Canadian oncologists on the selection and use of PARP inhibitors within the Canadian EOC treatment landscape.
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Affiliation(s)
- Anna V. Tinker
- Division of Medical Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada;
- Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Alon D. Altman
- Division of Gynecologic Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada;
- Department of Obstetrics Gynecology and Reproductive Sciences, University of Manitoba, Winnipeg, MB R3A 1R9, Canada
| | - Marcus Q. Bernardini
- Division of Gynecologic Oncology, Princess Margaret Cancer Center, University Health Network, Sinai Health System, Toronto, ON M5B 2M9, Canada;
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1X8, Canada;
| | - Prafull Ghatage
- Department of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary, AB T2N 4N2, Canada;
- Department of Gynecological Oncology, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Lilian T. Gien
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1X8, Canada;
- Division of Gynecologic Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
| | - Diane Provencher
- Institut du Cancer de Montréal, Centre Hospitalier de l’Université de Montréal (CHUM), Montreal, QC H2X 0A9, Canada;
- Division of Gynecologic Oncology, Université de Montréal, Montreal, QC H3T 1J4, Canada
| | - Shannon Salvador
- Department of Obstetrics and Gynecology, McGill University Jewish General Hospital, Montreal, QC H3T 1E2, Canada;
| | | | - Amit M. Oza
- Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1X8, Canada;
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada
- Correspondence:
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19
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Wang Y, Li N, Ren Y, Zhao J. Association of BRCA1/2 mutations with prognosis and surgical cytoreduction outcomes in ovarian cancer patients: An updated meta-analysis. J Obstet Gynaecol Res 2022; 48:2270-2284. [PMID: 35698734 DOI: 10.1111/jog.15326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/05/2022] [Accepted: 05/29/2022] [Indexed: 11/28/2022]
Abstract
AIM This meta-analysis was conducted to evaluate the impact of BRCA mutations on survival outcomes of ovarian cancer patients and assess whether the BRCA status was an independent predictor of complete cytoreduction. METHODS We searched the PubMed, Cochrane, EMBASE, Scopus, Web of Science, and Google Scholar databases for studies that evaluated the associations among BRCA mutations, ovarian cancer survival and surgical cytoreduction before August 2021 based on specific inclusion and exclusion criteria. RESULTS We identified 61 articles that compared the clinical features, survival outcomes, and optimal surgical cytoreduction rates between BRCA-positive patients and BRCA-negative patients. The results showed that BRCA mutation carriers were diagnosed with ovarian cancer at a younger age than the age at which nonmutation carriers were diagnosed. In addition, BRCA mutation carriers were more likely to be in the International Federation of Gynecology and Obstetrics (FIGO) stage III-IV, and the pathological grade was commonly grade 3. The pathological type of BRCA mutation carriers was more likely to be high-grade serous carcinoma. Patients with BRCA mutations had higher response rates to platinum-based chemotherapy than the noncarriers. However, patients in both groups had equivalent rates of surgical cytoreduction, and BRCA-positive patients had longer overall survival (OS) time (HR = 0.65; 95% confidence interval [CI]: 0.59, 0.73; p < 0.001) and longer progression-free survival (PFS) (HR = 0.72; 95% CI: 0.63, 0.82; p < 0.001). CONCLUSION BRCA mutations appear to be associated with improved OS and PFS in patients with ovarian cancer. However, we did not find any difference in the surgical resection rate between participants in the two groups.
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Affiliation(s)
- Yazhuo Wang
- Department of Gynaecology, Hebei General Hospital, Shijiazhuang, China
| | - Na Li
- Department of Gynaecology, Hebei General Hospital, Shijiazhuang, China
| | - Yanan Ren
- Department of Gynaecology, Hebei General Hospital, Shijiazhuang, China
| | - Jing Zhao
- Department of Gynaecology, Hebei General Hospital, Shijiazhuang, China
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20
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Paik ES, Heo EJ, Choi CH, Kim JH, Kim JW, Kim YM, Park SY, Lee JW, Kim JW, Kim BG. Prevalence and clinical characterization of BRCA1 and BRCA2 mutations in Korean patients with epithelial ovarian cancer. Cancer Sci 2021; 112:5055-5067. [PMID: 34657357 PMCID: PMC8645710 DOI: 10.1111/cas.15166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/24/2022] Open
Abstract
This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian cancer (EOC). Two‐hundred and ninety‐eight Korean women diagnosed with high‐grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first‐line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.
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Affiliation(s)
- E Sun Paik
- Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Jin Heo
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chel Hun Choi
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Hoon Kim
- Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University School of Medicine, Seoul, Korea
| | - Jae-Weon Kim
- Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul National University School of Medicine, Seoul, Korea
| | - Yong-Man Kim
- Department of Obstetrics and Gynecology, Asan Medical Center, Ulsan University School of Medicine, Seoul, Korea
| | - Sang-Yoon Park
- Center for Uterine Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Jeong-Won Lee
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Won Kim
- Department of Clinical Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byoung-Gie Kim
- Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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21
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Berek JS, Renz M, Kehoe S, Kumar L, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum: 2021 update. Int J Gynaecol Obstet 2021; 155 Suppl 1:61-85. [PMID: 34669199 PMCID: PMC9298325 DOI: 10.1002/ijgo.13878] [Citation(s) in RCA: 209] [Impact Index Per Article: 52.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSC). Stage IC is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies.
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Affiliation(s)
- Jonathan S. Berek
- Stanford Women’s Cancer CenterStanford Cancer InstituteStanford University School of MedicineStanfordCaliforniaUSA
| | - Malte Renz
- Stanford Women’s Cancer CenterStanford Cancer InstituteStanford University School of MedicineStanfordCaliforniaUSA
| | - Sean Kehoe
- Oxford Gynecological Cancer CenterChurchill HospitalOxfordUK
- St Peter’s CollegeOxfordUK
| | - Lalit Kumar
- Department of Medical OncologyAll India Institute of Medical SciencesNew DelhiIndia
| | - Michael Friedlander
- Royal Hospital for WomenSydneyAustralia
- Prince of Wales Clinical SchoolUniversity of New South WalesSydneyAustralia
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22
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Radu MR, Prădatu A, Duică F, Micu R, Creţoiu SM, Suciu N, Creţoiu D, Varlas VN, Rădoi VE. Ovarian Cancer: Biomarkers and Targeted Therapy. Biomedicines 2021; 9:693. [PMID: 34207450 PMCID: PMC8235073 DOI: 10.3390/biomedicines9060693] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 12/25/2022] Open
Abstract
Ovarian cancer is one of the most common causes of death in women as survival is highly dependent on the stage of the disease. Ovarian cancer is typically diagnosed in the late stage due to the fact that in the early phases is mostly asymptomatic. Genomic instability is one of the hallmarks of ovarian cancer. While ovarian cancer is stratified into different clinical subtypes, there still exists extensive genetic and progressive diversity within each subtype. Early detection of the disorder is one of the most important steps that facilitate a favorable prognosis and a good response to medical therapy for the patients. In targeted therapies, individual patients are treated by agents targeting the changes in tumor cells that help them grow, divide and spread. Currently, in gynecological malignancies, potential therapeutic targets include tumor-intrinsic signaling pathways, angiogenesis, homologous-recombination deficiency, hormone receptors, and immunologic factors. Ovarian cancer is usually diagnosed in the final stages, partially due to the absence of an effective screening strategy, although, over the times, numerous biomarkers have been studied and used to assess the status, progression, and efficacy of the drug therapy in this type of disorder.
