Epithelial ovarian cancer: Evolution of management in the era of precision medicine.

Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

Functional analysis of the 1p34.3 risk locus implicates GNL2 in high-grade serous ovarian cancer.

The high-grade serous ovarian cancer (HGSOC) risk locus at chromosome 1p34.3 resides within a frequently amplified genomic region signifying the presence of an oncogene. Here, we integrate in silico variant-to-function analysis with functional studies to characterize the oncogenic potential of candidate genes in the 1p34.3 locus. Fine mapping of genome-wide association statistics identified candidate causal SNPs local to H3K27ac-demarcated enhancer regions that exhibit allele-specific binding for CTCF in HGSOC and normal fallopian tube secretory epithelium cells (FTSECs). SNP risk associations colocalized with eQTL for six genes (DNALI1, GNL2, RSPO1, SNIP1, MEAF6, and LINC01137) that are more highly expressed in carriers of the risk allele, and three (DNALI1, GNL2, and RSPO1) were upregulated in HGSOC compared to normal ovarian surface epithelium cells and/or FTSECs. Increased expression of GNL2 and MEAF6 was associated with shorter survival in HGSOC with 1p34.3 amplifications. Despite its activation of ß-catenin signaling, RSPO1 overexpression exerted no effects on proliferation or colony formation in our study of ovarian cancer and FTSECs. Instead, GNL2, MEAF6, and SNIP1 silencing impaired in vitro ovarian cancer cell growth. Additionally, GNL2 silencing diminished xenograft tumor formation, whereas overexpression stimulated proliferation and colony formation in FTSECs. GNL2 influences 60S ribosomal subunit maturation and global protein synthesis in ovarian cancer and FTSECs, providing a potential mechanism of how GNL2 upregulation might promote ovarian cancer development and mediate genetic susceptibility of HGSOC.

Ovarian cancer statistics, 2018.

In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population-based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non-Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non-Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5-year cause-specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5-year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and tumorigenesis to facilitate strategies for prevention and early detection. CA Cancer J Clin 2018;68:284-296. © 2018 American Cancer Society.

Use of chemotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There are few data on international variation in chemotherapy use, despite it being a key treatment type for some patients with cancer. Here, we aimed to examine the presence and size of such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), eight Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring from within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in chemotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 893 461 patients with a new diagnosis of one of the studied cancers, 111 569 (12·5%) did not meet the inclusion criteria, and 781 892 were included in the analysis. There was large interjurisdictional variation in chemotherapy use for all studied cancers, with wide 95% PIs: 47·5 to 81·2 (pooled estimate 66·4%) for ovarian cancer, 34·9 to 59·8 (47·2%) for oesophageal cancer, 22·3 to 62·3 (40·8%) for rectal cancer, 25·7 to 55·5 (39·6%) for stomach cancer, 17·2 to 56·3 (34·1%) for pancreatic cancer, 17·9 to 49·0 (31·4%) for lung cancer, 18·6 to 43·8 (29·7%) for colon cancer, and 3·5 to 50·7 (16·1%) for liver cancer. For patients with stage 3 colon cancer, the interjurisdictional variation was greater than that for all patients with colon cancer (95% PI 38·5 to 78·4; 60·1%). Patients aged 85-99 years had 20-times lower odds of chemotherapy use than those aged 65-74 years, with very large interjurisdictional variation in this age difference (odds ratio 0·05; 95% PI 0·01 to 0·19). There was large variation in median time to first chemotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation, particularly for rectal cancer (95% PI -15·5 to 193·9 days; pooled estimate 89·2 days). Patients aged 85-99 years had slightly shorter median time to first chemotherapy compared with those aged 65-74 years, consistently between jurisdictions (-3·7 days, 95% PI -7·6 to 0·1). INTERPRETATION: Large variation in use and time to chemotherapy initiation were observed between the participating jurisdictions, alongside large and variable age group differences in chemotherapy use. To guide efforts to improve patient outcomes, the underlying reasons for these patterns need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

Risk-prediction models in postmenopausal patients with symptoms of suspected ovarian cancer in the UK (ROCkeTS): a multicentre, prospective diagnostic accuracy study.

