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High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1-4 patterned by distinct mutational processes5,6, tumour heterogeneity7-9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11-13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFß signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.
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Evasão da Resposta Imune , Mutação , Neoplasias Ovarianas , Feminino , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Cistadenocarcinoma Seroso/patologia , Recombinação Homóloga , Evasão da Resposta Imune/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral , Fator de Crescimento Transformador beta , Genes BRCA1 , Genes BRCA2RESUMO
INTRODUCTION: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result. METHODS: GIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020-August 2023. Clinical data were abstracted from the medical record. RESULTS: Of 477 HRD test results identified, 57 (12%) were inconclusive. High-grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high-grade serous histology; no cases with clear cell or endometrioid histology were HRD-positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self-reported race, and histology were not associated with an inconclusive result. CONCLUSIONS: Surgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.
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OBJECTIVES: Mesonephric (MA) and mesonephric-like (MLA) adenocarcinomas are rare cancers, and data on clinical behavior and response to therapy are limited. We sought to report molecular features, treatment, and outcomes of MA/MLA from a single institution. METHODS: Patients with MA (cervix) or MLA (uterus, ovary, other) treated at Memorial Sloan Kettering Cancer Center (MSK) from 1/2008-12/2021 underwent pathologic re-review. For patients with initial treatment at MSK, progression-free survival (PFS1) was calculated as time from initial surgery to progression or death; second PFS (PFS2) was calculated as time from start of treatment for recurrence to subsequent progression or death. Overall survival (OS) was calculated for all patients. Images were retrospectively reviewed to determine treatment response. Somatic genetic alterations were assessed by clinical tumor-normal sequencing (MSK-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]). RESULTS: Of 81 patients with confirmed gynecologic MA/MLA, 36 received initial treatment at MSK. Sites of origin included cervix (n = 9, 11%), uterus (n = 42, 52%), ovary (n = 28, 35%), and other (n = 2, 2%). Of the 36 patients who received initial treatment at MSK, 20 (56%) recurred; median PFS1 was 33 months (95% CI: 17-not evaluable), median PFS2 was 8.3 months (95% CI: 6.9-14), and median OS was 87 months (95% CI: 58.2-not evaluable). Twenty-six of the 36 patients underwent MSK-IMPACT testing, and 25 (96%) harbored MAPK pathway alterations. CONCLUSION: Most patients diagnosed with early-stage disease ultimately recurred. Somatic MAPK signaling pathway mutations appear to be highly prevalent in MA/MLA, and therapeutics that target this pathway are worthy of further study.
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Adenocarcinoma , Humanos , Feminino , Estudos Retrospectivos , Adenocarcinoma/genética , Adenocarcinoma/terapia , Adenocarcinoma/patologia , Mutação , Ovário/patologia , Colo do Útero/patologiaRESUMO
OBJECTIVE: HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment. METHODS: We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed. RESULTS: This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated. CONCLUSIONS: We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy. CLINICALTRIALS: govidentifier: NCT04513665.
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Anticorpos Biespecíficos , Carcinossarcoma , Neoplasias do Endométrio , Feminino , Humanos , Receptor ErbB-2/metabolismo , Hibridização in Situ Fluorescente , Recidiva Local de Neoplasia/patologia , Trastuzumab , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Carcinossarcoma/tratamento farmacológico , Carcinossarcoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVES: To compare oncologic outcomes of secondary cytoreductive surgery (SCS) before and after FDA approval of Poly(ADP-ribose) polymerase inhibitor (PARPi) and bevacizumab maintenance therapies for platinum-sensitive recurrent ovarian cancer (PS-ROC). METHODS: Patients who underwent SCS for first recurrence of PS-ROC from 1/1/2013-1/1/2020 were identified. Exclusion criteria included prior chemotherapy for recurrence, bowel obstruction procedures, and palliative surgery. Data were dichotomized pre/post 1/2017, relative to FDA approval of PARPi and bevacizumab maintenance for ROC. Second progression-free survival (PFS2), the primary endpoint, was estimated using Kaplan-Meier method. RESULTS: Overall, 245 patients underwent SCS-131 (53%) pre- and 114 (47%) post-approval. Most patients had high-grade serous tumors (83% and 90%, respectively; p = 0.13). Deleterious BRCA1/2 alterations were identified in 27% (32/120) and 28% (32/113) of tested patients, respectively (p = 0.88). Disease-free intervals pre- and post-approval were: 6-12 months, 16% and 18%; 12-30 months, 56% and 59%; and >30 months, 28% and 24%, respectively (p = 0.73). Overall, 85% and 86% of patients, respectively, achieved complete gross resection (CGR; p > 0.99). PARPi maintenance use increased from 3.8% to 27% (p < 0.001) following approval, and bevacizumab from 1.5% to 12% (p < 0.001). Median PFS2 was 19 and 20.1 months, respectively. In the post group, 1-year PFS2 rate was 84.5% (95% CI, 75.7-90.4%) for patients with CGR vs 56.2% (95% CI, 29.5-76.2%) for those with residual disease; 3-year PFS2 rates were 31.3% (95% CI, 21.6-41.4%) and 12.5% (95% CI, 2.1-32.8%), respectively (p = 0.001). CONCLUSIONS: CGR during SCS is associated with improved PFS2 compared to suboptimal resection. Prospective randomized trials are warranted to elucidate the role of SCS as more therapeutics become available.