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Affiliation(s)
- Mihaela Raluca Radu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
| | - Alina Prădatu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
| | - Florentina Duică
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
| | - Romeo Micu
- Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Sanda Maria Creţoiu
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Nicolae Suciu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
- Division of Obstetrics, Gynecology and Neonatology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, 020395 Bucharest, Romania;
| | - Dragoş Creţoiu
- Fetal Medicine Excellence Research Center, Alessandrescu-Rusescu National Institute for Mother and Child Health, 020395 Bucharest, Romania; (M.R.R.); (A.P.); (F.D.); (N.S.)
- Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Valentin Nicolae Varlas
- Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, 01171 Bucharest, Romania
- Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 030167 Bucharest, Romania
| | - Viorica Elena Rădoi
- Department of Obstetrics and Gynecology, Alessandrescu-Rusescu National Institute for Mother and Child Health, Polizu Clinical Hospital, 020395 Bucharest, Romania;
- Department of Medical Genetics, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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23
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Toss A, Piombino C, Tenedini E, Bologna A, Gasparini E, Tarantino V, Filieri ME, Cottafavi L, Giovanardi F, Madrigali S, Civallero M, Marcheselli L, Marchi I, Domati F, Venturelli M, Barbieri E, Grandi G, Tagliafico E, Cortesi L. The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study. Diagnostics (Basel) 2021; 11:565. [PMID: 33801055 PMCID: PMC8003908 DOI: 10.3390/diagnostics11030565] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 12/17/2022] Open
Abstract
Previous research involving epithelial ovarian cancer patients showed that, compared to germline BRCA (gBRCA) mutations, somatic BRCA (sBRCA) mutations present a similar positive impact with regard to overall survival (OS) and platinum and PARP (poly (ADP-ribose) polymerase) inhibitor sensitivity. Nevertheless, molecular testing in these studies did not include copy number variation (CNV) analyses of BRCA genes. The aim of this study was to explore the prognostic and predictive role of sBRCA mutations as compared to gBRCA mutations in patients who were also tested for CNVs. Among the 158 patients included in the study, 17.09% of patients carried a pathogenic or likely pathogenic gBRCA variant and 15.19% of patients presented pathogenetic or likely pathogenic sBRCA variants and/or CNVs. Overall, 81.6% of the patients included in this study were diagnosed with a serous histotype, and 77.2% were in advanced stages. Among women diagnosed in advanced stages, gBRCA patients showed better progression-free survival and OS as compared to sBRCA and wild-type patients, whereas sBRCA patients did not show any advantage in outcome as compared to wild-type patients. In this study, the introduction of CNV analyses increased the detection rate of sBRCA mutations, and the resulting classification among gBRCA, sBRCA and wild-type patients was able to properly stratify the prognosis of OC patients. Particularly, sBRCA mutation patients failed to show any outcome advantage as compared to wild-type patients.
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Affiliation(s)
- Angela Toss
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Transplant Surgery, Oncology and Regenerative Medicine Relevance, University of Modena and Reggio Emilia, 41124 Modena, Italy;
| | - Claudia Piombino
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
| | - Elena Tenedini
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (E.T.); (E.T.)
| | - Alessandra Bologna
- Department of Oncology, Arcispedale S. Maria Nuova IRCCS, 42123 Reggio Emilia, Italy; (A.B.); (E.G.)
| | - Elisa Gasparini
- Department of Oncology, Arcispedale S. Maria Nuova IRCCS, 42123 Reggio Emilia, Italy; (A.B.); (E.G.)
| | - Vittoria Tarantino
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, 41124 Modena, Italy;
| | | | - Luca Cottafavi
- Oncology Unit, Azienda Unità Sanitaria Locale di Modena, Ramazzini Hospital, 41012 Carpi, Italy;
| | - Filippo Giovanardi
- Medical Oncology Unit, Azienda Unità Sanitaria Locale, IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (F.G.); (S.M.)
| | - Stefano Madrigali
- Medical Oncology Unit, Azienda Unità Sanitaria Locale, IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy; (F.G.); (S.M.)
| | - Monica Civallero
- Department of Surgery, Medicine, Dentistry and Morphological Sciences with Transplant Surgery, Oncology and Regenerative Medicine Relevance, University of Modena and Reggio Emilia, 41124 Modena, Italy;
| | - Luigi Marcheselli
- Fondazione Italiana Linfomi (FIL), Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy;
| | - Isabella Marchi
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
| | - Federica Domati
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
| | - Marta Venturelli
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
| | - Elena Barbieri
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
| | - Giovanni Grandi
- Department of Obstetrics, Gynecology and Pediatrics, Obstetrics and Gynecology Unit, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy;
| | - Enrico Tagliafico
- Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, 41124 Modena, Italy; (E.T.); (E.T.)
- Department of Laboratory Medicine and Pathology, Diagnostic Hematology and Clinical Genomics Unit, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy
- Center for Genome Research University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Laura Cortesi
- Department of Oncology and Hematology, Azienda Ospedaliero Universitaria di Modena, 41124 Modena, Italy; (A.T.); (C.P.); (I.M.); (F.D.); (M.V.); (E.B.)
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24
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BECN1 and BRCA1 Deficiency Sensitizes Ovarian Cancer to Platinum Therapy and Confers Better Prognosis. Biomedicines 2021; 9:biomedicines9020207. [PMID: 33670664 PMCID: PMC7922320 DOI: 10.3390/biomedicines9020207] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/21/2021] [Accepted: 02/12/2021] [Indexed: 12/13/2022] Open
Abstract
Background: BRCA1, BECN1 and TP53 are three tumor suppressor genes located on chromosome 17 and frequently found deleted, silenced, or mutated in many cancers. These genes are involved in autophagy, apoptosis, and drug resistance in ovarian cancer. Haploinsufficiency or loss-of-function of either TP53, BRCA1 or BECN1 correlates with enhanced predisposition to cancer development and progression, and chemoresistance. Expectedly, the combined altered expression of these three tumor suppressor genes worsens the prognosis of ovarian cancer patients. However, whether such a genotypic pattern indeed affects the chemo-responsiveness to standard chemotherapy thus worsening patients’ survival has not been validated in a large cohort of ovarian cancer patients. Aim: We interrogated datasets from the TCGA database to analyze how the expression of these three tumor suppressor genes impacts on the clinical response to platinum-based chemotherapy thus affecting the survival of ovarian cancer patients. Results and conclusion: Compared to EOC with homozygous expression of BECN1 and BRCA1, tumors expressing low mRNA expression of these two tumor suppressor genes (either because of shallow (monoallelic) co-deletion or of promoter hypermethylation), showed higher sensitivity to platinum-based therapies and were associated with a better prognosis of ovarian cancer-bearing patients. This outcome was independent of TP53 status, though it was statistically more significant in the cohort of patients with mutated TP53. Thus, sensitivity to platinum therapy (and probably to other chemotherapeutics) correlates with low expression of a combination of critical tumor suppressor genes. Our study highlights the importance of thoroughly assessing the genetic lesions of the most frequently mutated genes to stratify the patients in view of a personalized therapy. More importantly, the present findings suggest that targeting the function of both BECN1 and BRCA1 could be a strategy to restore chemosensitivity in refractory tumors.