BACKGROUND: Multiple risk-prediction models are used in clinical practice to triage patients as being at low risk or high risk of ovarian cancer. In the ROCkeTS study, we aimed to identify the best diagnostic test for ovarian cancer in symptomatic patients, through head-to-head comparisons of risk-prediction models, in a real-world setting. Here, we report the results for the postmenopausal cohort. METHODS: In this multicentre, prospective diagnostic accuracy study, we recruited newly presenting female patients aged 16-90 years with non-specific symptoms and raised CA125 or abnormal ultrasound results (or both) who had been referred via rapid access, elective clinics, or emergency presentations from 23 hospitals in the UK. Patients with normal CA125 and simple ovarian cysts of smaller than 5 cm in diameter, active non-ovarian malignancy, or previous ovarian malignancy, or those who were pregnant or declined a transvaginal scan, were ineligible. In this analysis, only postmenopausal participants were included. Participants completed a symptom questionnaire, gave a blood sample, and had transabdominal and transvaginal ultrasounds performed by International Ovarian Tumour Analysis consortium (IOTA)-certified sonographers. Index tests were Risk of Malignancy 1 (RMI1) at a threshold of 200, Risk of Malignancy Algorithm (ROMA) at multiple thresholds, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX) at thresholds of 3% and 10%, IOTA SRRisk model at thresholds of 3% and 10%, IOTA Simple Rules (malignant vs benign, or inconclusive), and CA125 at 35 IU/mL. In a post-hoc analysis, the Ovarian Adnexal and Reporting Data System (ORADS) at 10% was derived from IOTA ultrasound variables using established methods since ORADS was described after completion of recruitment. Index tests were conducted by study staff masked to the results of the reference standard. The comparator was RMI1 at the 250 threshold (the current UK National Health Service standard of care). The reference standard was surgical or biopsy tissue histology or cytology within 3 months, or a self-reported diagnosis of ovarian cancer at 12 month follow-up. The primary outcome was diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C-index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN17160843). FINDINGS: Between July 13, 2015, and Nov 30, 2018, 1242 postmenopausal patients were recruited, of whom 215 (17%) had primary ovarian cancer. 166 participants had missing, inconclusive, or other reference standard results; therefore, data from a maximum of 1076 participants were used to assess the index tests for the primary outcome. Compared with RMI1 at 250 (sensitivity 82·9% [95% CI 76·7 to 88·0], specificity 87·4% [84·9 to 89·6]), IOTA ADNEX at 10% was more sensitive (difference of -13·9% [-20·2 to -7·6], p<0·0001) but less specific (difference of 28·5% [24·7 to 32·3], p<0·0001). ROMA at 29·9 had similar sensitivity (difference of -3·6% [-9·1 to 1·9], p=0·24) but lower specificity (difference of 5·2% [2·5 to 8·0], p=0·0001). RMI1 at 200 had similar sensitivity (difference of -2·1% [-4·7 to 0·5], p=0·13) but lower specificity (difference of 3·0% [1·7 to 4·3], p<0·0001). IOTA SRRisk model at 10% had similar sensitivity (difference of -4·3% [-11·0 to -2·3], p=0·23) but lower specificity (difference of 16·2% [12·6 to 19·8], p<0·0001). IOTA Simple Rules had similar sensitivity (difference of -1·6% [-9·3 to 6·2], p=0·82) and specificity (difference of -2·2% [-5·1 to 0·6], p=0·14). CA125 at 35 IU/mL had similar sensitivity (difference of -2·1% [-6·6 to 2·3], p=0·42) but higher specificity (difference of 6·7% [4·3 to 9·1], p<0·0001). In a post-hoc analysis, when compared with RMI1 at 250, ORADS achieved similar sensitivity (difference of -2·1%, 95% CI -8·6 to 4·3, p=0·60) and lower specificity (difference of 10·2%, 95% CI 6·8 to 13·6, p<0·0001). INTERPRETATION: In view of its higher sensitivity than RMI1 at 250, despite some loss in specificity, we recommend that IOTA ADNEX at 10% should be considered as the new standard-of-care diagnostic in ovarian cancer for postmenopausal patients. FUNDING: UK National Institute of Heath Research.

Dietary phytoestrogen intake and ovarian cancer risk: a prospective study in the prostate, lung, colorectal and ovarian (PLCO) cohort.

