Family History Of Ovarian Cancer Research Articles

Universal Genetic Testing for Newly Diagnosed Invasive Breast Cancer

Between 5% and 10% of breast cancer cases are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene (BCSG), which could alter local and systemic therapy recommendations. Traditional genetic testing criteria misses a proportion of these cases. To evaluate the prevalence and clinicopathological associations of GPVs in 2 groups of BCSGs among an ethnically diverse cohort of women with newly diagnosed breast cancer. This cross-sectional study, conducted at 3 Montreal hospitals between September 2019 and April 2022, offered universal genetic counseling and testing to all women with a first diagnosis of invasive breast cancer. Women were offered an obligatory primary panel of BRCA1, BRCA2, and PALB2 (B1B2P2) and an optional secondary panel of 14 additional BCSGs. Eligible participants were women 18 years of age or older who received a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study. Data were analyzed from November 2023 to June 2024. Of 1017 referred patients, 805 were eligible and offered genetic counseling and testing, and 729 of those 805 (90.6%) consented to be tested. The median age at breast cancer diagnosis was 53 years (range, 23-91 years), and 65.4% were White and of European ancestry. Fifty-four GPVs were identified in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2 and 15 patients (2.1%) with 6 of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status included being younger than 40 years of age at diagnosis (odds ratio [OR], 6.83; 95% CI, 2.22-20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20-8.43), high grade disease (OR, 1.68; 95% CI, 1.05-2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65-35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. In this cross-sectional universal genetic testing study of women with newly diagnosed invasive breast cancer, the prevalence of GPVs was 7.3%, with 5.3% of patients testing positive for B1B2P2. Among B1B2P2-women women, one-third were eligible for PARP inhibitors.

Incidence of peritoneal cancer after oophorectomy among BRCA1 and BRCA2 mutation carriers

Abstract Background To estimate the incidence of primary peritoneal cancer after preventive bilateral oophorectomy in women with a BRCA1 or BRCA2 mutation. Methods A total of 6310 women with a BRCA1 or BRCA2 mutation who underwent a preventive bilateral oophorectomy were followed for a mean of 7.8 years from oophorectomy. The 20-year cumulative incidence of peritoneal cancer post-oophorectomy was estimated using the Kaplan-Meier method. A left-truncated Cox proportional hazards analysis was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) associated with the age at oophorectomy, year of oophorectomy, and family history of ovarian cancer as well as hormonal and reproductive risk factors. Results Fifty-five women developed primary peritoneal cancer (n = 45 in BRCA1, 8 in BRCA2, and 2 in women with a mutation in both genes). Their mean age at oophorectomy was 48.9 years. The annual risk of peritoneal cancer was 0.14% for women with a BRCA1 mutation and 0.06% for women with a BRCA2 mutation. The 20-year cumulative risk of peritoneal cancer from the date of oophorectomy was 2.7% for BRCA1 carriers and 0.9% for BRCA2 mutation carriers. There were no peritoneal cancers in BRCA1 carriers who had the operation before age 35 or in BRCA2 carriers who had the operation before age 45. Conclusions For BRCA1 mutation carriers, the annual risk of peritoneal cancer for 20 years post-oophorectomy is 0.14% per year. The risk is lower for BRCA2 carriers (0.06% per year).

Clinical and outcome patterns in epithelial ovarian cancer (EOC) within a Latin American cohort.

e23308 Background: Epithelial Ovarian Cancer (EOC) is an heterogenous disease which is usually diagnosed inadvanced stages. Despite the advent of new therapies, the outcomes for this disease remain poor in certain scenarios. We describe the clinical features and survival outcomes in a developing country. Methods: Retrospective study based on case review of women with newly diagnosed EOC between 2015 and 2017 at Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima- Peru. Descriptive analysis was conducted for clinical characteristics, epidemiological factors and treatment. PFS was calculated from the date of diagnosis until the first documented progression and OS from the date of diagnosis to death. Both were calculated using the Kaplan Meier curve. Results: 234 patients were included, the most common histology subtype was high grade serous carcinoma (47,5%), followed by mucinous (15.9%) and clear cell carcinoma (15.4%). Median age was 55.7 yo (range 19-88). Breast and ovarian cancer family history were reported in 3.8% and 3.0%, respectively. 35.8% of patients were overweight, and 12.5% were obese. Most patients (61.5%) were diagnosed at advanced disease (III-IV) and the most common site of metastasis was liver (43.6%) and lung/pleural (28.2%). BCRA testing was performed only in 6% of patients, and 4/14 patients had a pathologic mutation. Ca125 was elevated in 86.2% of patients. Regarding treatment, all patients with early stage disease (I-II) underwent surgical staging. For advanced stage disease, 47.6% (69/145) of patients underwent upfront surgery and 41.4% (60/145) received platinum-based chemotherapy in neoadjuvant setting; 57.3% (35/61) of these patients achieved optimal secondary cytoreduction. With a median follow up of 74,4 months, median PFS was 32.61 months (0.6-474) and global median OS was 58.13 months. Median OS for early disease (I-II) was not reached and for advanced disease (III-IV) was 33.73 months. Survival rate at 5y for all stages was 45.2%; 60.8% and 28.4% for early and advanced disease, respectively. Conclusions: These findings highlight the prevalence of high-grade serous carcinoma and the significance of advanced-stage diagnosis in the survival outcomes. In the era of targeted therapies, the lack of access to BRCA detection tests restricts therapeutic options and, consequently, hinders responses in this group of patients.

