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OBJECTIVE: Our goal was to compare molecular and immune profiles of vulvovaginal melanoma (VVM) with cutaneous melanoma (CM) and explore the significance of immune checkpoint inhibitor (ICI) agents on survival. METHODS: Samples from VVM and CM tumors underwent comprehensive molecular and immune profiling. Treatment and survival data were extracted from insurance claims data and OS was calculated from time of ICI treatment to last contact. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. RESULTS: Molecular analysis was performed on 142 VVM and 3823 CM tumors. VVM demonstrated significantly (q < 0·01) less frequent BRAF and more frequent KIT, ATRX, and SF3B1 mutations. Alterations in pathways involving DNA damage and mRNA splicing were more common in VVM, while alterations in cell cycle and chromatin remodeling were less common. Immunogenicity of VVM was lower than CM, with an absence of high TMB (0% vs 46.9%) and lower PD-L1 positivity (18·0% vs 29·5%). Median immune checkpoint gene expression was lower in VVM, as were cell fractions for type I macrophages and CD8+ T-cells(q < 0·01). Myeloid dendritic cells were increased in VVM(q < 0·01). Median OS was shorter for VVM than for CM patients treated with ICIs (17·6 versus 37·9 months, HR:1·65 (95% CI 1·02-2·67) p = 0·04). CONCLUSIONS: VVM has a distinct molecular and immune profile compared to CM, which may contribute to the worse survival in VVM compared to CM patients treated with ICI therapy. Though ICIs have been a mainstay of treatment in recent years, our findings suggest that new therapeutic strategies are needed.
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OBJECTIVE: Investigate racial disparities in outcomes and molecular features in Black and White patients with endometrioid endometrial carcinoma (EEC). METHODS: Black and White patients diagnosed with EEC who underwent hysterectomy ± adjuvant treatment in SEER, National Cancer Database (NCDB), the Genomics Evidence Neoplasia Information Exchange (GENIE) project (v.13.0), and eight NCI-sponsored randomized phase III clinical trials (RCTs) were studied. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for cancer-related death (CRD), non-cancer death (NCD), and all-cause death. RESULTS: Black (n = 4397) vs. White (n = 47,959) patients in SEER had a HR (95% CI) of 2.04 (1.87-2.23) for CRD and 1.22 (1.09-1.36) for NCD. In NCDB, the HR (95% CI) for death in Black (n = 13,468) vs. White (n = 155,706) patients was 1.52 (1.46-1.58) dropping to 1.29 (1.23-1.36) after propensity-score matching for age, comorbidity, income, insurance, grade, stage, LVSI, and treatment. In GENIE, Black (n = 109) vs. White (n = 1780) patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR, CCND1, and PI3K-pathway-related gene mutations. In contrast, TP53 and DNA-repair-related gene mutation frequency as well as tumor mutational burden-high status were similar in Black and White patients. In RCTs, Black (n = 187) vs. White (n = 2877) patients were more likely to have advanced or recurrent disease, higher grade, worse performance status and progressive disease. Risk of death in Black vs. White patients in RCTs was 2.19 (1.77-2.71) persisting to 1.32 (1.09-1.61) after matching for grade, stage, and treatment arm while balancing age and performance status. CONCLUSIONS: Differences exist in clinical presentation, outcomes, and molecular features in Black vs. White patients with EEC in real-world registries and RCTs. Targeted-drug development, strategies to modify social determinants, and diverse inclusion in RCTs are approaches to reduce disparities.
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Negro ou Afro-Americano , Carcinoma Endometrioide , Progressão da Doença , Neoplasias do Endométrio , População Branca , Humanos , Feminino , População Branca/estatística & dados numéricos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/terapia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/etnologia , Carcinoma Endometrioide/mortalidade , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/terapia , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos/epidemiologia , Programa de SEER , Sistema de Registros , Ensaios Clínicos Fase III como Assunto , AdultoRESUMO
PURPOSE: We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities. METHODS: Non-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC). RESULTS: This study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at ≥65 years old was more common in Black vs. White patients (26% vs. 13%, respectively). CONCLUSIONS: Histology matters in survival disparities and diagnosis at ≥65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors.