Estrogen plays a crucial role in ovarian tumorigenesis. Phytoestrogens (PEs) are a type of daily dietary nutrient for humans and possess a mild estrogenic characteristic. This study aimed to assess the correlation of the consumption of dietary PEs with ovarian cancer risk using data in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Participants were enrolled in PLCO from 1993 to 2001. Hazard ratios (HR) and 95% confidence intervals (CI) were utilized to determine the association between the intake of PEs and ovarian cancer occurrence, which were calculated by the Cox proportional hazards regression analysis. In total, 24 875 participants were identified upon completion of the initial dietary questionnaire (DQX). Furthermore, the analysis also included a total of 45 472 women who filled out the diet history questionnaire (DHQ). Overall, after adjustment for confounders, the dietary intake of total PEs was significantly associated with the risk of ovarian cancer in the DHQ group (HRQ4vsQ1 = 0.69, 95% CI: 0.50-0.95; P for trend = 0.066). Especially, individuals who consumed the highest quartile of isoflavones were found to have a decreased risk of ovarian cancer in the DHQ group (HRQ4vsQ1 = 0.68, 95% CI: 0.50-0.94; P for trend = 0.032). However, no such significant associations were observed for the DQX group. In summary, this study suggests that increased dietary intake of total PEs especially isoflavones was linked with a lower risk for developing ovarian cancer. More research is necessary to validate the findings and explore the potential mechanisms.

Ovarian cancer survival in sub-Saharan Africa by human development index and histological subtypes: A population-based registry study.

Ovarian cancer (OC) is the fourth most common cancer of women in sub-Saharan Africa (SSA), although few data have been published on population-level survival. We estimate ovarian cancer survival in SSA by human development index and histological subtype, using data from seven population-based cancer registries in six countries: Kenya (Nairobi and Eldoret), Mauritius, Uganda (Kampala), Cote d'Ivoire (Abidjan), Ethiopia (Addis Ababa) and South Africa (Eastern Cape). A total of 644 cases diagnosed during 2008-2014 were included, with 77% being of epithelial subtypes (range 47% [Abidjan]-80% [Mauritius]). The overall observed survival in the study cohort was 73.4% (95% CI: 69.8, 77.0) at 1 year, 54.4% (95% CI: 50.4, 58.7) at 3 years and 45.0% (95% CI: 41.0, 49.4) at 5 years. Relative survival at Year 1 ranged from 44.4% in Kampala to 86.3% in Mauritius, with a mean for the seven series of 67.4%. Relative survival was highest in Mauritius at 72.2% and lowest in Kampala, Uganda at 19.5%, with a mean of 47.8%. There was no difference in survival by age at diagnosis. Patients from high and medium HDI countries had significantly better survival than those from low HDI countries. Women with cancers of epithelial cell origin had much lower survival compared to women with other histological subtypes (p = .02). Adjusted for the young age of the African patients with ovarian cancer (44% aged <50) survival is much lower than in USA or Europe, and underlines the need for improvements in the access to diagnosis and treatment of OC in SSA.

Association between coffee and tea consumption and ovarian cancer incidence: A prospective analysis in the PLCO dataset.

Epidemiological evidence regarding the relationship between coffee and tea consumption and the risk of ovarian cancer (OC) is inconsistent. Therefore, we aimed to quantitatively investigate this topic in a large prospective cohort study. This cohort study included 24,715 individuals recruited from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trials between 1993 and 2001. The data used for our analysis included the latest follow-up information collected up to 2015. Coffee intake of ≥4 cups/day (hazard ratio [HR], 0.586; 95% confidence interval [CI]: 0.356-0.966) or caffeine intake of 458.787 mg/day (HR, 0.607; 95% CI: 0.411-0.895) were associated with the lowest HR of incident OC in the fully adjusted model. Participants who consumed varying amounts of tea did not exhibit a statistically significant reduction in the risk of OC. Our findings suggest that a higher consumption of coffee or caffeine is associated with a reduced risk of OC. However, no statistically significant association was observed between tea consumption and the risk of OC.

Predicted 25-hydroxyvitamin D over the adult lifetime and the risk of ovarian cancer.

The evidence from previous studies of serum 25-hydroxyvitamin D (25(OH)D) and ovarian cancer risk is not conclusive. However, the 25(OH)D levels were generally only measured in late adulthood, which may not capture the etiologically relevant exposure periods. We investigated predicted 25(OH)D over the adult lifetime in relation to ovarian cancer risk in a population-based case-control study conducted from 2011 to 2016 in Montreal, Canada (n = 490 cases and 896 controls). Predicted 25(OH)D was computed using previously validated regression models. Unconditional multivariable logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% CIs for average predicted 25(OH)D over the adult lifetime and ovarian cancer risk. In addition, the relative importance of different periods of past 25(OH)D exposure was explored using a weighted cumulative exposure (WCE) model. For each 20-nmol/L increase in average predicted 25(OH)D over the adult lifetime, the aOR (95% CI) was 0.73 (0.55-0.96). In WCE analyses, the inverse association was strongest for exposures 5 to 20 years and 35 to 55 years prior to diagnosis, with aORs (95% CIs) of 0.82 (0.69-0.94) and 0.79 (0.66-1.02), respectively, for each 20-nmol/L increase in predicted 25(OH)D. These results support an inverse association between 25(OH)D levels in adulthood and ovarian cancer risk. This article is part of a Special Collection on Gynecological Cancers.

