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Kim SR, Parbhakar A, Li X, Bernardini MQ, Hogen L, May T. Primary cytoreductive surgery compared with neoadjuvant chemotherapy in patients with BRCA mutated advanced high grade serous ovarian cancer: 10 year survival analysis. Int J Gynecol Cancer 2024; 34:879-885. [PMID: 38548312 DOI: 10.1136/ijgc-2023-005065] [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] [Indexed: 06/05/2024] Open
Abstract
OBJECTIVES Given the high response to platinum based chemotherapy in BRCA 1/2 mutated high grade serous ovarian cancers, there is uncertainty about the relative benefits of primary cytoreductive surgery versus neoadjuvant chemotherapy in this population. We aimed to compare the survival outcomes for women with BRCA 1/2 mutated high grade serous ovarian cancers undergoing either primary cytoreductive surgery or neoadjuvant chemotherapy. METHODS We conducted a retrospective cohort study of all stage III/IV BRCA mutated high grade serous ovarian cancers treated with primary cytoreductive surgery or neoadjuvant chemotherapy at a single tertiary cancer center between 1991 and 2020. Baseline demographics, initial disease burden, surgical complexity, and survival outcomes were examined. RESULTS Of 314 women with germline or somatic BRCA mutations, 194 (62%) underwent primary cytoreductive surgery and 120 (38%) underwent neoadjuvant chemotherapy followed by interval cytoreductive surgery. Those undergoing primary cytoreductive surgery were younger (median age 53 years (range 47-59) vs 59 years (50-65), p<0.001), but there were no differences in functional status or underlying comorbidities. The initial disease burden was lower (disease score high (40% vs 44%; p<0.001) but surgical complexity was higher (surgical complexity score high (18% vs 3%; p<0.001) in the primary cytoreductive surgery cohort. The rate of optimal or complete cytoreduction was similar in both groups (89% vs 90%; p=0.23) as well as the rate of poly (ADP-ribose) polymerase inhibitor use (62% vs 68%; p=0.3). The 10 year overall survival and recurrence free survival were superior in the primary cytoreductive surgery cohort (overall survival 49% vs 25%, p<0.001 and progression free survival 25% vs 10%, p<0.001). After controlling for confounders, primary cytoreductive surgery remained a significant predictor of improved overall survival (hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.27 to 0.74; p=0.002) and recurrence free survival (HR 0.55; 95% CI 0.37 to 0.80; p=0.002). CONCLUSIONS Primary cytoreductive surgery was associated with improved survival in women with stage III/IV BRCA mutated high grade serous ovarian cancers compared with neoadjuvant chemotherapy.
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Affiliation(s)
- Soyoun Rachel Kim
- Division of Gynaecologic Oncology, Princess Margaret Cancer Centre/University Health Network/Sinai Health Systems, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | | | - Xuan Li
- Department of Biostatistics, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - Marcus Q Bernardini
- Princess Margaret Cancer Centre/University Health Network/Sinai Health Systems, Princess Margaret Hospital, Toronto, Ontario, Canada
| | - Liat Hogen
- Gynaecologic Oncology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - Taymaa May
- Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada
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Peters I, Marchetti C, Scambia G, Fagotti A. New windows of surgical opportunity for gynecological cancers in the era of targeted therapies. Int J Gynecol Cancer 2024; 34:352-362. [PMID: 38438181 DOI: 10.1136/ijgc-2023-004580] [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] [Indexed: 03/06/2024] Open
Abstract
Precision medicine through molecular profiling has taken a prominent role in the treatment of solid tumors and it is widely expected that this will continue to expand. With respect to gynecological cancers, a major change has particularly been observed in the treatment landscape of epithelial ovarian, endometrial, and cervical cancers. Regarding the former, maintenance therapy with either poly(ADP-ribose) polymerase inhibitors (PARPi) and/or bevacizumab has become an indispensable treatment option following the traditional combination of cytoreductive surgery and platinum-based chemotherapy. Considering endometrial cancer, the molecular classification system has now been incorporated into virtually every guideline available and molecular-directed treatment strategies are currently being researched, presumably leading to a further transformation of its treatment paradigm. After all, treatment with immune-checkpoint inhibitors that target the programmed cell death 1 (PD-1) receptor has already been shown to significantly improve disease outcomes in these patients, especially in those with mismatch repair deficient, microsatellite stability-high (MMRd-MSI-H) disease. Similarly, in recurrent/metastatic cervical cancer patients, these agents elicited improved survival rates when being added to platinum-based chemotherapy with or without bevacizumab. Interestingly, implications of these targeted therapies for surgical management have been touched on to a minor extent, but are at least as intriguing. This review therefore aims to address the wide-ranging opportunities the molecular tumor characteristics and their corresponding targeted therapies have to offer for the surgical management of epithelial ovarian, endometrial, and cervical cancers, both in the primary and recurrent setting.