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Negro ou Afro-Americano , Carcinoma de Células Escamosas , Neoplasias do Colo do Útero , População Branca , Humanos , Feminino , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/etnologia , Neoplasias do Colo do Útero/mortalidade , População Branca/estatística & dados numéricos , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/etnologia , Carcinoma de Células Escamosas/mortalidade , Adulto , Adenocarcinoma/patologia , Adenocarcinoma/etnologia , Adenocarcinoma/mortalidade , Estados Unidos/epidemiologia , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Fatores Socioeconômicos , Modelos de Riscos Proporcionais , Estadiamento de NeoplasiasRESUMO
OBJECTIVE: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets. METHODS: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses. GTN samples encompassed complete moles, choriocarcinoma, epithelioid trophoblastic tumors (ETT), and placental site trophoblastic tumors (PSTT). RESULTS: We analyzed 30 cases of GTN including 15 choriocarcinoma, 7 ETT, 5 PSTT, 1 invasive mole and 2 mixed histologies. The median age was 41.5. GTN samples were found to be PD-L1 positive (92.3%), tumor mutational burden (TMB) low (92.8%), and microsatellite stable (MSS) (100%). Forty-six percent of choriocarcinoma specimens contained a genomic alteration including TP53 (33%) and homologous recombination repair (HRR) (13%) genes. Alterations in RTK-RAS pathway signaling was present in 40% of ETT cases. CONCLUSIONS: The high rate of PD-L1 positivity in this real-world database and reported in prior literature support continued clinical trial development evaluating immunotherapy for treatment of GTN. Other potential targeted treatments identified include Wee1, PARP and MEK inhibitors based on molecular alterations in TP53, HRR genes, and RTK-RAS pathways respectively.
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Doença Trofoblástica Gestacional , Humanos , Feminino , Doença Trofoblástica Gestacional/genética , Doença Trofoblástica Gestacional/tratamento farmacológico , Doença Trofoblástica Gestacional/patologia , Adulto , Gravidez , Pessoa de Meia-Idade , Sequenciamento do Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Terapia de Alvo Molecular/métodos , Antígeno B7-H1/genética , Antígeno B7-H1/antagonistas & inibidores , Adulto Jovem , Coriocarcinoma/genética , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologiaRESUMO
OBJECTIVE: This study investigated the risk of an aggressive endometrial cancer (EC) diagnosis by race, ethnicity, and country of origin to further elucidate histologic disparities in non-Hispanic Black (NHB), Hispanic, Asian/Pacific Islander (API), American Indian/Alaskan Native (AIAN) vs. non-Hispanic White (NHW) patients, particularly in Hispanic or API subgroups. METHODS: Patient diagnosed between 2004 and 2020 with low grade (LG)-endometrioid endometrial cancer (ECC) or an aggressive EC including grade 3 EEC, serous carcinoma, clear cell carcinoma, mixed epithelial carcinoma, or carcinosarcoma in the National Cancer Database were studied. The odds ratio (OR) and 95% confidence interval (CI) for diagnosis of an aggressive EC histology was estimated using logistic modeling. RESULTS: There were 343,868 NHW, 48,897 NHB, 30,013 Hispanic, 15,015 API and 1646 AIAN patients. The OR (95% CI) for an aggressive EC diagnosis was 3.07 (3.01-3.13) for NHB, 1.08 (1.06-1.11) for Hispanic, 1.17 (1.13-1.21) for API and 1.07 (0.96-1.19) for AIAN, relative to NHW patients. Subset analyses by country of origin illustrated the diversity in the OR for an aggressive EC diagnosis among Hispanic (1.18 for Mexican to 1.87 for Dominican), Asian (1.14 Asian Indian-Pakistani to 1.48 Korean) and Pacific Islander (1.00 for Hawaiian to 1.33 for Samoan) descendants. Hispanic, API and AIAN patients were diagnosed 5-years younger that NHW patients, and the risk for an aggressive EC histology were all significantly higher than NHW patients after correcting for age. Insurance status was another independent risk factor for aggressive histology. CONCLUSIONS: Risk of an aggressive EC diagnosis varied by race, ethnicity, and country of origin. NHB patients had the highest risk, followed by Dominican, South/Central American, Cuban, Korean, Thai, Vietnamese, and Filipino descendants.