Indicators of cure for women living after uterine and ovarian cancers: a population-based study.

This study aims to estimate long-term survival, cancer prevalence, and several cure indicators for Italian women with gynecological cancers. Thirty-one cancer registries, representing 47% of the Italian female population, were included. Mixture cure models were used to estimate net survival, cure fraction, time to cure (when 5-year conditional net survival becomes > 95%), cure prevalence (women who will not die of cancer), and already cured (living longer than time to cure). In 2018, 0.4% (121 704) of Italian women were alive after diagnosis of corpus uteri cancer, 0.2% (52 551) after cervical cancer, and 0.2% (52 153) after ovarian cancer. More than 90% of patients with uterine cancers and 83% with ovarian cancer will not die from their neoplasm (cure prevalence). Women with gynecological cancers have a residual excess risk of death <5% at 5 years after diagnosis. The cure fraction was 69% for corpus uteri, 32% for ovarian, and 58% for cervical cancer patients. Time to cure was ≤10 years for women with gynecological cancers aged <55 years; 74% of patients with cervical cancer, 63% with corpus uteri cancer, and 55% with ovarian cancer were already cured. These results can contribute to improving follow-up programs for women with gynecological cancers and supporting efforts against discrimination of already cured ones. This article is part of a Special Collection on Gynecological Cancers.

Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

BACKGROUND: Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. METHODS: Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. RESULTS: TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] = 1.90 [CI, 1.24-2.92; p = .003] and 1.26 [1.17-1.36; p < .0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI] = 0.77 [0.76-0.79; p < .001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho = 0.10; p = .0003). CONCLUSIONS: Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases.

PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT). METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven. RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%). CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.

Racial and socioeconomic disparities in survival among women with advanced-stage ovarian cancer who received systemic therapy.

PURPOSE: The purpose of this study was to assess the association between race/ethnicity and all-cause mortality among women with advanced-stage ovarian cancer who received systemic therapy. METHODS: We analyzed data from the National Cancer Database on women diagnosed with advanced-stage ovarian cancer from 2004 to 2015 who received systemic therapy. Race/ethnicity was categorized as Non-Hispanic (NH) White, NH-Black, Hispanic, NH-Asian/Pacific Islander, and Other. Income and education were combined to form a composite measure of socioeconomic status (SES) and categorized into low-, mid-, and high-SES. Multivariable Cox proportional hazards models were used to assess whether race/ethnicity was associated with the risk of death after adjusting for sociodemographic, clinical, and treatment factors. Additionally, subgroup analyses were conducted by SES, age, and surgery receipt. RESULTS: The study population comprised 53,367 women (52.4% ages ≥ 65 years, 82% NH-White, 8.7% NH-Black, 5.7% Hispanic, and 2.7% NH-Asian/Pacific Islander) in the analysis. After adjusting for covariates, the NH-Black race was associated with a higher risk of death versus NH-White race (aHR: 1.12; 95% CI: 1.07,1.18), while Hispanic ethnicity was associated with a lower risk of death compared to NH-White women (aHR: 0.87; 95% CI: 0.80, 0.95). Furthermore, NH-Black women versus NH-White women had an increased risk of mortality among those with low-SES characteristics (aHR:1.12; 95% CI:1.03-1.22) and mid-SES groups (aHR: 1.13; 95% CI:1.05-1.21). CONCLUSIONS: Among women with advanced-stage ovarian cancer who received systemic therapy, NH-Black women experienced poorer survival compared to NH-White women. Future studies should be directed to identify drivers of ovarian cancer disparities, particularly racial differences in treatment response and surveillance.

Breast cancer after ovarian cancer in BRCA1 and BRCA2 pathogenic variant heterozygotes: Lower rates for 5 years post chemotherapy.