Analysis of the occurrence of germline mutations BRCA1\2, PALB2, CHEK2, NBN in patients with pancreatic malignancies. Single-center cohort non-randomized retrospective study

Objective. To analyze the frequency of carriage of BRCA1\2, PALB2, CHEK2, NBN mutations in patients with malignant neoplasms of pancreas. Materials and methods. The single-center cohort non-randomized retrospective study is based on the data of 82 patients who were examined and treated in Russian Research Center of Radiology and Surgical Technologies named after academician A.M. Granov from 2020 to 2022. Patients with confirmed ductal adenocarcinoma of pancreas were included into the study group. Screening of mutations in exons 2,10, 18, 19 of BRCA1 gene and exon 11 of BRCA2 gene was performed in these patients. In addition, oncological family histories were studied. Results. Analysis of medical documentation data showed that 18 (22 %) patients with pancreatic cancer had a hereditary oncological history. In this cohort of patients, 5 (28 %) had relatives with pancreatic cancer, 9 (50 %) had a family history of ovarian cancer, 2 (11 %) female relatives of patients in the study group were diagnosed with breast cancer before the age of 50, also 2 (11 %) patients had a history of more than 2 relatives who suffered from breast cancer and / or prostate cancer. When evaluating the results of revealing the mutations in the entire study group (82 patients), BRCA1 (c.5266dupC) was revealed in 8 patients (9.7 %), PALB-2 (c.1592delT) – in 2 patients (2.4 %), mutations CHEK2, NBN and BRCA2 were not diagnosed in any patient. 5 (6 %) patients who were BRCA1 mutation carriers and one patient with an established PALB2 mutation, according to the analysis of case histories, had no oncological history. None of the patients in the study group was a carrier of the BRCA2, CHEK2 and NBN mutations. Conclusions. Some patients with pancreatic cancer are carriers of germline mutations. Considering our data on the trend of association between germline mutations and pancreatic cancer, we can make an assumption about the prospect of using this indicator as one of the markers for early detection of pancreatic cancer not only in patients with hereditary risk factors for neoplasia, but also in patients without cancer anamnesis. To obtain the results, further observation of patients in the study group and randomized multicenter studies are required.

Positivity of BRCA 1 & 2 Mutations in Ovarian Cancer

Aim: Ovarian cancer is a significant gynecological malignancy, with mutations in BRCA1 and BRCA2 genes contributing to its development and progression. Methods: This descriptive cross-sectional study was conducted at JPMC Hospital, Karachi, over six months. It involved 159 women aged 18 to 75 years with histopathologically confirmed ovarian cancer. The study employed non-probability consecutive sampling and next-generation sequencing to identify BRCA mutations. Results: The study found a low percentage of participants with a family history of ovarian cancer, a few identified with BRCA1 mutations, none with BRCA2 alone, and a minor proportion with mutations in both genes, suggesting a higher incidence of non-mutation- associated ovarian cancer. Conclusion: The findings indicate a relatively low rate of BRCA1 and BRCA2 variations within those suffering from ovarian cancer in Pakistan, pointing to the need for further research to understand the genetic underpinning of ovarian carcinoma in this population and to develop targeted prevention and treatment strategies. Keywords: BRCA mutations, ovarian cancer, genetic testing, Pakistan, prevalence, cross- sectional study.