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25
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Shui L, Ren H, Yang X, Li J, Chen Z, Yi C, Zhu H, Shui P. The Era of Radiogenomics in Precision Medicine: An Emerging Approach to Support Diagnosis, Treatment Decisions, and Prognostication in Oncology. Front Oncol 2021; 10:570465. [PMID: 33575207 PMCID: PMC7870863 DOI: 10.3389/fonc.2020.570465] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 12/08/2020] [Indexed: 02/05/2023] Open
Abstract
With the rapid development of new technologies, including artificial intelligence and genome sequencing, radiogenomics has emerged as a state-of-the-art science in the field of individualized medicine. Radiogenomics combines a large volume of quantitative data extracted from medical images with individual genomic phenotypes and constructs a prediction model through deep learning to stratify patients, guide therapeutic strategies, and evaluate clinical outcomes. Recent studies of various types of tumors demonstrate the predictive value of radiogenomics. And some of the issues in the radiogenomic analysis and the solutions from prior works are presented. Although the workflow criteria and international agreed guidelines for statistical methods need to be confirmed, radiogenomics represents a repeatable and cost-effective approach for the detection of continuous changes and is a promising surrogate for invasive interventions. Therefore, radiogenomics could facilitate computer-aided diagnosis, treatment, and prediction of the prognosis in patients with tumors in the routine clinical setting. Here, we summarize the integrated process of radiogenomics and introduce the crucial strategies and statistical algorithms involved in current studies.
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Affiliation(s)
- Lin Shui
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Haoyu Ren
- Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany
| | - Xi Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Li
- Department of Pharmacy, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, China
| | - Ziwei Chen
- Department of Nephrology, Chengdu Integrated TCM and Western Medicine Hospital, Chengdu, China
| | - Cheng Yi
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Pixian Shui
- School of Pharmacy, Southwest Medical University, Luzhou, China
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Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, Elkhanany A, Friedman S, Goggins M, Hutton ML, Karlan BY, Khan S, Klein C, Kohlmann W, Kurian AW, Laronga C, Litton JK, Mak JS, Menendez CS, Merajver SD, Norquist BS, Offit K, Pederson HJ, Reiser G, Senter-Jamieson L, Shannon KM, Shatsky R, Visvanathan K, Weitzel JN, Wick MJ, Wisinski KB, Yurgelun MB, Darlow SD, Dwyer MA. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:77-102. [DOI: 10.6004/jnccn.2021.0001] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.
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Affiliation(s)
| | - Tuya Pal
- 2Vanderbilt-Ingram Cancer Center
| | - Michael P. Berry
- 3St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center
| | | | - Patricia Dickson
- 5Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | | | - Michael Goggins
- 9The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | - Seema Khan
- 12Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | | | | | | | | | | | | | - Holly J. Pederson
- 22Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
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You Y, Li L, Lu J, Wu H, Wang J, Gao J, Wu M, Liang Z. Germline and Somatic BRCA1/2 Mutations in 172 Chinese Women With Epithelial Ovarian Cancer. Front Oncol 2020; 10:295. [PMID: 32211327 PMCID: PMC7077344 DOI: 10.3389/fonc.2020.00295] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 02/20/2020] [Indexed: 12/17/2022] Open
Abstract
Objective: Despite several nationwide cohort studies of germline BRCA1/2 mutations and several small cohort studies of somatic BRCA1/2 mutations in Chinese epithelial ovarian cancer (EOC) patients, little is known about the impact of these findings on survival outcomes in this population. In this study of 172 retrospectively recruited Chinese EOC patients, germline and somatic BRCA1/2 mutations and their value for predicting survival outcomes were evaluated. Methods: Unselected patients who visited the study center from January 1, 2011, to January 1, 2015, were recruited and asked to provide peripheral blood samples for this study if they were pathologically confirmed to have primary EOC. All patients received staging surgeries or debulking surgeries involving systemic platinum-based chemotherapy, and the patients were then followed up to December 1, 2017. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections and peripheral blood and sequenced for somatic and germline testing, respectively. The demographic and clinicopathological characteristics of the patients were collected to analyze the distribution of BRCA mutations in subgroups. Survival outcomes were compared among various BRCA mutation statuses using univariate and multivariate models. Results: In 58 (33.7%) patients, 63 variants were identified, including variants of unknown significance (VUS) in 18 patients (10.5%) and pathogenic or likely pathogenic variants in a partially overlapping set of 41 patients (23.8%). Germline BRCA mutations, somatic BRCA mutations, BRCA1 mutations in general, and BRCA2 mutations in general were found in 35 (20.3%), 7 (4.1%), 28 (16.3%), and 13 (7.6%) patients, respectively. Five recurrent mutations were identified. Personal and family cancer histories as well as hereditary breast and ovarian cancer (HBOC) criteria were associated with deleterious BRCA mutations both overall and in the germline specifically, whereas only age at diagnosis of EOC was associated with somatic BRCA mutations. In univariate and Cox regression analyses, patients with BRCA1/2 mutations in general had significant improvements in progression-free survival (PFS) and overall survival (OS). Conclusions: In Chinese EOC patients, the distributions and risk factors associated with germline and somatic BRCA1/2 mutations were similar to those previously reported in international studies. Deleterious BRCA mutations in general were associated with improved survival outcomes in this cohort.
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Affiliation(s)
- Yan You
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Lei Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Junliang Lu
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Huanwen Wu
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Jing Wang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Jie Gao
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Ming Wu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
| | - Zhiyong Liang
- Department of Pathology, Molecular Pathology Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China
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Amin N, Chaabouni N, George A. Genetic testing for epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol 2020; 65:125-138. [PMID: 32122773 DOI: 10.1016/j.bpobgyn.2020.01.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 01/06/2020] [Accepted: 01/08/2020] [Indexed: 12/11/2022]
Abstract
As the treatment of epithelial ovarian cancer (OC) moves further into personalised medicine, the importance of determining the presence or absence of inherited mutations in cancer susceptibility genes has grown. It is now becoming routine to test for germline mutations in the BRCA1 and BRCA2 genes, which are responsible for a significant proportion of hereditary epithelial OC and are established predictive biomarkers of potential benefit from poly ADP ribose polymerase (PARP) inhibitors. The identification of patients with hereditary OC allows the patient to benefit from personalised treatment, while allowing family members to undergo cascade testing, where identification of unaffected carriers can allow early detection, risk-reduction or prevention for both breast and OC, and ultimately improve long-term outcomes. Other susceptibility genes, include the Lynch Syndrome (mismatch repair) genes and several other genes involved in the homologous recombination pathway (HRD genes), are implicated in OC genesis, and are also becoming of increasing interest as therapeutic options grow for these patients. This review will highlight the importance of the early detection of a germline gene pathogenic variant, which informs on the clinical course of disease in a particular patient, and therefore, guides therapeutic management including risk reducing and personalised treatment.
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Affiliation(s)
- Noa Amin
- Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
| | - Narda Chaabouni
- Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
| | - Angela George
- Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK; The Institute of Cancer Research, Cotswold Road, London SM2 5NG, UK.