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Neoplasias do Endométrio , Humanos , Feminino , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/patologia , Pessoa de Meia-Idade , Idoso , Estados Unidos/epidemiologia , Adulto , População Branca/estatística & dados numéricos , Hispânico ou Latino/estatística & dados numéricos , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/etnologia , Adenocarcinoma de Células Claras/epidemiologia , Carcinossarcoma/patologia , Carcinossarcoma/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico/estatística & dados numéricos , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/etnologia , Idoso de 80 Anos ou mais , Etnicidade/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/etnologia , Negro ou Afro-Americano/estatística & dados numéricosRESUMO
OBJECTIVE: HER2 status is not routinely evaluated in endometrioid endometrial cancer (E-EMCA), though it is frequently overexpressed or amplified in high grade E-EMCA and uterine serous carcinoma. Defining characteristics and survival outcomes of HER2+ E-EMCA could reveal subsets of patients who may benefit from targeted therapies. METHODS: 2927 E-EMCA tumors from the Caris Life Sciences database were analyzed by next-generation sequencing and whole exome sequencing, whole transcriptome sequencing, and immunohistochemistry for molecular and genomic features in a CLIA/CAP-certified laboratory (Caris Life Sciences, Phoenix, AZ). HER2 status was determined by transcriptomic cutoff extrapolated from uterine serous carcinoma. The relationship between HER2 status and patient outcomes was determined by Kaplan-Meier analysis. RESULTS: HER2 positivity was detected in 5.47% of E-EMCA. Differences in molecular alterations based on HER2 status were most apparent in microsatellite stable (MSS) tumors, which displayed increased TP53 mutations and loss of heterozygosity (LOH) and decreased PTEN and CTNNB1 mutations. HER2+ tumors had increased immune checkpoint gene expression and immune cell infiltration, particularly among MSS tumors. All HER2+ tumors displayed increased MAPK pathway activation scores (MPAS) and patients with HER2+ tumors experienced worse overall survival. CONCLUSIONS: HER2 positivity in E-EMCA corresponds with a unique molecular landscape, particularly in MSS tumors. HER2+ tumors are also associated with increased MAPK pathway activation and exhibit features of a more active immune microenvironment. These findings suggest a potential benefit of HER2 and MAPK targeted therapies as well as immunotherapies in this patient population.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Neoplasias Uterinas , Feminino , Humanos , Neoplasias do Endométrio/patologia , Carcinoma Endometrioide/patologia , Neoplasias Uterinas/patologia , Prognóstico , Mutação , Microambiente TumoralRESUMO
Importance: Disparities in survival exist between non-Hispanic Black (hereafter, Black) and non-Hispanic White (hereafter, White) patients with uterine cancer. Objective: To investigate factors associated with racial disparities in survival between Black and White patients with uterine cancer. Design, Setting, and Patients: This cohort study used data from the National Cancer Database on 274â¯838 Black and White patients who received a diagnosis of uterine cancer from January 1, 2004, to December 31, 2017, with follow-up through December 2020. Statistical analysis was performed in July 2022. Main Outcomes and Measures: Overall survival by self-reported race and evaluation of explanatory study factors associated with hazard ratio (HR) reduction for Black vs White patients. A propensity scoring approach was applied sequentially to balance racial differences in demographic characteristics, comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, and treatment. Results: The study included 32â¯230 Black female patients (mean [SD] age at diagnosis, 63.8 [10.0] years) and 242â¯608 White female patients (mean [SD] age at diagnosis, 63.5 [10.5] years) and had a median follow-up of 74.0 months (range, 43.5-113.8 months). Black patients were more likely than White patients to have low income (44.1% vs 14.0%), be uninsured (5.7% vs 2.6%), present with nonendometrioid histologic characteristics (46.1% vs 21.6%), have an advanced disease stage (34.1% vs 19.8%), receive first-line chemotherapy (33.8% vs 18.2%), and have worse 5-year survival (58.6% vs 78.5%). Among patients who received a diagnosis at younger than 65 years of age, the HR for death for Black vs White patients was 2.43 (95% CI, 2.34-2.52) in a baseline demographic-adjusted model and 1.29 (95% CI, 1.23-1.35) after balancing other factors. Comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, treatment, and unexplained factors accounted for 0.8%, 7.2%, 11.5%, 53.1%, 5.8%, 1.2%, and 20.4%, respectively, of the excess relative risk (ERR) among the younger Black vs White patients. Among patients 65 years or older, the HR for death for Black vs White patients was 1.87 (95% CI, 1.81-1.93) in the baseline model and 1.14 (95% CI, 1.09-1.19) after balancing other factors. Comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, treatment, and unexplained factors accounted for 3.0%, 7.5%, 0.0%, 56.2%, 10.6%, 6.9%, and 15.8%, respectively, of the ERR among Black vs White patients aged 65 years or older. Conclusions and Relevance: This study suggests that histologic subtype was the dominant factor associated with racial survival disparity among patients with uterine cancer, while insurance status represented the main modifiable factor for women younger than 65 years. Additional studies of interactions between biology and social determinants of health are merited.