Abstract PO1-09-03: Clinical Impact of Multigene Panel Testing in Patients with a Personal or Family History of Breast or Ovarian Cancer Previously Negative for BRCA1/2 Genes

Abstract Rapid developments in cancer genetics and hereditary cancer risk assessments have enabled the identification of individuals at elevated risk for hereditary malignancies to guide enhanced cancer screening and prevention efforts. Multigene panel testing has emerged as the standard approach as emphasized in the National Comprehensive Cancer Network (NCCN) guidelines. The purpose of this study was to investigate the frequency of other pathogenic mutations identified through multigene panel testing in individuals who previously tested negative for germline BRCA1/2 and assess the clinical impact of panel testing. Patients either previously diagnosed with breast cancer or with a family history of breast or ovarian cancer that had also been seen by Oncology Genetics at a single institution and tested negative for BRCA1/2 genes but had not undergone prior multigene panel testing were invited via a letter to return for an additional genetic counseling visit to discuss multigene panel testing. Patients were also able to opt-in to a survey component of the study and received an email to fill out the Multidimensional Impact of Cancer Risk Assessment (MICRA) and Cancer Worry Scale (CWS). Surveys were completed prior to the initial genetic counseling appointment and repeated after discussion of the multigene panel test results. A total 24 women met with a genetic counselor of which 22 (92%) had a personal history of breast cancer, 1 (4%) had a family history of breast cancer, and 1 (4%) had a family history of ovarian cancer. The mean age was 52.6 years (range, 42-68) and 100% of women were Caucasian. Of the 24 women, 17 (71%) completed multigene panel testing. Of the women that underwent testing, 7 (41%) had negative results, 6 (35%) had variants of unknown significance (VUS), and 4 (24%) had a pathogenic mutation identified in another gene (CDKN2A, CHEK2, and CFTR). There was no significant change in MICRA or CWS scores after multigene panel results were reviewed in the 9 patients that completed both pre- and post-genetic testing surveys. The mean/median summary MICRA scores pre- and post-counselling were 30 (SD 12.4), median 26 (min 18, max 56), and 21.2 (SD 15.4), median 21 (min 3, max 43), respectively (p=0.19, Wilcoxon signed ranks test). The mean/median summary CWS scores pre- and post-counselling were 14.3 (SD 5), median 15 (min 7, max 24), and 13.6 (SD 2.59), median 14 (min 10, max 17), respectively (p=0.53, Wilcoxon signed ranks test). Of the 4 patients with newly identified pathogenic mutations, 2 started new screening protocols and 1 underwent a prophylactic mastectomy. In conclusion, multigene panel testing identified pathogenic mutations in a subset of individuals who previously tested negative for BRCA1/2 genes leading to changes in clinical management. The completion of multigene panel testing did not lead to a significant increase in MICRA or CWS scores. Key limitations of this study include a small sample size and an all Caucasian population. Citation Format: Devon Miller, Stephanie Pritzl, Angela Tess, Jessica Gooding, Lisa Barroilhet, Lori Dubenske, Kari Wisinski. Clinical Impact of Multigene Panel Testing in Patients with a Personal or Family History of Breast or Ovarian Cancer Previously Negative for BRCA1/2 Genes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-09-03.

Abstract PO3-09-04: Identification of germline pathogenic variants to guide systemic therapy: Prevalence and spectrum of PVs among Mexican patients with metastatic breast cancer