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Bevacizumab , Procedimentos Cirúrgicos de Citorredução , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Procedimentos Cirúrgicos de Citorredução/métodos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Idoso , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Intervalo Livre de Progressão , Quimioterapia de Manutenção/métodos , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologiaRESUMO
OBJECTIVE: Mirvetuximab soravtansine may be a potentially effective therapeutic option for ovarian low-grade serous carcinoma (LGSC), but the prevalence of folate receptor alpha (FRα) overexpression in this tumor type is unknown. We sought to characterize FRα expression in LGSC and its association with clinical and molecular features. METHODS: FRα immunohistochemistry was performed on a tissue microarray comprised of 89 LGSCs and 42 ovarian serous borderline tumors (SBTs). Clinical tumor-normal panel-based sequencing was performed on 78 LGSCs. Associations between FRα-high status and clinicopathologic characteristics and survival outcomes were examined. RESULTS: Of 89 LGSCs, 36 (40%) were FRα-high (≥75% of viable tumor cells exhibiting moderate-to-strong membranous expression). Of 9 patients with LGSC and samples from different timepoints, 4 (44%) had discordant results, with conversion from FRα-negative to FRα-high in 3 (33%) cases. There was no association between FRα-high status with age, race, or progression-free/overall survival. A MAPK pathway genetic alteration, most commonly involving KRAS (n = 23), was present in 45 (58%) LGSCs. Those lacking MAPK pathway alterations were more likely to be FRα-high compared to MAPK-altered LGSCs (61% vs 20%, p < 0.001). In SBTs, FRα-high expression was associated with high-risk (micropapillary) histology and/or subsequent LGSC recurrence compared to conventional SBTs without malignant recurrence (53% vs 9%, p = 0.008). CONCLUSIONS: Future studies of FRα-directed therapy in patients with LGSC are warranted. Discordant FRα status at recurrence suggests potential benefit for retesting. A biomarker-driven approach to direct treatment selection in LGSC is recommended. As high FRα expression is more common amongst tumors lacking MAPK pathway genetic alterations, FRα testing to determine eligibility for mirvetuximab soravtansine therapy is particularly recommended for this subgroup.
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Cistadenocarcinoma Seroso , Receptor 1 de Folato , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/tratamento farmacológico , Receptor 1 de Folato/genética , Receptor 1 de Folato/biossíntese , Receptor 1 de Folato/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Gradação de Tumores , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Imuno-Histoquímica , Idoso de 80 Anos ou mais , ImunoconjugadosRESUMO
OBJECTIVE: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC). METHODS: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020. PR status was evaluated via immunohistochemistry. Eligible patients had PR expression ≥1% on tissue collected within 3 years of enrollment. Patients received 50 mg of onapristone-XR twice daily until disease progression or treatment discontinuation. Adverse events were graded by Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints were response duration, clinical benefit rate (CBR), and safety. RESULTS: Five patients with LGSOC and 1 with EEC enrolled, but both cohorts closed early due to slow accrual. Fourteen patients with aGCT enrolled and completed stage 1 accrual. No responses were observed. Four patients with LGSOC were evaluable, with median PFS of 4.4 months (range, 1.8-NE) and CBR of 50% (range, 6.8%-93.2%). All 14 patients with aGCT were evaluable, with median PFS of 2.8 months (range, 1.6-4.9), 6-month PFS rate of 21.4% (range, 5.2%-44.8%), 12-month PFS rate of 14.3% (range, 2.3%-36.6%), and a CBR of 35.7% (range, 12.8%-64.9%). CONCLUSIONS: The study did not meet its primary endpoint. While onapristone-XR was well tolerated in all 3 arms, no objective responses were observed.