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População Negra , Neoplasias Uterinas , População Branca , Feminino , Humanos , Estudos de Coortes , Estadiamento de Neoplasias , Neoplasias Uterinas/epidemiologia , Pessoa de Meia-Idade , Idoso , Análise de SobrevidaRESUMO
OBJECTIVE: HER2 is an important prognostic and therapeutic target in uterine serous carcinoma (USC). Optimal HER2 testing platforms have not been defined and guidelines for testing have changed over time. Our objective is to assess the concordance of HER2 positivity based on chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) and to determine the rate of downstream mutations that may affect response to HER2 directed therapy. METHODS: Utilizing the Caris tumor registry, 2192 USC tumors were identified and analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), IHC, and CISH. PD-L1 expression was tested by IHC. Microsatellite instability was tested by fragment analysis, IHC, and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor. HER2 positivity through IHC and CISH was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. RESULTS: There was a higher rate of HER2 positivity by IHC when using the 2018 guidelines compared to the 2007 guidelines (16.3% vs 12.3%). Concordance between IHC and CISH was 98.9%. ERBB2 amplification was identified by NGS in 10.5% of tumors. Compared to CISH results, this corresponds to a concordance rate of 91.6% and a positive predictive value (PPV) of 60.3%. Single gene alterations in HER2 amplified tumors that may implicate HER2 therapy resistance included PI3K (33.1%), KRAS (2.5%), and PTEN (1.3%). CONCLUSIONS: There was high concordance between HER2 positivity based on CISH and IHC. Rate of HER2 positivity is the lowest by NGS. Ultimately these testing platforms need to be validated by response to targeted therapy.
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Cistadenocarcinoma Seroso , Receptor ErbB-2 , Neoplasias Uterinas , Feminino , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Amplificação de Genes , Hibridização In Situ , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: The Laparoscopic Approach to Cervical Cancer (LACC) trial found that minimally invasive radical hysterectomy compared to open radical hysterectomy compromised oncologic outcomes and was associated with worse progression-free survival (PFS) and overall survival (OS) in early-stage cervical carcinoma. We sought to assess oncologic outcomes at multiple centers between minimally invasive (MIS) radical hysterectomy and OPEN radical hysterectomy. METHODS: This is a multi-institutional, retrospective cohort study of patients with 2009 FIGO stage IA1 (with lymphovascular space invasion) to IB1 cervical carcinoma from 1/2007-12/2016. Patients who underwent preoperative therapy were excluded. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinomas were included. Appropriate statistical tests were used. RESULTS: We identified 1093 cases for analysis-715 MIS (558 robotic [78%]) and 378. OPEN procedures. The OPEN cohort had more patients with tumors >2 cm, residual disease in the hysterectomy specimen, and more likely to have had adjuvant therapy. Median follow-up for the MIS and OPEN cohorts were 38.5 months (range, 0.03-149.51) and 54.98 months (range, 0.03-145.20), respectively. Three-year PFS rates were 87.9% (95% CI: 84.9-90.4%) and 89% (95% CI: 84.9-92%), respectively (P = 0.6). On multivariate analysis, the adjusted HR for recurrence/death was 0.70 (95% CI: 0.47-1.03; P = 0.07). Three-year OS rates were 95.8% (95% CI: 93.6-97.2%) and 96.6% (95% CI: 93.8-98.2%), respectively (P = 0.8). On multivariate analysis, the adjusted HR for death was 0.81 (95% CI: 0.43-1.52; P = 0.5). CONCLUSION: This multi-institutional analysis showed that an MIS compared to OPEN radical hysterectomy for cervical cancer did not appear to compromise oncologic outcomes, with similar PFS and OS.