PURPOSE: The identification of germline BRCA1/BRCA2 pathogenic variants (PV) infer high remaining lifetime breast/ovarian cancer risks, but there is paucity of studies assessing breast cancer risk after ovarian cancer diagnosis. METHODS: We reviewed the history of breast cancer in 895 PV heterozygotes (BRCA1 = 541). Cumulative annual breast cancer incidence was assessed at 2, 5, 10, and >10 years after ovarian cancer diagnosis date. RESULTS: Breast cancer annual rates were evaluated in 701 assessable women with no breast cancer at ovarian diagnosis (BRCA1 = 425). Incidence was lower at 2 years (1.18%) and 2 to 5 years (1.13%) but rose thereafter for BRCA1 with incidence post 10 years in excess of 4% annually. Breast cancer pathology in BRCA1 PV heterozygotes showed less high-grade triple-negative breast cancer and more lower-grade hormone-receptor-positive cancer than women with no prior ovarian cancer. In the prospective cohort from ovarian cancer diagnosis, <4% of all deaths were caused by breast cancer, although 50% of deaths in women with breast cancer after ovarian cancer diagnosis were due to breast cancer. CONCLUSION: Women can be reassured that incidence of breast cancer after ovarian cancer diagnosis is relatively low. It appears likely that this effect is due to platinum-based chemotherapy. Nonetheless women need to be aware that incidence increases thereafter, especially after 10 years.

Germline mutations in BRCA1 and BRCA2 among Brazilian women with ovarian cancer treated in the Public Health System.

BACKGROUND: Germline mutations in BRCA1 and BRCA2 genes are among the main causes of hereditary ovarian cancer. Identifying these mutations may reduce cancer risk, facilitate early detection, and enable personalized treatment. However, genetic testing is limited in the Brazilian Public Health System, and data regarding germline mutations in many regions are scarce. Therefore, the study aimed to investigate the prevalence of germline mutations in BRCA1 and BRCA2 in women with ovarian cancer treated in the Public Health System in Pernambuco, Brazil. METHODS: A cross-sectional study was conducted in the Hereditary Cancer Program from two reference oncological centers in Pernambuco. Women (n = 45) with high-grade serous ovarian cancer underwent genetic counseling and DNA sequencing for BRCA1 and BRCA2 genes. RESULTS: The prevalence of deleterious mutations in the BRCA1 and BRCA2 genes was 33%. Of the 15 germline mutations found, 13 were in BRCA1 and 2 in BRCA2; two mutations of unknown clinical significance were also found in BRCA2. Mutations c.5266dupC and c.2215 A > T were the most frequent; each was mutation observed in three patients. Additionally, the mutations c.7645dupT and c.921dupT were reported for the first time. CONCLUSION: One in three women showed a pathogenic mutation, demonstrating a significant prevalence of germline mutations in this sample. Additionally, the small sample revealed an interesting number of mutations, indicating the need to explore more regions of the country.

The incidence risk of gynecological cancer by antipsychotic use: a meta-analysis of 50,402 patients.

BACKGROUND: Female gynecological cancers represent a serious public health problem, with 1,398,601 new diagnoses and 671,875 deaths per year worldwide. Antipsychotics are often used in psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. It is estimated that the prescription of these drugs is linked to 1,800 deaths a year in the United States, but their association with cancer remains controversial. METHODS: We searched PubMed, Scopus, and Web of Science databases for studies reporting the correlation in the incidence risk of gynecological cancer by antipsychotic use. We used DerSimonian and Laird random-effect models to compute logit transformed odds ratio (OR) for the primary binary endpoint with 95% confidence interval (CI). Heterogeneity was assessed through effect size width along with I-squared and Tau-squared statistics. Review Manager 5.4.1. was used for statistical analyses. A p-value of < 0.05 denoted statistically significant. RESULTS: 50,402 patients were included, of whom 778 (1,54%) took antipsychotic medication for at least 1 year. 1,086 (2,15%) with ovarian cancer and 49,316 (97,85%) with endometrial cancer. Antipsychotic use (OR 1.50; 1.06 to 2.13 95% CI; p-value 0.02), hypertension (OR 1.50; 95% CI 1.06 to 2.13; p-value < 0.01), nulliparity (OR 1.98; 95% CI 1.53 to 2.57; p-value < 0.01) and multiparity (OR 0.53; 95% CI 0.41 to 0.69; p-value < 0.01) showed significantly different distributions between groups of cancer and cancer-free patients. The primary endpoint of incidence risk of gynecological cancer by antipsychotic therapy showed a statistically significant difference (OR 1.67; 95% CI 1.02 to 2.73; p-value < 0.05) against the use of antipsychotic drugs. CONCLUSIONS: Our meta-analysis showed that the use of antipsychotic drugs increases the risk of gynecological cancers, particularly endometrial cancer. This result should be weighed against the potential effects of treatment for a balanced prescribing decision.