Abstract BACKGROUND Currently, international genetic cancer risk assessment (GCRA) guidelines recommend genetic testing for the identification of germline pathogenic variants (PVs) in patients with metastatic breast cancer (MBC) to guide systemic therapy. Patients with PVs in BRCA genes are candidates to receive poly(adenosine diphosphate–ribose) polymerase inhibitors (PARPi). The prevalence of PVs in patients with HER2-negative MBC has been reported to be 10%. The proportion of MBC in low- and middle-income countries (LMIC) is higher. However, access to genetic testing in LMIC is limited and contributes to the gap in genetic epidemiology knowledge. We aimed to describe the frequency of germline PVs in breast cancer associated genes and clinic-pathologic characteristics of Mexican women with MBC. METHODS This retrospective study included Mexican women from 7 centers in Mexico, who were diagnosed with MBC and had genetic testing. Pathogenic and likely pathogenic variants were reported. Demographic, histopathological characteristics, family history and access to treatment with PARPi, were obtained from chart review. RESULTS From August 2017 to May 2023, 114 Mexican women with MBC were included, median age at diagnosis was 47 years (range 24-80 y), 42% had de novo metastatic, and 58% recurrent disease. 86.8% had infiltrating ductal carcinoma, 51.3% had HR+HER2- (n=58), 4.4% HR+HER+ (n=5), 5.3% HR-HER2+ (n=6), and 38.6% triple negative tumors (n=44). Sites of metastatic disease were as follows: 61.4% non-regional nodes (n=70), 57% bone (n=65), 40.3% lung (n=46), 30.7% liver (n=35), 15.8% central nervous system (n=18) and 7% peritoneal carcinomatosis (n=8). The frequency of PVs was 22% (25/114); 84% of the PVs were heterozygous, mainly identified in BRCA genes (BRCA1 n=12, BRCA2 n=9), and in 4 patients in other genes (PALB2 n=2, PTEN n=1, MUTYH n=1). Among PARPi candidates, 40% (10/25) received Olaparib, the majority received it on the second or subsequent lines of treatment (7/10) with a median progression free survival of 6 months (3-13 m). BRCA carriers were younger at BC diagnosis (38.5 vs. 49 years, p=0.00694) and had a significant higher proportion of family history of ovarian cancer (p=0.00039), but not for breast (p=0.06), prostate (p=0.71) or pancreatic cancer (p=0.098), compared to non-carriers. CONCLUSION We found a high frequency of PVs in BRCA genes in Mexican women with MBC. Access to the genetic testing and targeted therapy should be improve in the Mexican population in order to decrease disparities in cancer care in the Mexican Population. In addition, genetic testing allows to identify other family members at risk with cascade testing and to recommend them risk reduction strategies. Citation Format: Jose Luis Rodriguez-Olivares, Maria Fernanda Esparza-Orozco, Jose Alfredo Ramirez-Gonzalez, Roberto Ivan Sanchez-Reyes, Enrique Isay Talamantes-Gamez, Gregorio Quintero-Beulo, Gilberto Lopez-Rosas, Karla Alicia Centelles-López, Brizio Moreno-Jaime, Daniela Vazquez-Juarez, Ana Maria Hernandez-Murillo, Ilana de la Puente Tawil, Jeffrey Weitzel, Cynthia Villareal Garza, Yanin Chavarri-Guerra. Identification of germline pathogenic variants to guide systemic therapy: Prevalence and spectrum of PVs among Mexican patients with metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-04.

Abstract 2195: Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study

Abstract Introduction: Ovarian, fallopian tube, and primary peritoneal cancers (hereafter referred to as ovarian cancer) are the most fatal gynecologic cancers. Thus, it is imperative to identify strategies that can reduce the risk of the disease. Several contraceptive methods have been shown to be associated with a reduced risk of ovarian cancer, including combined oral contraceptives, injectable progestins, and tubal ligation. However, the use of these contraceptive methods has been decreasing in the U.S., with a growing preference for intrauterine devices (IUDs) for pregnancy prevention. Previous case-control studies on the association between IUD use and ovarian cancer risk have found inconsistent results. Notably, previous studies had small sample sizes and did not restrict to invasive epithelial tumors. The current analysis assessed the association between IUD use and risk of invasive epithelial ovarian cancer in a large population-based case-control study. Methods: This analysis used data from 1,713 people diagnosed with primary invasive epithelial ovarian cancer (cases) and 2,348 cancer-free people (controls) participating in a case-control study conducted in Los Angeles, CA from 1992-2010. The study consisted of four waves of recruitment with similar enrollment and data collection methods. Logistic regression models were fit to assess the association between IUD use and risk of invasive epithelial ovarian cancer. All models were adjusted for age, race/ethnicity, education, first-degree family history of ovarian cancer, endometriosis, body mass index, duration of combined oral contraceptive use, parity, duration of breastfeeding, tubal ligation, and study wave. Heterogeneity across the study waves and the ovarian cancer histotypes was evaluated using standard meta-analysis techniques. Results: There was no statistically significant association between IUD use and risk of invasive epithelial ovarian cancer (odds ratio=1.09, 95% confidence interval 0.93-1.28). This result was consistent across the study waves and the ovarian cancer histotypes (p-values for heterogeneity>0.05). Conclusion: IUD use was not associated with the risk of invasive epithelial ovarian cancer. Analysis by IUD type (i.e., hormone-releasing vs copper IUDs) was not possible in this study as these data were not collected. Future research should examine whether the type of IUD (i.e. copper versus hormone-releasing) may have different effects on risk of ovarian cancer. Citation Format: Minh Tung Phung, Yuting Wang, Alice W. Lee, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Intrauterine device use and risk of invasive epithelial ovarian cancer: A population-based case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2195.

Association Between Germline BRCA1/2 Gene Variants and Clinicopathological Features of Ovarian Cancer.