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Laparoscopia , Neoplasias do Colo do Útero , Intervalo Livre de Doença , Feminino , Humanos , Histerectomia/métodos , Laparoscopia/métodos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias do Colo do Útero/patologiaRESUMO
OBJECTIVES: Disparate outcomes exist between Black and White patients with endometrial cancer (EC). One contributing factor is the disproportionately low representation of Black patients in clinical trials and in tumor molecular profiling studies. Our objective was to investigate molecular profiles of ECs in a cohort with a high proportion of tumors from Black patients. METHODS: A total of 248 EC samples and self-reported race data were collected from 6 institutions. Comprehensive tumor profiling and analyses were performed by Caris Life Sciences. RESULTS: Tumors from 105 (42%) Black and 143 (58%) White patients were included. Serous histology (58% vs 36%) and carcinosarcoma (25% vs 16%), was more common among Black patients, and endometrioid was less common (17% vs 48%) (p < 0.01). Differences in gene mutations between cohorts corresponded to observed histologic differences between races. Specifically, TP53 mutations were predominant in serous tumors. In endometrioid tumors, mutations in ARID1A were the most common, and high rates of MSI-H, MMRd, and TMB-H were observed. In carcinosarcoma tumors, hormone receptor expression was high in tumors of Black patients (PR 23.4%, ER 30.8%). When stratified by histology, there were no significant differences between tumors from Black and White women. CONCLUSIONS: This cohort had a high proportion of tumors from Black women. Distinct molecular profiles were driven primarily by more aggressive histologic subtypes among Black women. Continued effort is needed to include Black women and other populations under-represented in EC molecular profiling studies as targeted therapies and personalized medicine become mainstream.
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Carcinoma Endometrioide , Carcinossarcoma , Neoplasias do Endométrio , População Negra , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Carcinossarcoma/genética , Carcinossarcoma/patologia , Neoplasias do Endométrio/patologia , Feminino , Humanos , Instabilidade de Microssatélites , MutaçãoRESUMO
OBJECTIVE: To describe the participation of minority women in clinical trials using immunologic agents for breast and gynecologic cancers. METHODS: A retrospective review of completed clinical trials involving immunotherapy for breast and gynecologic cancers was performed. Completed trials were examined for data on race, tumor type, and start year. Minority enrollment was stratified by tumor site. Based on Center for Disease Control and Prevention age-adjusted incidence for race, expected and observed ratios of racial participation were calculated and compared using Χ2 testing, p≤0.05. RESULTS: A total of 53 completed immunotherapy clinical trials involving 8820 patients were reviewed. Breast cancer trials were most common (n=24) and involved the most patients (n=6248, 71%). Racial breakdown was provided in 41 studies (77%) for a total of 7201 patients. Race reporting was lowest in uterine (n=4, 67%) and cervical cancer trials (n=6, 67%), and highest in ovarian cancer trials (n=12, 86%). White patients comprised 70% (n=5022) of all the patients included. Only 5% of patients involved were black (n=339), and 83% of these patients (n=282) were enrolled in breast cancer trials. Observed enrollment of black women was 32-fold lower for ovarian, 19-fold lower for cervical, 15-fold lower for uterine, and 11-fold lower for breast cancer than expected. While all trials reported race between 2013 and 2015, no consistent trend was seen towards increasing race reporting or in enrollment of black patients over time. CONCLUSION: Racial disparities exist in clinical trials evaluating immunologic agents for breast and gynecologic cancers. Recruitment of black women is particularly low. In order to address inequity in outcomes for these cancers, it is crucial that significant attention be directed towards minority representation in immuno-oncologic clinical trials.
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Neoplasias da Mama/etnologia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Neoplasias dos Genitais Femininos/etnologia , Disparidades nos Níveis de Saúde , Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias da Mama/imunologia , Feminino , Neoplasias dos Genitais Femininos/imunologia , Hispânico ou Latino/estatística & dados numéricos , Humanos , Imunoterapia , Seleção de Pacientes , Estudos Retrospectivos , População Branca/estatística & dados numéricosRESUMO
OBJECTIVE: To investigate racial disparities in uterine carcinosarcoma (UCS) and ovarian carcinosarcoma (OCS) in Commission on Cancer®-accredited facilities. METHODS: Non-Hispanic Black (NHB) and non-Hispanic White (NHW) women in the National Cancer Database diagnosed with stage I-IV UCS or OCS between 2004 and 2014 were eligible. Differences by disease site or race were compared using Chi-square test and multivariate Cox analysis. RESULTS: There were 2830 NHBs and 7366 NHWs with UCS, and 280 NHBs and 2586 NHWs with OCS. Diagnosis of UCS was more common in NHBs (11.5%) vs. NHWs (3.7%) and increased with age (P < .0001). OCS diagnosis remained <5% in both races and all ages. NHBs with UCS or OCS were more common in the South and more likely to have a comorbidity score ≥ 1, low neighborhood income and Medicaid or no insurance (P < .0001). Diagnosis at stage II-IV was more common in NHBs than NHWs with UCS but not OCS. NHBs with both UCS and OCS were less likely to undergo surgery and to achieve no gross residual disease with surgery (P = .002). Risk of death in NHB vs. NHW patients with UCS was 1.38 after adjustment for demographic factors and dropped after sequential adjustment for comorbidity score, neighborhood income, insurance status, stage and treatment by 4%, 16%, 7%, 19% and 10%, respectively, leaving 43.5% of the racial disparity in survival unexplained. In contrast, risk of death in NHBs vs. NHWs with OCS was 1.19 after adjustment for demographic factors and became insignificant after adjustment for comorbidity. Race was an independent prognostic factor in UCS but not in OCS. CONCLUSIONS: Racial disparities exist in characteristics, treatment and survival in UCS and OCS with distinctions that merit additional research.