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Nagasawa S, Ikeda K, Horie-Inoue K, Sato S, Takeda S, Hasegawa K, Inoue S. Identification of novel mutations of ovarian cancer-related genes from RNA-sequencing data for Japanese epithelial ovarian cancer patients. Endocr J 2020; 67:219-229. [PMID: 31748433 DOI: 10.1507/endocrj.ej19-0283] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Ovarian cancer has the highest mortality rate among gynecological cancers. Gene mutations are involved in the carcinogenesis, metastasis, and therapeutic response in ovarian cancer. However, the variety and proportion of gene mutation is not fully analyzed in Japanese ovarian cancer patients, especially, in those with recurrent tumors. In the present study, RNA-sequencing was performed for 32 clinical ovarian specimens obtained from 24 Japanese patients (24 primary cancer specimens and 8 recurrent specimens paired with corresponding primary cancer specimens). Mutations in 24 primary specimens were analyzed by comparing the sequence data mapped on RefSeq genes with those in the public online databases BRCA Exchange, COSMIC, ClinVar, and cBioportal. Mutations were observed in TP53 in 16 specimens (67%), BRCA1 in 9 (38%), BRCA2 in 13 (54%), ARID1A in 3 (13%), PIK3CA in 2 (8%), KRAS in 1 (4%), PTEN in 1 (4%), and CTNNB1 in 1 (4%), excluding synonymous mutations. Among those identified muations, 13 of 14 mutations in TP53, 10 of 11 mutations of BRCA1, 10 of 23 mutation positions of BRCA2, none of 7 mutations of ARID1A, 1 mutation of PIK3CA, and 1 mutation of CTNNB1 were consistent with those reported in the public online databases; however, the other mutations identified were novel. Comparison between matched-paired specimens of primary and recurrent tumors revealed the changes of mutational status in expressed RNAs. RNA-sequencing-based mutation analysis will be useful to reveal ethnic differences of gene mutations in ovarian cancer and to understand the contribution of gene mutations to recurrence.
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Affiliation(s)
- Saya Nagasawa
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241 Saitama, Japan
- Department of Obstetrics and Gynecology, Juntendo University, Bunkyo-ku, 113-8431 Tokyo, Japan
| | - Kazuhiro Ikeda
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241 Saitama, Japan
| | - Kuniko Horie-Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241 Saitama, Japan
| | - Sho Sato
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka 350-1298 Saitama, Japan
| | - Satoru Takeda
- Department of Obstetrics and Gynecology, Juntendo University, Bunkyo-ku, 113-8431 Tokyo, Japan
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka 350-1298 Saitama, Japan
| | - Satoshi Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241 Saitama, Japan
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku 173-0015 Tokyo, Japan
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Abstract
PURPOSE OF REVIEW This review summarizes recent advances in prostate cancer (PCa) genetics. RECENT FINDINGS Upwards of 20% of metastatic castration-resistant prostate tumors (mCRPC) carry homologous recombination (HR) repair gene mutations, of which ~ 10% are germline (inherited). Another ~ 5% exhibit microsatellite instability (MSI-H) and/or mismatch repair deficiency (MMRd). Pembrolizumab is approved for tumors with MMRd, thus patients with mCRPC and MMRd are candidates for pembrolizumab. Emerging data indicate that platinum chemotherapy and poly ADP-ribose polymerase inhibitors (PARPi) are effective in PCa exhibiting HR deficiency. NCCN guidelines now recommend germline and somatic tumor testing in specific clinical scenarios due to treatment and family implications. Genetic testing in PCa patients may inform prognosis, treatment options, and have implications for family counseling. PARPi, platinum chemotherapy, and immune checkpoint inhibitors are promising targeted therapies for PCa with specific molecular features. Therapeutic advances, along with importance to relatives, are driving genetic testing in prostate cancer.
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Affiliation(s)
- Alexandra O Sokolova
- Department of Medicine, University of Washington, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave E, Seattle, WA, 98109, USA
- VA Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA, 98108, USA
| | - Heather H Cheng
- Department of Medicine, University of Washington, Washington, USA.
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave E, Seattle, WA, 98109, USA.
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31
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Ovarian cancer: An update on imaging in the era of radiomics. Diagn Interv Imaging 2019; 100:647-655. [DOI: 10.1016/j.diii.2018.11.007] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 11/23/2018] [Accepted: 11/26/2018] [Indexed: 12/13/2022]
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Li W, Shao D, Li L, Wu M, Ma S, Tan X, Zhong S, Guo F, Wang Z, Ye M. Germline and somatic mutations of multi-gene panel in Chinese patients with epithelial ovarian cancer: a prospective cohort study. J Ovarian Res 2019; 12:80. [PMID: 31472684 PMCID: PMC6717355 DOI: 10.1186/s13048-019-0560-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 08/27/2019] [Indexed: 01/11/2023] Open
Abstract
Background Multiple targeted gene sequencing is seldom performed in both germline and somatic testing for ovarian cancer. This study is to evaluate the specific genetic alterations, including both somatic and germline mutations, in Chinese patients with epithelial ovarian cancer (EOC) in a prospective cohort study. Materials and methods Mutations in a customed 21-gene panel that included BRCA1, BRCA2, and 19 other tumor suppressor genes related to homologous recombination (HR) deficiency or non-HR deficiency were detected by targeted exon capture and next-generation sequencing (NGS) technology across all coding exons and exon-intron (±20 base pairs) boundaries. Patients were enrolled consecutively and unselectively without age or family history consideration. Sixty-two unselected patients with epithelial ovarian cancer were enrolled in our study to be tested for paired somatic and germline mutations. All patients were tested using a 21-gene panel that included BRCA1, BRCA2, CHEK2, PALB2, BRIP1, TP53, PTEN, STK11, CDH1, ATM, BARD1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PMS1, PMS2, RAD50, and RAD51C. Results Mutation analysis revealed that 77.4% (48/62) of patients carried one or more of 64 identified genetic alterations, including 19 germline and 45 somatic deleterious mutations. Twelve individuals shared both germline and somatic mutations. BRCA mutants existed in 17 of 62 (27.4%) patients. Of the 64 mutations detected, 46 (74.2%) were in 7 other HR or non-HR genes, including TP53, PTEN, ATM, CHEK2, PALB2, RAD51C, and STK11. In somatic mutation analysis, TP53 showed frequent pathogenic or likely pathogenic mutations in 56.5% (35/62) of enrolled cases, among which six cases harbored a loss of heterozygosity. Conclusions This is the first report of multi-gene panel testing for germline and somatic mutations among Chinese EOC patients, which revealed a broader deleterious variants than only BRCA testing. Registration Registration No. NCT03015376, clinicaltrials.gov, registered on January 10, 2017. Electronic supplementary material The online version of this article (10.1186/s13048-019-0560-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wenhui Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China
| | - Di Shao
- BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China.,BGI-Guangzhou Medical Laboratory, BGI-Shenzhen, Guangzhou, 510006, China
| | - Lei Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
| | - Ming Wu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.
| | - Shuiqing Ma
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China
| | - Xianjie Tan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China
| | - Sen Zhong
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China
| | - Fengming Guo
- BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China.,BGI-Guangzhou Medical Laboratory, BGI-Shenzhen, Guangzhou, 510006, China
| | - Zhe Wang
- BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China
| | - Mingzhi Ye
- BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China.,BGI-Guangzhou Medical Laboratory, BGI-Shenzhen, Guangzhou, 510006, China
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Jorge S, Swisher EM, Norquist BM, Pennington KP, Gray HJ, Urban RR, Garcia RL, Doll KM. Patterns and duration of primary and recurrent treatment in ovarian cancer patients with germline BRCA mutations. Gynecol Oncol Rep 2019; 29:113-117. [PMID: 31467964 PMCID: PMC6710556 DOI: 10.1016/j.gore.2019.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/03/2019] [Accepted: 08/06/2019] [Indexed: 12/17/2022] Open
Abstract
The objectives of this study were to describe the patterns and duration of primary and recurrent treatment in patients with ovarian cancer (OC) harboring germline BRCA1 and BRCA2 (BRCA) mutations. A retrospective review of BRCA mutation carriers with advanced, high-grade OC diagnosed between 2004 and 2014 with at least 3 years of follow-up (or until death) was undertaken. Descriptive statistics were calculated and a Swimmer's Plot used to depict disease course. Forty BRCA mutation carriers (26 BRCA1, 14 BRCA2) were identified. Mean age was 54 (range 32–77). All had cytoreductive surgery and received platinum chemotherapy. Median platinum-free interval was 11.9 months (IQR 3.6–21.9). Among 28 patients who recurred, median number of treatment lines was 4 (IQR 3–6), with a median of 2 (IQR 2–3) platinum lines. On average, patients who recurred spent 32% (IQR 20–43%) of their time after diagnosis receiving cytotoxic chemotherapy and 54% (IQR 42–67%) of the time on some cancer-directed therapy, including maintenance. Median overall survival was 79.1 months from diagnosis and 25.4 months after first recurrence. In conclusion, beyond first-line therapy, there was treatment and outcome heterogeneity for BRCA-mutated OC. After OC diagnosis, patients spent close to half their life on treatment.