To investigate the relationship between BRCA1/2 gene mutation and clinicopathological features in ovarian cancer patients, so as to develop precise individualized treatment plan for patients. Patients diagnosed with ovarian cancer between January 2018 and July 2023 who underwent BRCA1/2 genetic testing were retrospectively analyzed. The clinicopathological characteristics (age, body mass index (BMI), family history of ovarian cancer, pregnancy history, menopause status, tumor size, histopathology, Federation of Gynecology and Obstetrics (FIGO) staging, and ascites) of non-carriers and BRCA1/2 variant carriers were compared. Logistic regression analysis was used to explore the relationship between BRCA1/2 variants and clinicopathological characteristics of ovarian cancer. A total of 284 ovarian cancer patients were collected, and the subjects were divided into two groups, 197 non-carriers and 87 BRCA1/2 variants carriers. The proportion of serous ovarian carcinoma in BRCA1/2 variant carriers is higher than that in non-BRCA variant carriers (78.2% vs 60.9%, p=0.015). There were 51 patients with BRCA pathogenic or likely pathogenic variant, 22 patients with BRCA likely benign variant, and 14 patients with BRCA variants of uncertain significance (VUS). The proportion of serous ovarian carcinoma in patients with BRCA pathogenic/likely pathogenic variant is higher than that in patients with BRCA likely benign variant and BRCA VUS (94.1% vs 50.0% and 64.3%. p<0.001). There were no statistically significant differences in BMI, family history of ovarian cancer, pregnancy history, menopause status, maximum diameter of the tumor lesion, FIGO stage, and ascites among patients with different grades of variants. Multivariate logistic regression analysis showed that serous ovarian carcinoma was related to BRCA mutation (Serous carcinoma vs non-serous carcinoma: OR 2.145, 95% CI: 1.044-4.407) (p=0.038). Patients with BRCA1 variant develop ovarian cancer at a younger age than those with the BRCA2 variant. The proportion of FIGO stage III-IV in patients with BRCA pathogenic + likely pathogenic variant was significantly higher than those in patients with other variants. Germline BRCA1/2 variants were most frequently identified in serous ovarian carcinoma patients.

Risk of ovarian cancer in women using ovarian induction protocols for infertility treatment.

Abstract: Cancer is rapidly becoming a major cause of morbidity and mortality worldwide, &amp; Infertility has been found to be an important risk factor for ovarian cancer. However, the association between infertility drugs and ovarian cancer needs to be addressed with consideration of other factors such as age, body mass index, parity, genetic factors (i.e. family history for ovarian cancer), and etiology of the infertility, along with longer followup times Aim of the study:To rule out or to prove that; the ovulation induction in infertility treatments and can cause ovarian cancer . Design: Retrospective randomized study Setting: Data were obtained from the patient records of those who were diagnosed as ovarian problem, which indicate surgical intervention, at lamis hospital for infertility &amp; Gyn. Misurata -libya. From January 1, 2017 to December 31, 2023. (seven years). Our study contained 110 patients operated with ovarian tumors &amp; 3608 patients treated for infertility by ovulation induction drugs &amp; icsi . Results: The age range of patients with ovarian tumors in our study was from 24 to 72 years, and the highest incidence of ovarian tumors was seen between 46 to 60 years. Most of the patients were at postmenopaus. More than half of the patient with ovarian pathology (58.2%) were multiparous; while nulliparous &amp; patients delivered up to three kids were 8.2% &amp; 33.6% consecutively. The main complain that the patient with ovarian pathology presented with abnormal vaginal bleeding (38.2%) ,lower abdominal pain (26.4%), abnormal vaginal discharge (23.6%) &amp; pelvic mass (21.8%), Some patients were with more than one complains. Only two patient out of 110 included at this study , received ovulation induction drugs (1.8%), while 98.2% of patient with ovarian pathology they never use any drugs for ovarian stimulation. Out of (110) patient there 38 patient were their diagnosis confirmed by histopathology as ovarian cancer of different types, tow patients were received ovulation induction drugs. Only one of them with history of icsi &amp; ovum retrieval (1/3608) I.e. 0.027%, she also had family history of breast cancer.(3608 are the number of cases done ovum retrieval for icsi at lamis infertility clinic at the period from January 2017 up to December 2023.) Conclusions: Although ,the question of whether ovarian stimulation increases the incidence of ovarian cancer, as an independent factor remains unanswered , We confirmed that ovulation induction drugs as treatment of infertility &amp; ovum retrieval for icsi are not a risk factors for ovarian cancer, and we observed no increase incidence of ovarian cancer , Further larger studies are recommended to confirm such findings

Protocol to evaluate sequential electronic health record-based strategies to increase genetic testing for breast and ovarian cancer risk across diverse patient populations in gynecology practices