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População Negra/estatística & dados numéricos , Carcinossarcoma/etnologia , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde/estatística & dados numéricos , Neoplasias Ovarianas/etnologia , Neoplasias Uterinas/etnologia , População Branca/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinossarcoma/mortalidade , Carcinossarcoma/patologia , Comorbidade , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVES: Increasing grade of endometrioid endometrial cancer (EEC) is associated with aggressive behavior and poor prognosis. The traditional classification system is limited in its ability to guide treatment planning and prognostication. We identify distinct immune biomarker phenotypes using known markers of immunogenicity to identify patients who may benefit from immune therapy (IT). METHODS: 621 tumors were analyzed by multiplatform profiling. NextGen sequencing was performed on 592 genes. Tumor mutational burden (TMB) was defined as high (H) ≥10mutations/megabase. Microsatellite Instability (MSI) by NGS was ≥46 loci. PD-L1 positivity was ≥2+, >5% by IHC. Chi-square tests were used. RESULTS: Overall, MSI-H was found in 33% of EECs, most frequent in grade 3 (G3), followed by grade 2 (G2) and grade 1 (G1) tumors (G3: 37%, G2: 32%, G1: 22%, p = 0.007). TMB-H was identified in 25% of EECs. TMB-H was most common in G3, followed by G2 and G1 tumors (G3: 34%, G2: 23%, G1: 13%, p = 0.006). Overall, PD-L1 expression was found in 5.5% of EECs. G3 EECs had the most frequent PD-L1 expression, followed by G2 and G1 tumors (G3: 12%, G2: 3.0%, G1: 0.9%, p < 0.0001). We identified POLE mutations in 4.5% (28/618). All POLE mutated tumors harbored TMB-H phenotypes but MSI-H and PD-L1 were only present in 10.7% and 14.8% of tumors respectively, suggesting upregulation of T-cell immune response in only a fraction of POLE mutated EECs. Triple negative (TN) biomarker phenotype (ER-/PR-/Her2-) was evaluated as a potential surrogate marker of tumor immunogenicity. We identified TN phenotype in 4% of G1 EEC compared with 9% in G2 and 33% in G3, suggesting loss of hormone expression and possible greater immunogenicity with increasing tumor grade. CONCLUSIONS: High grade tumors appear to be more immunogenic than low grade tumors and may preferentially benefit from IT.
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Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/imunologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Fenótipo , Estudos RetrospectivosRESUMO
OBJECTIVE: For women with uterine cancer with metastases isolated to the adnexa (stage IIIA) optimal adjuvant therapy is unknown. We performed a population-based analysis to examine the use of chemotherapy, vaginal brachytherapy, and external beam therapy (in women with stage IIIA uterine cancer. METHODS: The National Cancer Database was used to identify women with stage IIIA uterine cancer with ovarian metastasis from 2004 to 2012. We explored the use of chemotherapy, vaginal brachytherapy, and external beam therapy over time. Multivariable models were developed to examine factors associated with survival. RESULTS: We identified 4088 women with uterine cancer and ovarian metastases. Overall, 56.2% of women received chemotherapy. Vaginal brachytherapy was used in 11.1%, while 36.6% received external beam therapy. Five-year survival was 64.7 % (95% CI, 62.9% to 66.5%). In a multivariable model, chemotherapy was associated with a 38% decrease in mortality (HR = 0.62; 95% CI, 0.54 to 0.71). Similarly, both external beam therapy (HR = 0.74; 95% CI, 0.65 to 0.85) and vaginal brachytherapy (HR = 0.67; 95% CI, 0.53 to 0.85) were associated with improved survival. When the cohort was limited to women who received chemotherapy, radiation was associated with improved overall survival (HR 0.74, 95% CI 0.61 to 0.90). There was no difference in survival between the use of external beam therapy and vaginal brachytherapy. CONCLUSIONS: Chemotherapy was associated with a decrease in mortality in women with endometrial cancer and ovarian metastases. The addition of radiation therapy was associated with improved overall survival, although there was no difference between external beam therapy and vaginal brachytherapy.