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Affiliation(s)
- Inge Peters
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Claudia Marchetti
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Giovanni Scambia
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Anna Fagotti
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
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Peters I, Marchetti C, Fagotti A, Scambia G. PARP inhibitors in epithelial ovarian cancer: what are their potential implications for surgical management? EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:106973. [PMID: 37414629 DOI: 10.1016/j.ejso.2023.06.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 06/28/2023] [Indexed: 07/08/2023]
Affiliation(s)
- Inge Peters
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy
| | - Claudia Marchetti
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy
| | - Anna Fagotti
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy
| | - Giovanni Scambia
- Department of Woman's and Child Health and Public Health Sciences, Gynecologic Oncology Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy.
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Imyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, Ivantsov AO, Aleksakhina SN. Hereditary cancer syndromes. World J Clin Oncol 2023; 14:40-68. [PMID: 36908677 PMCID: PMC9993141 DOI: 10.5306/wjco.v14.i2.40] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.
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Affiliation(s)
- Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Ekaterina S Kuligina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Anna P Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Evgeny N Suspitsin
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Grigoriy A Yanus
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Aglaya G Iyevleva
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Alexandr O Ivantsov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Svetlana N Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
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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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Thomas QD, Quesada S, D’Hondt V, Belaroussi I, Laas E, Classe JM, Fabbro M, Colombo PE, Fiteni F. Combinaison de la chirurgie et du traitement médical du cancer de l’ovaire : y a-t-il une stratégie optimale ? Bull Cancer 2022; 109:197-215. [DOI: 10.1016/j.bulcan.2021.11.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 11/18/2021] [Accepted: 11/26/2021] [Indexed: 12/19/2022]
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Imyanitov EN. Cytotoxic and targeted therapy for BRCA1/2-driven cancers. Hered Cancer Clin Pract 2021; 19:36. [PMID: 34454564 PMCID: PMC8399736 DOI: 10.1186/s13053-021-00193-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 08/17/2021] [Indexed: 12/24/2022] Open
Abstract
Tumors arising in BRCA1/2 germline mutation carriers usually demonstrate somatic loss of the remaining BRCA1/2 allele and increased sensitivity to platinum compounds, anthracyclines, mitomycin C and poly (ADP-ribose) polymerase inhibitors (PARPi). Exposure to conventional platinum-based therapy or PARPi results in the restoration of BRCA1/2 function and development of resistance to systemic therapy, therefore, there is a need for other treatment options. Some studies suggested that the use of specific drug combinations or administration of high-dose chemotherapy may result in pronounced tumor responses. BRCA1/2-driven tumors are characterized by increased immunogenicity; promising efficacy of immune therapy has been demonstrated in a number of preclinical and clinical investigations. There are outstanding issues, which require further consideration. Platinum compounds and PARPi have very similar mode of antitumor action and are likely to render cross-resistance to each other, so their optimal position in cancer treatment schemes may be a subject of additional studies. Sporadic tumors with somatically acquired inactivation of BRCA1/2 or related genes resemble hereditary neoplasms with regard to the spectrum of drug sensitivity; the development of user-friendly BRCAness tests presents a challenge. Many therapeutic decisions are now based on the BRCA1/2 status, so the significant reduction of the turn-around time for predictive laboratory assays is of particular importance.
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Affiliation(s)
- Evgeny N Imyanitov
- N.N. Petrov Institute of Oncology, Pesochny, Saint-Petersburg, 197758, Russia. .,St.-Petersburg Pediatric Medical University, Saint Petersburg, 194100, Russia. .,I.I. Mechnikov North-Western Medical University, St.-Petersburg, 191015, Russia.
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Imyanitov E, Sokolenko A. Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors. World J Clin Oncol 2021; 12:544-556. [PMID: 34367927 PMCID: PMC8317650 DOI: 10.5306/wjco.v12.i7.544] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/04/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene. Consequently, BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly (ADP-ribose) polymerase inhibitors (PARPi). Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations, which restore the open-reading frame of the affected allele. This platinum/PARPi cross-resistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies. There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance; however, their actual clinical relevance remains to be established. In addition, studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells. These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure, but become outcompeted by BRCA1-deficient cells during therapy holidays. Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches, which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.