There was considerable heterogeneity of treatments and outcomes for BRCA-mutated ovarian carcinoma. While 15% of women had first remissions exceeding 5 years, 10% were platinum resistant. Women spent nearly half their life after ovarian cancer diagnosis on some form of cancer-directed therapy.
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Affiliation(s)
- Soledad Jorge
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Elizabeth M Swisher
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Barbara M Norquist
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Kathryn P Pennington
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Heidi J Gray
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Renata R Urban
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Rochelle L Garcia
- Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Kemi M Doll
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, USA
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Hao D, Li J, Wang J, Meng Y, Zhao Z, Zhang C, Miao K, Deng C, Tsang BK, Wang L, Di LJ. Non-classical estrogen signaling in ovarian cancer improves chemo-sensitivity and patients outcome. Theranostics 2019; 9:3952-3965. [PMID: 31281524 PMCID: PMC6587348 DOI: 10.7150/thno.30814] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 03/29/2019] [Indexed: 12/15/2022] Open
Abstract
Deficiency in homologous recombination repair (HRR) is frequently associated with hormone-responsive cancers, especially the epithelial ovarian cancer (EOC) which shows defects of HRR in up to half of cases. However, whether there are molecular connections between estrogen signaling and HRR deficiency in EOC remains unknown. Methods: We analyzed the estrogen receptor α (ERα) binding profile in EOC cell lines and investigated its association with genome instability, HRR deficiency and sensitivity to chemotherapy using extensive public datasets and in vitro/in vivo experiments. Results: We found an inverse correlation between estrogen signaling and HRR activity in EOC, and the genome-wide collaboration between ERα and the co-repressor CtBP. Though the non-classical AP-1-mediated ERα signaling, their targets were highly enriched by HRR genes. We found that depleting ERα in EOC cells up-regulates HRR activity and HRR gene expression. Consequently, estrogen signaling enhances the sensitivity of ovarian cancer cells to chemotherapy agents in vitro and in vivo. Large-scale analyses further indicate that estrogen replacement and ESR1 expression are associated with chemo-sensitivity and the favorable survival of EOC patients. Conclusion: These findings characterize a novel role of ERα in mediating the molecular connection between hormone and HRR in EOC and encourage hormone replacement therapy for EOC patients.
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35
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Kim SI, Lee M, Kim HS, Chung HH, Kim JW, Park NH, Song YS. Effect of BRCA mutational status on survival outcome in advanced-stage high-grade serous ovarian cancer. J Ovarian Res 2019; 12:40. [PMID: 31064392 PMCID: PMC6505247 DOI: 10.1186/s13048-019-0511-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 04/11/2019] [Indexed: 12/21/2022] Open
Abstract
Objective To evaluate impact of germline BRCA mutational status on prognosis in patients with advanced ovarian cancer. Methods A total of 128 patients diagnosed with FIGO stage III-IV high-grade serous ovarian cancer (HGSOC) between 2008 and 2017 and underwent BRCA1/2 gene testing at the time of or within two years from cancer diagnosis were included in this study. We compared patients’ clinicopathological characteristics and survival outcomes after primary treatment according to germline BRCA mutational status. Treatment-related factors that might affect patients’ survival outcome were also investigated. Results Germline BRCA1/2 mutations were observed in 51 women (39.8%). There were no differences in age and serum CA-125 levels at the time of HGSOC diagnosis, use of neoadjuvant chemotherapy (NAC), extent of debulking surgery, and overall survival (OS) between the BRCA mutation and wild-type BRCA groups. In contrast, the BRCA mutation group displayed longer progression-free survival (PFS) (median, 22.9 vs. 16.9 months, P = 0.001). Multivariate analyses identified germline BRCA1/2 mutation as an independent favorable prognostic factor for PFS (adjusted HR, 0.502; 95% CI, 0.318–0.795; P = 0.003). In the wild-type BRCA group, patients who received NAC as the primary treatment had shorter PFS compared to those who received primary debulking surgery (PDS) (median, 14.2 vs. 16.9 months, P = 0.003). However, in the BRCA mutation group, PFS did not differ between the NAC and PDS groups (P = 0.082). Conclusions In advanced-stage HGSOC, patients with germline BRCA1/2 mutations have better prognosis with longer PFS than those lacking BRCA mutations. Prognosis after NAC was different according to the BRCA mutational status. Electronic supplementary material The online version of this article (10.1186/s13048-019-0511-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Se Ik Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Maria Lee
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea.
| | - Hee Seung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Hyun Hoon Chung
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Jae-Weon Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Noh Hyun Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
| | - Yong-Sang Song
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul, 03080, Republic of Korea
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Lavie O, Chetrit A, Novikov I, Sadetzki S. Fifteen-year survival of invasive epithelial ovarian cancer in women with BRCA1/2 mutations – the National Israeli Study of Ovarian Cancer. Gynecol Oncol 2019; 153:320-325. [DOI: 10.1016/j.ygyno.2019.02.022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 02/04/2019] [Accepted: 02/20/2019] [Indexed: 12/24/2022]
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Guy H, Walder L, Fisher M. Cost-Effectiveness of Niraparib Versus Routine Surveillance, Olaparib and Rucaparib for the Maintenance Treatment of Patients with Ovarian Cancer in the United States. PHARMACOECONOMICS 2019; 37:391-405. [PMID: 30478649 PMCID: PMC6386009 DOI: 10.1007/s40273-018-0745-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
OBJECTIVES The aim was to evaluate the cost-effectiveness of niraparib compared with routine surveillance (RS), olaparib and rucaparib for the maintenance treatment of patients with recurrent ovarian cancer (OC). METHODS A decision-analytic model estimated the cost per quality-adjusted life-year (QALY) gained for niraparib versus RS, olaparib, and rucaparib from a US payer perspective. The model considered recurrent OC patients with or without germline BRCA mutations (gBRCAmut and non-gBRCAmut), who were responsive to their last platinum-based chemotherapy regimen. Model health states were: progression-free disease, progressed disease and dead. Mean progression-free survival (PFS) was estimated using parametric survival distributions based on ENGOT-OV16/NOVA (niraparib phase III trial), ARIEL3 (rucaparib phase III trial) and Study 19 (olaparib phase II trial). Mean overall survival (OS) benefit was estimated as double the mean PFS benefit based on the relationship between PFS and OS observed in Study 19. Costs included: drug, chemotherapy, monitoring, adverse events, and terminal care. EQ-5D utilities were estimated from trial data. RESULTS Compared to RS, niraparib was associated with an incremental cost-effectiveness ratio (ICER) of US$68,287/QALY and US$108,287/QALY for gBRCAmut and non-gBRCAmut, respectively. Compared to olaparib and rucaparib, niraparib decreased costs and increased QALYs, with a cost saving of US$8799 and US$22,236 versus olaparib and US$198,708 and US$73,561 versus rucaparib for gBRCAmut and non-gBRCAmut, respectively. CONCLUSIONS Niraparib was estimated to be less costly and more effective compared to olaparib and rucaparib, and the ICER fell within an acceptable range compared to RS. Therefore, niraparib may be considered a cost-effective maintenance treatment for patients with recurrent OC.