Assuntos
Braquiterapia/mortalidade , Quimioterapia Adjuvante/mortalidade , Neoplasias do Endométrio/mortalidade , Neoplasias Ovarianas/mortalidade , Padrões de Prática Médica/estatística & dados numéricos , Neoplasias Uterinas/mortalidade , Neoplasias Vaginais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Terapia Combinada , Bases de Dados Factuais , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Seguimentos , Humanos , Histerectomia/mortalidade , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Assistência ao Paciente , Prognóstico , Taxa de Sobrevida , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Neoplasias Vaginais/patologia , Neoplasias Vaginais/terapiaRESUMO
OBJECTIVE: Primary cytoreduction for ovarian cancer often requires extended radical procedures and is associated with significant morbidity. In 2010, neoadjuvant chemotherapy was shown to have similar survival to primary cytoreduction but with less need for radical surgery. We hypothesized that the increased use of neoadjuvant chemotherapy would decrease the use of radical cytoreductive procedures and thus examined trends in the performance of radical cytoreductive procedures. METHODS: We used the Nationwide Inpatient Sample to determine the annual number of extended procedures (colon, small intestine, liver, diaphragm, spleen, and gastric resection, ileostomy, colostomy) performed in women undergoing surgery for ovarian cancer from 1998 to 2013. Estimates were weighted to provide national averages. To account for changes in incidence over time, we used national incidence rates and report procedures performed per 1000 new cases of ovarian cancer. Trends were assessed using Cochrane-Armitage tests. RESULTS: We identified 274,639 ovarian cancer patients who underwent surgery, ranging from 15,720 to 18,714 procedures performed each year. We identified a significant increase in the use of extended procedures over this period. These differences were significant for absolute numbers of procedures, rate per 1000 new ovarian cancer cases, and percent per hysterectomy/bilateral salpingoophorectomy for rectosigmoid resection, diaphragm resection, splenectomy, ileostomy, and liver resection. Specifically, the use of these procedures rose from 1998 to 2010, declined in 2011, and rose again in 2012 and 2013. CONCLUSIONS: Although there was a transient decrease in the use of extended cytoreductive procedures from 2010 to 2011 after the publication of randomized neoadjuvant trial data, use of these procedures again rose in 2012 and 2013.
Assuntos
Procedimentos Cirúrgicos de Citorredução/tendências , Neoplasias Ovarianas/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Estudos de Coortes , Procedimentos Cirúrgicos de Citorredução/estatística & dados numéricos , Feminino , Procedimentos Cirúrgicos em Ginecologia/estatística & dados numéricos , Procedimentos Cirúrgicos em Ginecologia/tendências , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/estatística & dados numéricos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos/epidemiologiaAssuntos
Atenção à Saúde , Neoplasias dos Genitais Femininos/terapia , Ginecologia/economia , Custos de Cuidados de Saúde , Oncologia/economia , Guias de Prática Clínica como Assunto , Oncologia Cirúrgica/economia , Análise Custo-Benefício , Medicina Baseada em Evidências , Feminino , Neoplasias dos Genitais Femininos/economia , Ginecologia/normas , Humanos , Oncologia/normas , Oncologia Cirúrgica/normas , Estados UnidosRESUMO
STUDY OBJECTIVE: Laparoscopic port site metastases (PSMs) have an incidence of .5% to 2%. The management of an isolated PSM (iPSM), without evidence of recurrence elsewhere, remains unclear. The aim of this study was to elucidate practices regarding iPSMs. DESIGN: A 23-item survey was created using commercially available survey software. Over the course of January 2016 the survey was e-mailed to the members of the Society of Gynecologic Oncology with 2 follow-up reminder e-mails. (Canadian Task Force classification III.) SETTING: Online survey. MEASUREMENTS AND MAIN RESULTS: Of the 709 surveys sent, 132 were returned. Providers practicing for <5 years saw fewer PSMs and those who performed more minimally invasive surgeries (MISs) saw more PSMs. Comparing providers who have or have not seen PSMs, no differences in pneumoinsufflation pressure, the mode of delivery of the specimen, the use of local anesthesia at port site incisions, or the method of deflation were seen. If an iPSM was suspected, most providers indicated they would obtain imaging (computed tomography, 51%, or positron emission tomography/computed tomography, 43%) followed by an interventional radiology-guided biopsy (29%) or resection of the mass. Tendency for treatment is to surgically resect the lesion followed by adjuvant therapy. CONCLUSION: After controlling for time in practice, we did not find a strong risk factor for iPSMs other than performing >75% of oncologic surgeries by MIS. Most respondents performed imaging when suspecting iPSMs and use systemic adjuvant therapy after confirming iPSMs.