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Affiliation(s)
- Evgeny Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg 197758, Russia
- Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg 194100, Russia
- Department of Oncology, I.I. Mechnikov North-Western Medical University, Saint-Petersburg 191015, Russia
| | - Anna Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg 197758, Russia
- Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg 194100, Russia
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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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Gorodnova TV, Sokolenko AP, Kotiv KB, Sokolova TN, Ivantsov AO, Guseynov KD, Nekrasova EA, Smirnova OA, Berlev IV, Imyanitov EN. Neoadjuvant therapy of BRCA1-driven ovarian cancer by combination of cisplatin, mitomycin C and doxorubicin. Hered Cancer Clin Pract 2021; 19:14. [PMID: 33536037 PMCID: PMC7860626 DOI: 10.1186/s13053-021-00173-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 01/27/2021] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Cisplatin, mitomycin C and anthracyclines demonstrate high activity in BRCA1-deficient tumors. This study aimed to evaluate the efficacy of the triplet combination of these drugs in BRCA1-driven high-grade serous ovarian carcinomas (HGSOCs). METHODS Ten HGSOC patients with germ-line BRCA1 mutation received neoadjuvant chemotherapy (NACT) consisting of mitomycin C 10 mg/m2 (day 1), doxorubicin 30 mg/m2 (days 1 and 8) and cisplatin 80 mg/m2 (day 1), given every 4 weeks (MAP regimen). The comparator group included 16 women, who received standard NACT combination of paclitaxel 175 mg/m2 and carboplatin (6 AUC), given every 3 weeks (TCbP scheme). RESULTS None of the patients treated by the MAP scheme demonstrated complete pathologic response in ovaries, while 4 women showed absence of tumor cells in surgically excised omental specimens. When chemotherapy response scores (CRS) were considered, poor responsiveness (CRS 1) was not observed in the MAP group, but was common for the TCbP regimen (6/16 (38 %) for ovaries and 5/16 (31 %) for omentum; p = 0.05 and 0.12, respectively). Median treatment-free interval (TFI) was not reached in women treated by the MAP, but was 9.5 months for the TCbP scheme (p = 0.1). The rate of the recurrence within 1 year after the completion of the treatment was 4/10 (40 %) for the MAP and 10/13 (77 %) for the TCbP (p = 0.1). CONCLUSIONS The attempt to intensify NACT by administering combination of 3 drugs did not result in high rate of complete pathologic responses. However, there was a trend towards higher efficacy of the MAP regimen versus conventional TCbP scheme with regard to CRS and clinical outcomes.
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Affiliation(s)
| | - Anna P Sokolenko
- N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.,St.-Petersburg Pediatric Medical University, 194100, Saint-Petersburg, Russia
| | | | | | - Alexandr O Ivantsov
- N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.,St.-Petersburg Pediatric Medical University, 194100, Saint-Petersburg, Russia
| | | | | | - Olga A Smirnova
- N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia
| | - Igor V Berlev
- N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia.,I.I. Mechnikov North-Western Medical University, 195067, St.-Petersburg, Russia
| | - Evgeny N Imyanitov
- N.N. Petrov Institute of Oncology, 197758, Saint-Petersburg, Russia. .,St.-Petersburg Pediatric Medical University, 194100, Saint-Petersburg, Russia. .,I.I. Mechnikov North-Western Medical University, 195067, St.-Petersburg, Russia.
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Ponzone R. BRCA1/2 status and chemotherapy response score to tailor ovarian cancer surgery. Crit Rev Oncol Hematol 2020; 157:103128. [PMID: 33137578 DOI: 10.1016/j.critrevonc.2020.103128] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/29/2020] [Accepted: 10/09/2020] [Indexed: 12/13/2022] Open
Abstract
In advanced ovarian cancer (AOC) the complete eradication of all macroscopic disease at primary debulking surgery (PDS) is associated with the best outcome. If this cannot be achieved, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) can make complete cytoreduction possible while reducing postoperative morbidity. It is still debated if PDS and NACT- IDS are associated with similar survival and if they provide different outcomes when optimal cytoreduction is achieved. For a tailored surgical planning, accurate prediction of tumor's resectability, assessment of patient's performance status and in-depth knowledge of tumor biology are required. Both BRCA1/2 status and the "chemotherapy response score" are reliable markers of chemosensitivity and may thus improve our way to triage patients to PDS or NACT-IDS; furthermore, they could be used to modulate our surgical approach and define appropriate subgroups of patients for whom new therapies should be tested.