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Affiliation(s)
- Holly Guy
- FIECON Ltd, 3 College Yard, Lower Dagnall Street, St Albans, Hertfordshire, AL3 4PA, UK.
| | - Lydia Walder
- FIECON Ltd, 3 College Yard, Lower Dagnall Street, St Albans, Hertfordshire, AL3 4PA, UK
| | - Mark Fisher
- FIECON Ltd, 3 College Yard, Lower Dagnall Street, St Albans, Hertfordshire, AL3 4PA, UK
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Berek JS, Kehoe ST, Kumar L, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2018; 143 Suppl 2:59-78. [PMID: 30306591 DOI: 10.1002/ijgo.12614] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The Gynecologic Oncology Committee of FIGO in 2014 revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSC). Stage IC is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies.
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Affiliation(s)
- Jonathan S Berek
- Stanford Women's Cancer Center, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Sean T Kehoe
- Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
| | - Lalit Kumar
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Michael Friedlander
- Royal Hospital for Women, Randwick, Sydney, NSW, Australia.,University of New South Wales Clinical School, Sydney, NSW, Australia
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Faraoni I, Graziani G. Role of BRCA Mutations in Cancer Treatment with Poly(ADP-ribose) Polymerase (PARP) Inhibitors. Cancers (Basel) 2018; 10:E487. [PMID: 30518089 PMCID: PMC6316750 DOI: 10.3390/cancers10120487] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 11/29/2018] [Accepted: 11/30/2018] [Indexed: 12/29/2022] Open
Abstract
Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors.
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Affiliation(s)
- Isabella Faraoni
- Department of Systems Medicine, University of Rome Tor Vergata, 00173 Rom, Italy.
| | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, 00173 Rom, Italy.
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Le Saux O, Decullier E, Freyer G, Glehen O, Bakrin N. Long-term survival in patients with epithelial ovarian cancer following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Int J Hyperthermia 2018; 35:652-657. [PMID: 30295114 DOI: 10.1080/02656736.2018.1518544] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
Abstract
OBJECTIVE Despite a high response rate to first-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. The objective of the present study was to evaluate the frequency of long-term survivors and to identify the prognostic factors associated with long-term survival in a French cohort of 566 patients. METHODS Patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for EOC in 13 French centers between 1991 and 2010 were included. Long-term survivors were defined as patients who survived more than 5 years after HIPEC and CRS, irrespective of relapse. RESULTS Seventy-eight long-term survivors were analyzed. The median follow-up was 74 months. Median age at the time of first HIPEC was 55.4 years (range [22.6-77.6]. Seven patients had advanced EOC and 71 patients had recurrent EOC (37 patients had platinum-resistant EOC and 32 had platinum-sensitive disease). More than half of the long-term survivors had high-grade serous ovarian cancer (HGSOC). In univariate analysis, age ≥50 years (p = .004), peritoneal cancer index (PCI) ≤ 8 (p = .049) and CA-125 < 100 (p = .02) were associated with long-term survival. There was a trend towards an association between higher CC-score and long-term survival (p = .057). CONCLUSION Age ≥50 years, PCI ≤8 and CA125 < 100 were associated with long-term survival in univariate analysis. There was a trend towards the significance of CC-score. Platinum-status was not associated with long-term survival.
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Affiliation(s)
- Olivia Le Saux
- a Medical oncology department , Hospices Civils de Lyon, Université de Lyon , Lyon , France
| | | | - Gilles Freyer
- a Medical oncology department , Hospices Civils de Lyon, Université de Lyon , Lyon , France
| | - Olivier Glehen
- c Department of General and Digestive Surgery , Centre Hospitalier Lyon Sud, Lyon 1 University , Lyon , France
| | - Naoual Bakrin
- c Department of General and Digestive Surgery , Centre Hospitalier Lyon Sud, Lyon 1 University , Lyon , France
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Rust K, Spiliopoulou P, Tang CY, Bell C, Stirling D, Phang T, Davidson R, Mackean M, Nussey F, Glasspool RM, Reed NS, Sadozye A, Porteous M, McGoldrick T, Ferguson M, Miedzybrodzka Z, McNeish IA, Gourley C. Routine germline BRCA1 and BRCA2 testing in patients with ovarian carcinoma: analysis of the Scottish real-life experience. BJOG 2018; 125:1451-1458. [PMID: 29460478 DOI: 10.1111/1471-0528.15171] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVE To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy. DESIGN Retrospective cohort study. SETTING Four cancer/genetics centres in Scotland. POPULATION Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria). METHODS Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria. MAIN OUTCOME MEASURES Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations. RESULTS Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of <15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged >70 years was 8.2%. CONCLUSIONS Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate. TWEETABLE ABSTRACT BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.
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Affiliation(s)
- K Rust
- Edinburgh Cancer Centre, Edinburgh, UK
| | | | - C Y Tang
- Department of Oncology, Ninewells Hospital, Dundee, UK
| | - C Bell
- Department of Medical Genetics, NHS Grampian, Aberdeen, UK
| | - D Stirling
- Department of Clinical Genetics, Western General Hospital, Edinburgh, UK
| | - Thf Phang
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - R Davidson
- Department of Genetics, Queen Elizabeth University Hospital, Glasgow, UK
| | - M Mackean
- Edinburgh Cancer Centre, Edinburgh, UK
| | - F Nussey
- Edinburgh Cancer Centre, Edinburgh, UK
| | | | - N S Reed
- Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - A Sadozye
- Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - M Porteous
- Department of Clinical Genetics, Western General Hospital, Edinburgh, UK
| | - T McGoldrick
- Department of Oncology, Aberdeen Royal Infirmary, Aberdeen, UK
| | - M Ferguson
- Department of Oncology, Ninewells Hospital, Dundee, UK
| | - Z Miedzybrodzka
- Department of Medical Genetics, NHS Grampian, Aberdeen, UK
- School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - I A McNeish
- Beatson West of Scotland Cancer Centre, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - C Gourley
- Edinburgh Cancer Centre, Edinburgh, UK
- Nicola Murray Centre for Ovarian Cancer Research, University of Edinburgh Cancer Research UK Centre, MRC IGMM, Western General Hospital, Edinburgh, UK
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Zhu Y, Zhai K, Ke J, Li J, Gong Y, Yang Y, Tian J, Zhang Y, Zou D, Peng X, Gong J, Zhong R, Huang K, Chang J, Miao X. BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population. Oncotarget 2018; 8:36033-36039. [PMID: 28415599 PMCID: PMC5482636 DOI: 10.18632/oncotarget.16422] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 03/15/2017] [Indexed: 01/24/2023] Open
Abstract
Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population. We found rs1799966 on BRCA1 was associated with poor prognosis of pancreatic cancer patients with hazard ratio being 1.23 (95% CI: 1.09–1.40, P = 0.0010). Further stratification analyses showed that significant correlation was particularly in locally advanced stage patients with hazard ratio being 1.36 (95% CI: 1.13–1.64, P = 0.0014), but not in patients in local stage (P = 0.1139) or metastatic stage (P = 0.5185). Two missense variants (rs766173 and rs144848) on BRAC2 showed no significant correlation with pancreatic cancer patients’ overall survival. In conclusion, we identified a germline missense variant on BRAC1 significantly associated with poor prognosis of pancreatic cancer patients with locally advanced stage. These results may contribute to the precision medicine of this disease.