BackgroundGermline genetic testing is recommended by the National Comprehensive Cancer Network (NCCN) for individuals including, but not limited to, those with a personal history of ovarian cancer, young-onset (< 50 years) breast cancer, and a family history of ovarian cancer or male breast cancer. Genetic testing is underused overall, and rates are consistently lower among Black and Hispanic populations. Behavioral economics-informed implementation strategies, or nudges, directed towards patients and clinicians may increase the use of this evidence-based clinical practice.MethodsPatients meeting eligibility for germline genetic testing for breast and ovarian cancer will be identified using electronic phenotyping algorithms. A pragmatic cohort study will test three sequential strategies to promote genetic testing, two directed at patients and one directed at clinicians, deployed in the electronic health record (EHR) for patients in OB-GYN clinics across a diverse academic medical center. We will use rapid cycle approaches informed by relevant clinician and patient experiences, health equity, and behavioral economics to optimize and de-risk our strategies and methods before trial initiation. Step 1 will send patients messages through the health system patient portal. For non-responders, step 2 will reach out to patients via text message. For non-responders, Step 3 will contact patients’ clinicians using a novel “pend and send” tool in the EHR. The primary implementation outcome is engagement with germline genetic testing for breast and ovarian cancer predisposition, defined as a scheduled genetic counseling appointment. Patient data collected through the EHR (e.g., race/ethnicity, geocoded address) will be examined as moderators of the impact of the strategies.DiscussionThis study will be one of the first to sequentially examine the effects of patient- and clinician-directed strategies informed by behavioral economics on engagement with breast and ovarian cancer genetic testing. The pragmatic and sequential design will facilitate a large and diverse patient sample, allow for the assessment of incremental gains from different implementation strategies, and permit the assessment of moderators of strategy effectiveness. The findings may help determine the impact of low-cost, highly transportable implementation strategies that can be integrated into healthcare systems to improve the use of genomic medicine.Trial registrationClinicalTrials.gov. NCT05721326. Registered February 10, 2023. https://www.clinicaltrials.gov/study/NCT05721326

A framework for assessing interactions for risk stratification models: the example of ovarian cancer.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Serous tubal intraepithelial carcinoma detected during benign gynecologic surgery: a case report

High-grade serous carcinoma (HGSC) is the most common type of pelvic cancer among women. Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion of HGSC. Herein, we report a rare occurrence of STIC in patients undergoing surgery for benign indications without a family history of ovarian cancer. A 77-year-old woman underwent total laparoscopic hysterectomy and bilateral salpingo-oophorectomy for uterine prolapse. Pathological examination revealed bilateral STIC without ovarian abnormalities, and no other abnormal findings were noted. Another patient, a 49-year-old woman, underwent laparoscopic total hysterectomy and bilateral salpingectomy for uterine fibroids. STIC lesions were observed in both fallopian tubes. Subsequently, a staging was performed. No additional lesions were found, and the patient was followedup through imaging and blood tests. As reports of STIC lesions are rare, data on their clinical outcomes and management strategies are limited. In this report, we present cases of incidental STIC in benign surgery and discuss its proper interpretation and management. Through the early detection of STIC lesions, patients with risk factors can be identified in advance, which will allow prevention and early detection of ovarian cancer. Opportunistic salpingectomy was also actively discussed in this regard.

Risk-reducing salpingo-oophorectomy for Japanese women with hereditary breast and ovarian cancer: a single-institution 10-year experience.

For women diagnosed with hereditary breast and ovarian cancer, the clinical guidelines recommend risk-reducing salpingo-oophorectomy at age 35-40years or after completion of childbearing. However, there is limited information regarding the current status of risk-reducing salpingo-oophorectomy in Japan. To clarify factors influencing decision-making for risk-reducing salpingo-oophorectomy among Japanese women diagnosed with hereditary breast and ovarian cancer and their clinical outcomes, we analyzed the medical records of 157 Japanese women with germline BRCA pathogenic variants (BRCA1 n=85, BRCA2 n=71 and both n=1) at our institution during 2011-21. Specimens obtained from risk-reducing salpingo-oophorectomy were histologically examined according to the sectioning and extensively examining the fimbriated end protocol. The risk-reducing salpingo-oophorectomy uptake rate was 42.7% (67/157). The median age at risk-reducing salpingo-oophorectomy was 47years. Older age, married state and parity were significantly associated with risk-reducing salpingo-oophorectomy (P<0.001, P=0.002 and P=0.04, respectively). History of breast cancer or family history of ovarian cancer did not reach statistical significance (P=0.18 and P=0.14, respectively). Multivariate analyses revealed that older age (≥45years) and married state may be independent factors associated with risk-reducing salpingo-oophorectomy. Interestingly, the annual number of risk-reducing salpingo-oophorectomy peaked in 2016-17 and has increased again since 2020. The rate of occult cancers at risk-reducing salpingo-oophorectomy was 4.5% (3/67): ovarian cancer (n=2) and serous tubal intraepithelial carcinoma (n=1). Age and marital status significantly affected decision-making for risk-reducing salpingo-oophorectomy. This is the first study to suggest possible effects of Angelina Jolie's risk-reducing salpingo-oophorectomy in 2015 and the National Health Insurance introduced for risk-reducing salpingo-oophorectomy in 2020. The presence of occult cancers at risk-reducing salpingo-oophorectomy supports clinical guidelines recommending risk-reducing salpingo-oophorectomy at younger ages.