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Affiliation(s)
- Riccardo Ponzone
- Gynaecological Oncology, Candiolo Cancer Institute, FPO - IRCCS, Strada Provinciale 142, Km 3.95, 10060, Candiolo, Italy.
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12
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Sokolenko AP, Sokolova TN, Ni VI, Preobrazhenskaya EV, Iyevleva AG, Aleksakhina SN, Romanko AA, Bessonov AA, Gorodnova TV, Anisimova EI, Savonevich EL, Bizin IV, Stepanov IA, Krivorotko PV, Berlev IV, Belyaev AM, Togo AV, Imyanitov EN. Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients. Breast Cancer Res Treat 2020; 184:229-235. [PMID: 32776218 DOI: 10.1007/s10549-020-05827-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 07/20/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles. METHODS We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis. RESULTS The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and "rare" BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women. CONCLUSION Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.
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Affiliation(s)
- Anna P Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia. .,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia.
| | - Tatiana N Sokolova
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical and Chemical Medicine, Moscow, Russia
| | - Valeria I Ni
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | - Elena V Preobrazhenskaya
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical and Chemical Medicine, Moscow, Russia
| | - Aglaya G Iyevleva
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical and Chemical Medicine, Moscow, Russia
| | - Svetlana N Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical and Chemical Medicine, Moscow, Russia
| | - Alexandr A Romanko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia
| | - Alexandr A Bessonov
- Department of Mammology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | - Tatiana V Gorodnova
- Department of Oncogynecology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | | | - Elena L Savonevich
- Department of Obstetrics and Gynecology, Grodno State Medical University, Grodno, Belarus
| | - Ilya V Bizin
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | - Ilya A Stepanov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | - Petr V Krivorotko
- Department of Mammology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | - Igor V Berlev
- Department of Oncogynecology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia
| | - Alexey M Belyaev
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Department of Oncology, I.I. Mechnikov North-Western Medical University, Saint-Petersburg, Russia
| | - Alexandr V Togo
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia.,Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Federal Research and Clinical Center of Physical and Chemical Medicine, Moscow, Russia
| | - Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, Saint-Petersburg, Russia.,Department of Oncology, I.I. Mechnikov North-Western Medical University, Saint-Petersburg, Russia
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13
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Gorodnova TV, Sokolenko AP, Kondratiev SV, Kotiv KB, Belyaev AM, Berlev IV, Imyanitov EN. Mitomycin C plus cisplatin for systemic treatment of recurrent BRCA1-associated ovarian cancer. Invest New Drugs 2020; 38:1872-1878. [PMID: 32591974 DOI: 10.1007/s10637-020-00965-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 06/16/2020] [Indexed: 10/24/2022]
Abstract
Background Previous studies on neoadjuvant therapy for BRCA1-driven ovarian cancer (OC) demonstrated higher efficacy of mitomycin C plus cisplatin combination as compared to standard drug schemes. These data call for evaluation of the utility of this regimen for the treatment of recurrent BRCA1-associated OC. Methods The study included 12 BRCA1 germ-line mutation carriers, whose disease relapsed after one (n = 4) or two (n = 8) lines of chemotherapy. The patients received cisplatin 100 mg/m2 and mitomycin C 10 mg/m2, given every four weeks, for 6 (n = 10), 8 (n = 1) or 5 (n = 1) cycles. Retrospective data on conventional treatment of OC relapses in BRCA1 heterozygotes (n = 47) served as a control. Results Grade 3-4 toxicities were observed in 4/12 (33%) cases. There were 6 complete responses (CR), 4 partial responses (PR) and 2 instances of stable disease (SD). Comparison of patients receiving mitomycin C plus cisplatin (n = 4) or conventional therapy (n = 44) at first relapse demonstrated marginal improvement of the progression-free survival (PFS) (16.6 months vs. 10.2 months, P = .067). Use of mitomycin C plus cisplatin (n = 8) for the treatment of second relapse resulted in significant prolongation of PFS as compared to standard regimens (n = 31) (14.8 months vs. 4.8 months, P = .002). Conclusions Mitomycin C plus cisplatin shows promising activity in recurrent BRCA1-driven ovarian cancer.