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OBJECTIVE: To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC. METHODS: We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015-12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset. RESULTS: Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1-6.0] vs. 1.2 mut/Mb [0.6-2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01). CONCLUSIONS: OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.
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Proteína BRCA1 , Neoplasias Ovarianas , Humanos , Feminino , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias Ovarianas/patologia , Mutação em Linhagem Germinativa , Recombinação Homóloga , Fenótipo , Células Germinativas/patologia , Predisposição Genética para DoençaRESUMO
OBJECTIVES: To develop a pre-operative tool to estimate the risk of peri-operative packed red blood cell transfusion in primary debulking surgery. METHODS: We retrospectively reviewed an institutional database to identify patients who underwent primary debulking surgery for ovarian cancer at a single center between January 1, 2001 and May 31, 2019. Receiver operating characteristic curve and area under the receiver operating characteristic curve (AUC) were calculated. Five-fold cross-validation was applied to the multivariate model. Significant variables were assigned a 'BLOODS' (BLood transfusion Over an Ovarian cancer Debulking Surgery) score of +1 if present. A total BLOODS score was calculated for each patient, and the odds of receiving a transfusion was determined for each score. RESULTS: Overall, 1566 patients met eligibility criteria; 800 (51%) underwent a peri-operative blood transfusion. Odds ratios (OR) were statistically significant for American Society of Anesthesiologists scores of 3 and 4 (OR 1.34, 95% confidence interval (95% CI) 1.09 to 1.63), pre-operative levels of cancer antigen 125 (CA125) (OR 2.43, 95% CI 1.98 to 2.99), platelets (OR 1.59, 95% CI 1.45 to 1.74), obesity (OR 0.76, 95% CI 0.60 to 0.96), presence of carcinomatosis (OR 2.45, 95% CI 1.93 to 3.11), bulky upper abdominal disease (OR 2.86, 95% CI 2.32 to 3.54), pre-operative serum albumin level (OR 0.31, 95% CI 0.24 to 0.40), and pre-operative hemoglobin level (OR 0.56, 95% CI 0.51 to 0.61). The corrected AUC was 0.748 (95% CI 0.693 to 0.804). BLOODS scores of 0 and 5 corresponded to 11% and 73% odds, respectively, of receiving a peri-operative blood transfusion. CONCLUSIONS: We developed a universal pre-operative scoring system, the BLOODS score, to help identify patients with ovarian cancer who would benefit from surgical planning and blood-saving techniques. The BLOODS score was directly proportional to the American Society of Anesthesiologists score, presence of upper abdominal disease, carcinomatosis, CA125 level, and platelets level. We believe this model can help physicians with surgical planning and can benefit patient outcomes.