Access disparities and underutilization of germline genetic testing in Chilean breast cancer patients

Latin American reports on genetic cancer risk assessments are scarce. In Chile, current breast cancer (BC) guidelines do not define strategies for germline genetic testing. Our study sought to quantify the disparities in access to genetic testing in Chilean BC patients, according to international standards and their clinical characteristics to explore improvement strategies. Retrospective analysis of invasive BC databases including patients treated in a Public Hospital (PH) and in an Academic Private Center (AC) in Santiago, Chile between 2012 and 2021. Of 5438 BC patients, 3955 had enough data for National Comprehensive Cancer Network (NCCN) categorization. From these, 1911 (48.3%) fulfilled NCCN criteria for germline testing, of whom, 300 were tested for germline mutations and 268 with multigene panels. A total of 65 pathogenic variants were found in this subset. As expected, BRCA1/2 mutations were the most frequent (17.7%). Access to genetic testing was higher in AC versus PH (19.6% vs. 10.3%, p = 0.0001). Other variables associated with germline genetic testing were BC diagnosis after 2018, being 45years old or younger at diagnosis, BC family history (FH), FH of ovarian cancer, non-metastatic disease, and triple-negative subtype. In our cohort, 15% of BC patients who met NCCN criteria for germline testing were effectively tested. This percentage was evenlower at the PH. Current recommendations encourage universal genetic testing for BC patients; however, our findings suggest that Chile is far from reaching such a goal and national guidelines in this regard are urgently needed. To our knowledge, this is the first study of its kind in Chile and Latin America.

Abstract P5-12-06: Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients

Abstract Background: Germline DNA damage repair (DDR) mutations has been associated with increased cancer risk, PARP inhibitor therapeutic opportunity for breast cancer (BC) patients. However, the profile of germline mutations in BC covering comprehensive DDR genes remains unclear. Methods: A total of 341 women with breast cancer who tested 102 germline related genes (including 50 DDR genes) between April 2021 to May 2022 in Guangdong Provincial People’s Hospital were identified. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. We defined pathogenic and likely pathogenic variants as deleterious mutations. Results: The median age of 341 breast cancer patients was 48 (range, 20-89) at the first diagnosis of BC. A total of 47 patients (13.78%) carried 53 deleterious germline variants in 21 cancer predisposition genes, 16 of which were DDR genes. DDR deleterious mutations were detected in genes including BRCA2 (n=18), BRCA1(n=7), FANCA (n=4), PMS2 (n=4), PALB2(n=2), RECQL4(n=2), PALB2 (n=2), etc. The younger age at diagnosis (less than 40-year-old) were significantly associated with deleterious mutations in DDR pathway(P=0.02). At least one VUS was identified in 238 (69.79%) patients. The top 5 DDR VUS genes were FANCM (n=21), ATM (n=20), RAD54L (n=17), FANCD2 (n=15) and ATR (n=14). Breast or ovarian cancer family history were significantly correlated with VUS germline mutations in DDR pathway(P=0.039). Interesting, we found that patients with pCR efficacy of neoadjuvant therapy were more likely to have VUS mutations in DDR pathway (table 1). Conclusion: We provided a comprehensive view of germline DDR gene mutations in BC patients and also analyzed the association between clinical characteristics and germline DDR mutation status. DDR mutations are prevalent in Chinese BC patients. Patients with younger and breast or ovarian cancer family history were more likely to carry DDR alterations. Moreover, patients with higher frequency of DDR VUS mutations may benefit from neoadjuvant therapy. Table 1. Clinicopathological characteristics between germline mutation carriers and non-carriers Citation Format: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao. Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-06.