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Affiliation(s)
- Ying Zhu
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kan Zhai
- Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Juntao Ke
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiaoyuan Li
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yajie Gong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Yang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianbo Tian
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Zhang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Danyi Zou
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiating Peng
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Gong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rong Zhong
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kun Huang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China
| | - Jiang Chang
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoping Miao
- Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Xu K, Yang S, Zhao Y. Prognostic significance of BRCA mutations in ovarian cancer: an updated systematic review with meta-analysis. Oncotarget 2018; 8:285-302. [PMID: 27690218 PMCID: PMC5352118 DOI: 10.18632/oncotarget.12306] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/22/2016] [Indexed: 12/12/2022] Open
Abstract
There is no consensus on the syntheses concerning the impact of BRCA mutation on ovarian cancer survival. A systematic review and meta-analysis of observational studies was conducted that evaluated the impact of BRCA mutations on the survival outcomes of patients with ovarian cancer. The primary outcome measure was overall survival (OS) and secondary outcome was progression-free survival (PFS). We presented data with hazard ratios (HRs) and 95% confidence interval (CI) and pooled them using the random-effects models. From 2,624 unique records, 34 eligible studies including 18,396 patients were identified. BRCA1/2 mutations demonstrated both OS and PFS benefits in patients with ovarian cancer (OS: HR = 0.67, 95% CI, 0.57 to 0.78, I2 = 76.5%, P <0.001; PFS: HR = 0.62, 95% CI, 0.53 to 0.73, I2 = 18.1%, P = 0.261). For BRCA1 mutation carriers, the HRs for OS and PFS benefits were 0.73 (95% CI, 0.63 to 0.86) and 0.68 (95% CI, 0.52 to 0.89), respectively. For BRCA2 mutation carriers, the HRs for OS and PFS benefits were 0.57 (95% CI, 0.45 to 0.73) and 0.48 (95% CI, 0.30 to 0.75), respectively. The results of subgroup analyses for OS stratified by study quality, tumor stage, study design, sample size, number of research center, duration of follow-up, baseline characteristics adjusted and tumor histology were mostly constant across BRCA1/2, BRCA1 and BRCA2 mutation subtypes. In summary, for patients with ovarian cancer, BRCA mutations were associated with improved OS and PFS. Further large-scale prospective cohort studies should be conducted to test its benefits in specific patients.
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Affiliation(s)
- Kai Xu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shouhua Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Yingchao Zhao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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Clinical characteristics and outcomes of patients with BRCA1 or RAD51C methylated versus mutated ovarian carcinoma. Gynecol Oncol 2018; 148:281-285. [DOI: 10.1016/j.ygyno.2017.12.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 11/28/2017] [Accepted: 12/04/2017] [Indexed: 02/08/2023]
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Herold N, Wappenschmidt B, Markiefka B, Keupp K, Kröber S, Hahnen E, Schmutzler R, Rhiem K. Non-small cell neuroendocrine carcinoma of the ovary in a BRCA2-germline mutation carrier: A case report and brief review of the literature. Oncol Lett 2018. [PMID: 29541174 PMCID: PMC5835890 DOI: 10.3892/ol.2018.7836] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Non-small cell neuroendocrine carcinomas (NSCNEC) account for 2% of gynecological cancer cases and are associated with a poor prognosis due to delayed diagnosis and aggressive tumor behavior. BRCA2-associated ovarian carcinomas predominantly possess a high-grade serous phenotype, which respond to platinum and targeted therapy with PARP inhibitors. Presented here is the case of an adult patient with NSCNEC of the ovaries associated with a deleterious BRCA2 germline mutation. The pathogenic mutation was also confirmed on the somatic level, while the wild-type allele had a high variant fraction, suggesting loss of heterozygosity. To the best of our knowledge, this is the first report of an adult BRCA2 germline mutation carrier with the rare NSCNEC of the ovary phenotype. Therefore, ovarian cancer patients with histological subtypes other than high-grade serous carcinomas should be tested for BRCA1/2 mutations, as they may benefit from targeted therapy with poly (ADP-ribose) polymerase inhibitors.
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Affiliation(s)
- Natalie Herold
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Barbara Wappenschmidt
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Birgid Markiefka
- Institute for Pathology, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Katharina Keupp
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Sandra Kröber
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Rita Schmutzler
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
| | - Kerstin Rhiem
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, D-50931 Cologne, Germany
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Abstract
OBJECTIVE A meta-analysis was performed to determine if BRCA1/2 mutations are associated with improved overall survival (OS) and progression-free survival (PFS) in patients with ovarian cancer. RESEARCH DESIGN AND METHODS Studies of patients with primary or recurrent ovarian cancer that examined the relationship between BRCA1/2 mutation status and outcomes were included. MAIN OUTCOME MEASURES The primary outcomes were OS and PFS of patients with and without BRCA1 and BRCA2 mutations. The secondary outcome was treatment response: complete response, partial response, and overall response. RESULTS Overall analysis revealed BRCA1/2 mutations were associated with improved OS [hazard ratio (HR) = 0.75; 95% confidence interval (CI): 0.64, 0.88; P < .001] and PFS (HR = 0.80; 95% CI: 0.64, 0.99; P = .039). BRCA1 mutations were significantly associated with improved OS (HR = 0.75) but not PFS, and BRCA2 mutations alone were not associated with either improved OS or PFS. The presence of BCRA1/2 mutations was associated with a better overall response rate, higher complete response rate, and lower partial response rate; however, BRCA1 or BRCA2 alone was not associated with overall response rate. CONCLUSIONS BRCA1 mutations appear to be associated with improved OS in patients with ovarian cancer. However, the effect of BRCA1 mutations on PFS and BRCA2 mutations alone on OS and PFS is less clear.
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Bartosch C, Clarke B, Bosse T. Gynaecological neoplasms in common familial syndromes (Lynch and HBOC). Pathology 2017; 50:222-237. [PMID: 29287922 DOI: 10.1016/j.pathol.2017.10.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 10/16/2017] [Accepted: 10/17/2017] [Indexed: 12/22/2022]
Abstract
Recognising hereditary predisposition in a cancer patient has implications both for the patient and the patient's kindred. For the latter, cascade germline testing can reassure those not-at-risk family members while carriers can be enrolled in cancer screening and prevention programs that are medically effective and economically sustainable for health care systems. Furthermore, in many of these syndromes, ramifications of molecular phenotypes are increasing, and it is now emerging that, in addition, they convey prognostic and predictive information. Although cancer predisposition syndromes are rare, these molecular phenotypes also occur as somatic events in sporadic cancer settings. The information obtained from these molecular phenotypes, regardless of germline or somatic origin, is being incorporated into clinical management in view of their manifold significance. Thus, increasingly, bespoke management of cancer patients involves testing for both germline and somatic mutations in tumours. Lynch syndrome and BRCA-1 and BRCA-2-associated hereditary breast and ovarian cancer are hereditary cancer syndromes frequently involving the gynaecological tract but tumours associated with similar molecular alterations may also occur sporadically. Thus, the molecular phenotype of mismatch repair deficiency, microsatellite instability or hypermutator phenotype may be attributable to germline or somatic events. Similarly, homologous recombination deficiency or 'BRCAness' in ovarian cancers may be syndromic or sporadic. While hereditary syndromes are well recognised, the prognostic and predictive implications of these molecular phenotypes have only recently been elucidated and these aspects will finally ensure that molecular screening may become standard of care. Thus, nowadays pathologists are asked to designate the molecular phenotype of these cancers and then determine whether it is due to hereditary or sporadic causes.