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Procedimentos Cirúrgicos de Citorredução , Neoplasias Ovarianas , Humanos , Feminino , Estudos Retrospectivos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Pessoa de Meia-Idade , Procedimentos Cirúrgicos de Citorredução/métodos , Idoso , Transfusão de Sangue/estatística & dados numéricos , Transfusão de Sangue/métodos , Medição de Risco/métodos , AdultoRESUMO
Low-grade serous carcinoma is a rare epithelial ovarian cancer subtype with distinct clinical, histologic, and molecular features. Improved understanding of this disease subtype has prompted recent advances in treatment options. Although low-grade serous carcinoma historically has been treated following a high-grade serous carcinoma paradigm, new data have called into question the utility of platinum retreatment, addressed the possibility of first-line hormonal treatment, and brought forth therapeutic options targeting the MAPK pathway and cyclin D kinase in low-grade tumors. Ongoing research efforts seek to leverage the unique features of low-grade serous carcinoma to refine treatment options for patients with this rare tumor subtype.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Padrão de Cuidado , Humanos , Feminino , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/tratamento farmacológico , Cistadenocarcinoma Seroso/terapia , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/diagnóstico , Gradação de Tumores , Carcinoma Epitelial do Ovário/terapia , Carcinoma Epitelial do Ovário/patologia , Terapia de Alvo MolecularRESUMO
BACKGROUND: Health outcomes are strongly impacted by social determinants of health, including social risk factors and patient demographics, due to structural inequities and discrimination. Primary care is viewed as a potential medical setting to assess and address individual health-related social needs and to collect detailed patient demographics to assess and advance health equity, but limited literature evaluates such processes. METHODS: We conducted an analysis of cross-sectional survey data collected from n = 507 Maryland Primary Care Program (MDPCP) practices through Care Transformation Requirements (CTR) reporting in 2022. Descriptive statistics were used to summarize practice responses on social needs screening and demographic data collection. A stepwise regression analysis was conducted to determine factors predicting screening of all vs. a targeted subset of beneficiaries for unmet social needs. RESULTS: Almost all practices (99%) reported conducting some form of social needs screening and demographic data collection. Practices reported variation in what screening tools or demographic questions were employed, frequency of screening, and how information was used. More than 75% of practices reported prioritizing transportation, food insecurity, housing instability, financial resource strain, and social isolation. CONCLUSIONS: Within the MDPCP program there was widespread implementation of social needs screenings and demographic data collection. However, there was room for additional supports in addressing some challenging social needs and increasing detailed demographics. Further research is needed to understand any adjustments to clinical care in response to identified social needs or application of data for uses such as assessing progress towards health equity and the subsequent impact on clinical care and health outcomes.
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Habitação , Medicare , Idoso , Humanos , Estados Unidos , Maryland , Estudos Transversais , Atenção Primária à Saúde , Coleta de DadosRESUMO
Low-grade serous ovarian cancer was initially described as a distinct type of rare epithelial ovarian cancer 20 years ago; however, only recently have physicians begun to leverage the understanding of the clinical behavior and molecular profile of this disease for treatment. The use of routine next-generation sequencing has allowed a deeper understanding of the molecular drivers of this disease and shown how molecular alterations in mitogen-activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies are changing the way this disease is viewed and treated. In addition, endocrine therapy can provide prolonged disease stability with generally mild toxicity, as well as promising response rates in recent studies examining combination therapy with CDK 4/6 inhibitors in the upfront and recurrent setting. Once seen merely as a chemo-resistant form of ovarian cancer, recent studies have worked to harness the unique features of low-grade serous ovarian cancer to provide individualized treatment options for patients with this disease.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/genética , Gradação de Tumores , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , MutaçãoRESUMO
BACKGROUND: Data on platinum sensitivity of low-grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease. METHODS: Patients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum-based chemotherapy and to second- to fifth-line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank-sum and two-tailed Fisher exact tests were employed. RESULTS: Of 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p = .027). The 15 remaining patients had stable disease on first-line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST-evaluable responses to second-line and 27 to third-line chemotherapy. Objective response rates to platinum-based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively. CONCLUSIONS: Primary platinum-based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Neoplasias Peritoneais , Feminino , Humanos , Neoplasias Ovarianas/patologia , Bevacizumab/uso terapêutico , Platina/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Peritoneais/terapiaRESUMO
OBJECTIVES: To compare outcomes of patients with high-grade epithelial ovarian cancer (EOC) who underwent secondary cytoreduction surgery (SCS) after up-front treatment with neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS) versus primary debulking surgery (PDS). METHODS: Patients with high-grade EOC who underwent SCS from 2/1/2004-10/31/2021 were classified by up-front treatment. Clinical and treatment characteristics were compared between cohorts. Progression-free survival (PFS2) and overall survival (OS2) following SCS were compared using a Cox model adjusted for stage, age at SCS, and number of years between end of chemotherapy and SCS. RESULTS: Of 374 patients, 62 (17%) underwent NACT-IDS and 312 (83%) PDS. Justification for NACT was disease extent (n = 57, 92%), comorbidities (n = 3, 5%), and thromboembolism (n = 2, 3%). The NACT-IDS cohort had a higher median age at SCS (64 years [IQR: 56-70] vs 59 years [IQR: 53-66]; P = .03), higher proportion of stage III/IV disease (100% vs 81%; P < .001), and shorter median interval between end of chemotherapy and SCS (1.5 years [IQR: 1.1-2.3] vs 1.9 years [IQR: 1.3-3.1]; P = .01). Achievement of complete gross resection at SCS did not differ between NACT-IDS and PDS (84% vs 88%; P = .18). PFS2 (HR: 1.19, 95% CI: 0.83-1.71) and OS2 (HR: 0.96, 95% CI: 0.57-1.63) did not vary by primary treatment modality after adjusting for clinically relevant covariates. CONCLUSIONS: Despite more extensive disease at presentation, patients with high-grade EOC who recur after NACT-IDS seem to have similar surgical and survival outcomes after SCS compared to patients who recur after PDS, suggesting that prior NACT-IDS should not preclude SCS.