Assuntos
Neoplasias dos Genitais Femininos/secundário , Procedimentos Cirúrgicos em Ginecologia/métodos , Ginecologia/estatística & dados numéricos , Laparoscopia/efeitos adversos , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Feminino , Neoplasias dos Genitais Femininos/cirurgia , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Humanos , Laparoscopia/métodos , Masculino , Procedimentos Cirúrgicos Minimamente Invasivos , Fatores de Risco , Sociedades Médicas , Inquéritos e QuestionáriosRESUMO
Endometrial carcinoma (EC) is traditionally characterized as endometrioid and nonendometrioid based on histopathologic phenotypes. Molecular-based classifications have been proposed, but are not widely implemented. Herein we examine molecular profiles between EC histologic subtypes. 3133 ECs were submitted between March 2011 and July 2014: 1634 Type I and 1226 Type II. In situ hybridization and immunohistochemistry were used to assess copy number and protein expression of selected genes. Sequenced variants in 47 genes were analyzed using the Illumina TruSeq Amplicon Cancer Panel. Type II EC included 628 cases of uterine serous cancer (USC), 136 cases of clear cell (CC), 361 cases of carcinosarcoma (CS), 38 cases of mucinous, and 36 cases of squamous cell. PI3K/Akt/mTOR pathway was most frequently dysregulated within Type I and mucinous histologies, least altered in CS and squamous. PD-L1 expression was highest in mucinous, absent in squamous. ER/PR expression was common in Type II, most frequent in USC, mucinous, and squamous. Receptor tyrosine kinase was frequently dysregulated in Type II disease: HER2 amplification highest in USC and CC, EGFR mutations exclusively seen in mucinous EC, KRAS mutations common in mucinous, squamous, and Type I, and c-MET overexpression high in CC and mucinous. BRCA1 and BRCA2 were most frequently mutated in CS. Grade 3 EC shares features of G1 tumor and Type II disease, most notably resembling CS. Endometrial carcinomas are a molecularly heterogeneous group of tumors. A histology-based molecular map can identify rational targets to optimize treatment and guide future clinical trials.
Assuntos
Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/patologia , Proteínas de Neoplasias/análise , Transcriptoma , Adenocarcinoma de Células Claras/química , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/secundário , Adenocarcinoma Mucinoso/química , Adenocarcinoma Mucinoso/patologia , Adenocarcinoma Mucinoso/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/química , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/secundário , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Carcinossarcoma/química , Carcinossarcoma/patologia , Carcinossarcoma/secundário , Reparo do DNA/genética , DNA de Neoplasias/genética , Neoplasias do Endométrio/química , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/secundário , Feminino , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Transdução de Sinais/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND: Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers. METHODS: In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel. RESULTS: In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B-Raf proto-oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF-mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD-L1 (56%) and PD-1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had KIT mutations, wild-type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A). CONCLUSIONS: The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333-1344. © 2016 American Cancer Society.
Assuntos
Melanoma/diagnóstico , Melanoma/genética , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/genética , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Mucosa/metabolismo , Mucosa/patologia , Mutação , Estadiamento de Neoplasias , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Adulto JovemRESUMO
BACKGROUND: Opportunistic bilateral salpingectomy (OBS) has been proposed as an ovarian cancer risk-reducing strategy. METHODS: A survey was emailed to 300 members of the American College of Obstetricians and Gynecologists. RESULTS: 125 (42%) surveys were returned: 60% female, 88% generalists, 67% private practice. Only 36% correctly identified the lifetime risk of ovarian cancer, only 23% understood the risk-reducing benefit of bilateral salpingo-oophorectomy. 75% perform salpingectomy during hysterectomy, 26-53% use for sterilization depending on approach. Concerns were increased operative time and complications. For BRCA mutations, 64% recommend BSO, 12% recommend a two-step risk-reducing strategy, and 14% refer to gynecologic oncology. CONCLUSIONS: We identified broad support and factors limiting willingness to perform OBS.