A comprehensive population-based study of malignant ovarian tumors, including histologic and immunohistochemical review, in children and adolescents 0-19 years old in Sweden between 1970 and 2014.

OBJECTIVES: Ovarian tumors in the pediatric population are rare. The incidence and frequency of subtypes differ between children and adults. Although not all tumors are aggressive, they may still lead to morbidity. The goal of this study was a comprehensive review of malignant ovarian tumors in children and adolescents diagnosed and registered in Sweden. METHODS: Individuals were identified through a search in the National Cancer Register, limited for ages 0-19, years 1970-2014. Stored tumor diagnostic material from regional biobanks was retrieved and reviewed. RESULTS: The study includes 345 individuals with ovarian tumors and 70.7% of them were between 15 and 19 years at time of diagnosis. No differences in incidence over time or geographic location were identified. The average follow-up time was 21.2 years and 5-year survival was 88.4%. Survival was similar in the different time periods, except for 1970-1979. Review was possible for 260 cases, resulting in 85 epithelial tumors, 121 GCTs, 47 SCSTs and 7 others. For age 0-4 years SCSTs dominated (85.7%), for 5-9- and 10-14-years GCTs dominated (70,8% and 75.0% respectively), and for age 15-19 years epithelial tumors dominated (43.8%). There was a strong agreement between review diagnosis and original diagnosis (Cohen's κ 0.944). Differentiating between entities within the sex cord-stromal group posed the biggest diagnostic challenge. CONCLUSIONS: Ovarian tumors in children and adolescents are rare and distinct from their adult counterparts regarding incidence and frequency. There was a strong concurrence between original and review diagnoses. The greatest diagnostic difficulty was subtyping of epithelial tumors and differentiating between tumors within the SCST group.

Risk of borderline ovarian tumors after fertility treatment - Results from a Danish cohort of infertile women.

OBJECTIVE: Results from previous studies examining the association between fertility treatment and borderline ovarian tumors are inconsistent. The aim of this study was to investigate the association between fertility treatment and borderline ovarian tumors in a cohort of infertile women. METHODS: This cohort study was based on the Danish Infertility Cohort and included all infertile women aged 20-45 years living in Denmark between 1 January 1995 and 31 December 2017 (n = 146,891). Information on use of fertility drugs, borderline ovarian tumors and cancer diagnoses, covariates, emigration, and vital status was obtained by linkage to national registers. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) with adjustment for potential confounders for overall borderline ovarian tumors and for serous- and mucinous borderline ovarian tumors separately. RESULTS: During a median 11.3 years of follow-up, 144 women developed a borderline ovarian tumor. No marked associations between ever use of clomiphene citrate, gonadotropins, gonadotropin-releasing hormone receptor modulators, human chorionic gonadotropin or progesterone and borderline ovarian tumors were observed, neither overall nor for serous and mucinous borderline ovarian tumors analysed separately. Further, no clear associations with borderline ovarian tumors were found according to cumulative dose, time since first use or parity status for any fertility drugs. CONCLUSIONS: No marked associations between use of fertility drugs and borderline ovarian tumors were observed. However, the cohort's relatively young age at end of follow-up emphasizes the importance of extending the follow-up period for women who have used fertility drugs.

Trends in ovarian, fallopian tube, and primary peritoneal cancer incidence, mortality, and survival: A 15-year population-based analysis.

OBJECTIVE: To characterize trends in ovarian, fallopian tube, and primary peritoneal cancer incidence and incidence-based mortality based on histology and site of origin. METHODS: We obtained age-adjusted incidence and incidence-based mortality for patients with ovarian, fallopian tube, and primary peritoneal cancer from 2000 to 2019 from the US SEER 17 database. Joinpoint 4.9.1.0 was used to characterize log-linear time trends. RESULTS: The incidence and incidence-based mortality of all cancers trended down during the study period. The incidence of epithelial cancers decreased from 2004 to 2019 (AAPC -1.2%, p < 0.001), including that of high-grade (2006-2019: APC -1.2%, p < 0.05) and low-grade (2003-2019: APC -2.4%, p < 0.05) epithelial cancers. There was no change in incidence or incidence-based mortality for ovarian stromal and germ cell cancers. CONCLUSION: There has been a decrease in the incidence and incidence-based mortality of ovarian, fallopian tube, and primary peritoneal cancer, primarily due to reductions in advanced stage epithelial cancers originating in the ovary, fallopian tube, or peritoneum.