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Neoplasias Ovarianas , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Procedimentos Cirúrgicos de Citorredução , Quimioterapia Adjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
OBJECTIVE: We previously developed preoperative and pre-chemotherapy modified versions of the male International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic model and assessed it in female patients with germ cell tumors (GCTs). We sought to validate these modified IGCCCG (mIGCCCG) models in a new cohort. METHODS: We queried institutional databases for female patients with GCTs treated at Memorial Sloan Kettering Cancer Center from 1/1/1990-6/1/2020. The mIGCCCG model classifies patients with non-dysgerminomas as good, intermediate, or poor risk based on tumor markers using male IGCCCG cutoffs and absence/presence of non-pulmonary/peritoneal visceral metastasis. In dysgerminomas, good- and intermediate-risk groups are defined by absence/presence of non-pulmonary/peritoneal visceral metastasis. Progression-free survival (PFS) and overall survival (OS) were estimated for each group in the validation and combined original and validation cohorts. Associations between individual clinical factors and outcomes were evaluated. RESULTS: Among 183 female patients with GCTs, clinical characteristics and outcomes were similar between the original (n = 93) and validation (n = 90) cohorts. In multivariable models, higher stage, older age, and non-dysgerminoma histology predicted worse PFS and OS (p < 0.05). Among 162 patients who received chemotherapy, preoperative and pre-chemotherapy mIGCCCG models were significantly associated with PFS and OS (p < 0.001 for all groups). With the preoperative model, 3-year PFS rates were 94%, 76%, and 50% in the good-, intermediate-, and poor-risk patients, respectively; OS rates were 96%, 86%, and 52%, respectively. Even within stage groups, mIGCCCG risk classifications were associated with clinical outcomes. CONCLUSIONS: A female-specific mIGCCCG risk model effectively stratifies patients and should be incorporated into clinical trials.
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Disgerminoma , Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Humanos , Masculino , Feminino , Prognóstico , Intervalo Livre de Progressão , Biomarcadores Tumorais , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVE: To assess postoperative complications after secondary cytoreductive surgery (SCS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), we conducted an exploratory analysis of patients with platinum-sensitive recurrent ovarian cancer enrolled in a randomized phase II trial. METHODS: Complications occurring within 30 days of surgery were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; only hemoglobin and platelet levels were assessed. Patients were grouped by CTCAE grade ≥ 3 and < 3 complications. RESULTS: Among 83 eligible patients, 33 (40%) had grade ≥ 3 complications and 50 (60%) had grade < 3 complications; anemia and abdominal infections were the most common. There were no perioperative mortalities. Time to initiation of postoperative chemotherapy for patients with grade ≥ 3 and grade < 3 events was 34 days (range, 18-60) and 31 days (range, 21-43), respectively (P = .017). Median progression-free survival (PFS) did not significantly differ between patients with grade ≥ 3 and grade < 3 complications (11.2 months [95% CI: 9.3-14.4] vs 14.9 months [95% CI: 11.3-16.5], respectively; P = .186), nor did median overall survival (OS) (46.9 months [95% CI: 34-NE] vs 68.2 months [95% CI: 52.1-NE], respectively; P = .053). CONCLUSION: Postoperative complications following SCS with or without HIPEC were associated with slight delays in chemotherapy initiation but did not significantly impact oncologic outcomes.