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Affiliation(s)
- Tatyana V Gorodnova
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia
| | - Anna P Sokolenko
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia. .,St.-Petersburg Pediatric Medical University, 194100, St.-Petersburg, Russia.
| | - Sergey V Kondratiev
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia
| | - Khristina B Kotiv
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia
| | - Alexey M Belyaev
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia
| | - Igor V Berlev
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia
| | - Evgeny N Imyanitov
- N.N. Petrov National Medical Research Center of Oncology, Leningradskaya, 68, Pesochny-2, 197758, St.-Petersburg, Russia.,St.-Petersburg Pediatric Medical University, 194100, St.-Petersburg, Russia.,I.I. Mechnikov North-Western Medical University, 191015, St.-Petersburg, Russia
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14
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Sokolenko AP, Bizin IV, Preobrazhenskaya EV, Gorodnova TV, Ivantsov AO, Iyevleva AG, Savonevich EL, Kotiv KB, Kuligina ES, Imyanitov EN. Molecular profiles of BRCA1-associated ovarian cancer treated by platinum-based therapy: Analysis of primary, residual and relapsed tumors. Int J Cancer 2019; 146:1879-1888. [PMID: 31693165 DOI: 10.1002/ijc.32776] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/14/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022]
Abstract
Our study aimed to analyze the evolution of molecular portraits of BRCA1-driven ovarian cancer (OC) during treatment. BRCA1 loss-of-heterozygosity status (LOH) and exome profiles were investigated in serial OC samples from 13 patients, which included primary tumors (n = 11) obtained before neoadjuvant therapy (NACT) or at primary debulking surgery, residual post-NACT cancer tissues (n = 13) and tumor relapses (16 samples from 13 patients). Loss of the wild-type BRCA1 allele was detected in 11/11 (100%) primary tumors, 6/13 (46%) residual post-NACT OC samples and 15/16 (94%) OC relapses. Full tumor triplets were available for four patients undergoing NACT; whereas primary carcinomas from these patients demonstrated BRCA1 LOH, the retention of the wild-type allele was detected in all four post-NACT residual tumors. These four women provided to the study 5 recurrent OC samples; 4 out of 5 tumor relapses had BRCA1 LOH thus resembling BRCA1 status observed in primary but not residual OC tissues. TP53 mutation was detected in 12 out of 13 patients and was retained across all serial samples. OC relapses tended to acquire additional intragenic mutations in genes involved in cell migration, adhesion and cell junction assembly. BRCA1-driven OCs demonstrate the plasticity of BRCA1 status during the treatment course. NACT results in rapid selection of pre-existing BRCA1-proficient cells. However, BRCA1 proficiency appears to be disadvantageous in the absence of platinum exposure, as tumor relapses usually re-acquire BRCA1 LOH during therapy holidays.
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Affiliation(s)
- Anna P Sokolenko
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia
| | - Ilya V Bizin
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
| | - Elena V Preobrazhenskaya
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia
| | - Tatiana V Gorodnova
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
| | - Alexander O Ivantsov
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
| | - Aglaya G Iyevleva
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia
| | - Elena L Savonevich
- Department of Obstetrics and Gynecology, Grodno State Medical University, Grodno, Belarus
| | - Khristina B Kotiv
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
| | - Ekaterina Sh Kuligina
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia
| | - Evgeny N Imyanitov
- Department of Tumour Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia.,Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia
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15
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Aleksakhina SN, Kashyap A, Imyanitov EN. Mechanisms of acquired tumor drug resistance. Biochim Biophys Acta Rev Cancer 2019; 1872:188310. [PMID: 31442474 DOI: 10.1016/j.bbcan.2019.188310] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2019] [Revised: 08/09/2019] [Accepted: 08/09/2019] [Indexed: 12/22/2022]
Abstract
Systemic therapy often results in the reduction of tumor size but rarely succeeds in eradicating all cancer cells. Drug efflux, persistence of cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and down-regulation of apoptosis are the most known general causes of therapy failure. Tumor escape from targeted compounds often involves pathway-specific mechanisms, which result in the restoration of the affected signaling cascade. The acquisition of drug resistance is mediated by mutations, changes in gene expression, alternative splicing, post-translational protein modifications, etc. Development of resistance to therapy may not necessary involve the emergence of new tumor clones: multiple studies demonstrate that even chemonaive neoplasms already have a small population of cells, which are capable of surviving therapeutic pressure and facilitating the disease progression. Use of combinations of cancer drugs, sequential therapy, adaptive therapy and topical ablation of drug-resistant malignant lumps may help to prolong the time to treatment failure. Many studies on mechanisms of drug resistance rely on the use of cell cultures and animal models. The development of approaches that allow efficient monitoring of the evolution of tumor phenotype in clinical setting presents a challenge.
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Affiliation(s)
- Svetlana N Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
| | - Aniruddh Kashyap
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
| | - Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; Department of Oncology, I.I. Mechnikov North-Western Medical University, St.-Petersburg 195067, Russia.
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