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Affiliation(s)
- Carla Bartosch
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
| | - Blaise Clarke
- Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, Ontario, Canada
| | - Tjalling Bosse
- Department of Pathology, Leiden University Medical Center, The Netherlands.
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Hoskins PJ, Gotlieb WH. Missed therapeutic and prevention opportunities in women with BRCA-mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature. CA Cancer J Clin 2017; 67:493-506. [PMID: 28881380 DOI: 10.3322/caac.21408] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 07/18/2017] [Accepted: 07/19/2017] [Indexed: 12/24/2022] Open
Abstract
Answer questions and earn CME/CNE Fifteen percent of women with epithelial ovarian cancer have inherited mutations in the BRCA breast cancer susceptibility genes. Knowledge of her BRCA status has value both for the woman and for her family. A therapeutic benefit exists for the woman with cancer, because a new family of oral drugs, the poly ADP-ribose polymerase (PARP) inhibitors, has recently been approved, and these drugs have the greatest efficacy in women who carry the mutation. For her family, there is the potential to prevent ovarian cancer in those carrying the mutation by using risk-reducing surgery. Such surgery significantly reduces the chance of developing this, for the most part, incurable cancer. Despite these potential benefits, referral rates for genetic counseling and subsequent BRCA testing are low, ranging from 10% to 30%, indicating that these therapeutic and prevention opportunities are being missed. The authors have reviewed the relevant available literature. Topics discussed are BRCA and its relation to ovarian cancer, the rates of referral for genetic counseling/BRCA testing, reasons for these low rates, potential strategies to improve on those rates, lack of effectiveness of current screening strategies, the pros and cons of risk-reducing surgery, other prevention options, and the role and value of PARP inhibitors. CA Cancer J Clin 2017;67:493-506. © 2017 American Cancer Society.
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Affiliation(s)
- Paul J Hoskins
- Medical Oncologist and Past President, Society of Gynecologic Oncology Canada, British Columbia Cancer Agency, Vancouver Center, BC, Canada
| | - Walter H Gotlieb
- Gynecologic Oncologist and President, Society of Gynecologic Oncology Canada, McGill University, Jewish General Hospital, Montreal, QC, Canada
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Ovarian cancer patients at high risk of BRCA mutation: the constitutional genetic characterization does not change prognosis. Fam Cancer 2017; 15:497-506. [PMID: 26833043 DOI: 10.1007/s10689-016-9873-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Ovarian neoplasms secondary to germline BRCA mutations had been described to have a more favourable survival. There is only few data concerning the prognosis of non mutated patients presenting clinical features evocative of BRCA alterations. We retrospectively collected data from patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. Patients considered at high risk of BRCA mutation were tested for BRCA1/2 germline mutations. We described clinical, pathological and therapeutic features and compared prognosis of BRCA mutation carriers and non-mutated patients. Out of 617 ovarian cancer patients, we identified 104 patients who were considered at high risk of mutation. The 33 mutated patients were more likely to present a personal (33 vs. 10 %, p = 0.003) or a family (42 vs. 24 %, p = 0.06) history of breast/ovarian cancers. BRCA1/2 mutation carriers and wild type patients displayed similar prognosis: median progression-free survival (PFS) of 20.9 versus 37.7 months (p = 0.21); median overall survival (OS) of 151.2 versus 122.5 months (p = 0.52). Personal history of breast cancer increased both PFS [HR = 0.45 (95CI 0.25-0.81)] and OS [HR = 0.35 (95CI 0.16-0.75)]. In multivariate analysis, this parameter was an independent prognostic feature, whereas the identification of a BRCA1/2 mutation was not. In our cohort, all patients at high risk of BRCA mutation share a similar prognosis, whatever is their germline mutation status. Prognosis seems to be more influenced by clinical history than by germline mutations identification. If it is confirmed in larger and independent series, this result suggests that the hypothesis of other BRCA pathway alterations (BRCAness phenotype) deserves to be deeply explored.
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Pomerantz MM, Spisák S, Jia L, Cronin AM, Csabai I, Ledet E, Sartor AO, Rainville I, O'Connor EP, Herbert ZT, Szállási Z, Oh WK, Kantoff PW, Garber JE, Schrag D, Kibel AS, Freedman ML. The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 2017; 123:3532-3539. [PMID: 28608931 PMCID: PMC5802871 DOI: 10.1002/cncr.30808] [Citation(s) in RCA: 209] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Revised: 04/11/2017] [Accepted: 04/19/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Breast cancer 2 (BRCA2)-associated breast and ovarian cancers are sensitive to platinum-based chemotherapy. It is unknown whether BRCA2-associated prostate cancer responds favorably to such treatment. METHODS A retrospective analysis of a single-institution cohort of men with castration-resistant, metastatic prostate cancer was performed to determine the association between carrier status of pathogenic BRCA2 germline variants and prostate-specific antigen response to carboplatin-based chemotherapy. From 2001 through 2015, 8081 adult men with prostate cancer who had a consultation and/or underwent treatment at Dana-Farber Cancer Institute provided blood samples and consented to analyses of biologic material and clinical records. A subgroup of 141 men received at least 2 doses of carboplatin and docetaxel for castration-resistant disease (94% were also taxane refractory). These patients were categorized according to the absence or presence of pathogenic germline mutations in BRCA2 based on DNA sequencing from whole blood. The primary outcome was the response rate to carboplatin/docetaxel chemotherapy, defined according to a decline in prostate-specific antigen that exceeded 50% within 12 weeks of initiating this regimen. Associations between BRCA2 mutation status and response to carboplatin-based chemotherapy were tested using the Fisher exact test, with a 2-sided P value < .05 as the threshold for significance. RESULTS Pathogenic germline BRCA2 variants were observed in 8 of 141 men (5.7%; 95% confidence interval, 2.5%-10.9%). Six of 8 BRCA2 carriers (75%) experienced prostate-specific antigen declines >50% within 12 weeks, compared with 23 of 133 noncarriers (17%; absolute difference, 58%; 95% confidence interval, 27%-88%; P < .001). Prostate cancer cell lines functionally corroborated these clinical findings. CONCLUSIONS BRCA2-associated, castration-resistant prostate cancer is associated with a higher likelihood of response to carboplatin-based chemotherapy than non-BRCA2-associated prostate cancer. Cancer 2017;123:3532-9. © 2017 American Cancer Society.
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Affiliation(s)
- Mark M Pomerantz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sandor Spisák
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Li Jia
- Department of Surgery, Division of Urology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Angel M Cronin
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Istvan Csabai
- Department of Physics of Complex Systems Eotvos Lorand University, Budapest, Hungary
| | - Elisa Ledet
- Department of Medicine, Tulane Cancer Center, New Orleans, Louisiana
| | - A Oliver Sartor
- Department of Medicine, Tulane Cancer Center, New Orleans, Louisiana
| | - Irene Rainville
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Edward P O'Connor
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Zachary T Herbert
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Zoltan Szállási
- Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts
| | - William K Oh
- Department of Medicine, Division of Hematology and Oncology, Tisch Cancer Institute, New York, New York
| | - Philip W Kantoff
- Department of Medicine, Memorial Sloan Kettering Cancer Institute, New York, New York
| | - Judy E Garber
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Deborah Schrag
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Adam S Kibel
- Department of Surgery, Division of Urology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Matthew L Freedman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
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