Assuntos
Hipertermia Induzida , Neoplasias Ovarianas , Humanos , Feminino , Quimioterapia Intraperitoneal Hipertérmica/efeitos adversos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Terapia Combinada , Hipertermia Induzida/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Morbidade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
OBJECTIVES: We assessed a conditional probability of survival (CPS) model to determine the probability of living 10 years after ovarian cancer diagnosis after having already survived 5 years. METHODS: We identified patients newly diagnosed with high-grade epithelial ovarian cancer from 1/1/2001-12/31/2009 and treated at our institution. Patients with <3 years follow-up were excluded. CPS was defined as the probability of surviving additional years (y) based on the condition a patient had already survived a given time (x): S(x + y)/S(x). Confidence intervals were estimated using a variation of Greenwood's formula. RESULTS: Of 916 patients meeting inclusion criteria, 473 (52%) were diagnosed from 2001 to 2005 and 443 (48%) from 2006 to 2009. Median age at diagnosis was 60 years (range, 25-95). The conventional 10-year OS rate for all patients was 29% (95% CI: 26%-32%)-75% (95% CI: 68%-82%) for stage I/II disease, 22% (95% CI: 19%-26%) for stage III, and 6.9% (95% CI: 3.9%-12%) for stage IV. For patients <65 years, the 10-year CPS for 5-year survivors was 65% (95% CI: 59%-70%); for those ≥65 years, it was 48% (95% CI: 38%-57%). For patients <65 years, the 10-year CPS for 5-year survivors by stage was: stage I/II, 89% (95% CI: 81%-94%); stage III, 58% (95% CI: 50%-66%); and stage IV, 26% (95% CI: 12%-42%). For patients ≥65 years, rates by stage were 78% (95% CI: 53%-91%), 42% (95% CI: 30%-53%), and 29% (95% CI: 7%-56%), respectively. CONCLUSIONS: For long-term survivors with high-grade epithelial ovarian cancer, CPS provides better prediction of survival than conventional methods.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Probabilidade , SobreviventesRESUMO
OBJECTIVE: We investigated the feasibility, safety, and survival outcomes of intrathoracic cytoreduction during primary debulking surgery (PDS) for advanced ovarian cancer. METHODS: We conducted a database review of patients with stage IIIB-IV ovarian (including fallopian tube and primary peritoneal) carcinoma who underwent PDS at our institution from 01/01/2006-9/30/2021. Patients who underwent intrathoracic cytoreduction as part of primary treatment were included. Patients who received neoadjuvant chemotherapy or surgery for reasons other than cytoreduction were excluded. RESULTS: Among 178 patients identified for inclusion, complete gross resection (CGR) in the abdomen and thorax was achieved in 131 (74%); 45 (25%) had optimal cytoreduction, and 2 (1%) had suboptimal cytoreduction. Thirty-one patients (17%) had at least one grade ≥ 3 complication; 8 were possibly related to intrathoracic cytoreduction. There were no deaths within 30 days following surgery. Median length of follow-up among survivors was 53.4 months. Among all patients, the median PFS was 33.6 months (95% CI: 24.7-61.9) and the 3-year PFS rate was 48.9% (95% CI: 41.2%-56.2%). Median OS was 81.3 months (95% CI: 68.9-103). When stratified by residual disease status, median PFS was 51.8 months when CGR was achieved versus 16.7 months with residual disease (HR: 2.17; P < .001) and median OS was 97.6 months when CGR was achieved versus 65.9 months with residual disease (HR: 2.05; P = .003). CONCLUSIONS: Intrathoracic cytoreduction during PDS for advanced ovarian cancer is both safe and feasible. CGR can be achieved in patients with intrathoracic disease if properly selected, and could significantly improve both PFS and OS.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/patologia , Procedimentos Cirúrgicos de Citorredução , Estudos Retrospectivos , Estadiamento de Neoplasias , Carcinoma Epitelial do Ovário/tratamento farmacológico , Terapia NeoadjuvanteRESUMO
OBJECTIVES: To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. METHODS: Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. RESULTS: Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1, BRCA2, RAD51C) and Lynch syndrome (MSH2, MSH6) genes had biallelic loss in tumors (n = 15). CONCLUSIONS: gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members.
Assuntos
Carcinossarcoma , Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias do Endométrio , Neoplasias Ovarianas , Humanos , Feminino , Carcinossarcoma/genética , Carcinossarcoma/patologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologiaRESUMO
Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade serous carcinoma diagnosis and treatment, a panel of experts convened for a workshop in October 2022 to develop a consensus document addressing pathology, translational research, epidemiology and risk, clinical management, and ongoing research. In addition, the patient perspective was discussed. The recommendations developed by this expert panel-presented in this consensus document-will guide practitioners in all settings regarding the clinical management of women with low-grade serous carcinoma and discuss future opportunities to improve research and patient care.