Abstract P4-01-04: Phase IV multicenter study evaluating RWE and the safety of talazoparib in patients with locally advanced or metastatic negative HER2 breast cancer and a BRCA1/2 mutation (ViTAL) - Cohort 2: patients treated according to the EMA

Abstract Background: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that has demonstrated clinical benefit in EMBRACA Phase III trial for patients with germline BRCA1/2 (BRCA1/2)-mutated locally advanced or metastatic HER2- breast cancer. Objective: The aim of the study is to ensure the effectiveness and safety of TALA in the real-world setting among patients with locally advanced or metastatic HER2- breast cancer, with somatic or germline BRCA1/2 mutation. Methods: ViTAL is an ambispective, multicentric, longitudinal, phase IV study. It includes two ambispective cohorts: - Cohort 1: patients treated through the French Early Access Program and inclusion of patients with somatic BRCA1/2 mutation was allowed. - Cohort 2: patients treated according to the European Marketing Approval granted in 09/21/2021. The primary endpoint of the study is the Time to Treatment Discontinuation (TTD) which is defined as time between the date of first dose of TALA and the date of last dose or death. Results: From November 2018 to May 2021, 85 patients were included in Cohort 2, Patients’ characteristics are: - a median age of 49.0 years; - 65.8% ER+ BC/34.2% TNBC; - 42.1% mBRCA1/55.3 % mBRCA2/2,6% mBRCA1 and mBRCA2. - 85.7% ECOG PS 0 or 1; - 23.4% de novo mBC. - Visceral, bones and CNS metastases were found in 59.0%, 61.5% and 10.3% of patients respectively. - No breast or ovarian cancer family history at 1st degree was found in 39 patients (50.0%). - 38.5% were chemo-naïve; - 21.8% received prior platinum in (neo)adjuvant or metastatic setting, with a median of prior cytotoxic regimen of 1 - For patients with ER+/HER2- ABC the median number of prior endocrine therapy was 1 and 62.0% of these patients received a CDK4/6 inhibitor prior to TALA. - 8 patients (10.3%) had CNS metastases. Out of the 78 treated patients, 57 patients (73.0%) experienced a TALA permanent discontinuation for Progressive disease (80.7%), toxicity (12.3%), cancer-related death (1.8%), or other reasons (1.8%). The median TTD for TALA is 9.6 months [6.7;10.8] with 34.5% of patients still on treatment at 12 months. After discontinuation of TALA, 59.0% of patients received a subsequent treatment with a TTD of 3.9 months [2.1; 45]. The most common subsequent treatments were non-platinum chemotherapy (67.4%), platinum therapy (6.5%) and other (26.1%). The Clinical Benefit Rate assessed by the investigators is 87.6% (Complete Response for 14.1%, Partial Response for 56.3% and Stable Disease for 17.2%). The median duration of CNS metastases control was 10.2 months, and 25.0% of patients had a control of CNS metastases. At least one adverse events (AEs) was recorded in 67.9% of patients. Hematologic adverse events (AEs) (any grade) occurred in 55.1% (anemia 37.2%, thrombocytopenia 16.7%, neutropenia 15.4%). Most common non-hematologic AEs were Nausea (15.4%) and asthenia (15.4%). Related Serious Hematologic AEs occurred in 6 patients (7.7%) including 3 (3.8%) thrombocytopenia and 3 (3.8%) anemia. Related Serious Non-hematologic AEs (metrorrhagia) were seen in 1 patient (1.3%). AEs associated with temporary drug interruption, dose modification and permanent drug discontinuation occurred in 26 (33.3%), 22 (28.2%), and 7 (12.3%) patients respectively. The mOS is not mature for this analysis. Conclusions: ViTAL is the largest study that reports real-word data with TALA. Outcomes and safety in Cohort 2 (patients treated with TALA according to the European Marketing Approval), are consistent with the results of EMBRACA study and with the Cohort 1. (Litton et al. NEJM 2018) Citation Format: Delphine Loirat, Marie Duboys de la barre, Cristian Villanueva, Audrey Mailliez, Nicolas Isambert, Lionel Moreau, Emmanuelle Jacquet, Dominique Spaëth, Anne Creisson, Christelle Jouannaud, Eric Legouffe, Miguel delbado, Laura Deiana, Pauline Soibinet, Ioana Hrab, Thomas grellety, Nadine Dohollou, Raffaele Longo, Jean-Christophe Thery, Jean-david Fumet, Sellam Zineb, Pascal Pujol, thibault DE LA MOTTE ROUGE. Phase IV multicenter study evaluating RWE and the safety of talazoparib in patients with locally advanced or metastatic negative HER2 breast cancer and a BRCA1/2 mutation (ViTAL) - Cohort 2: patients treated according to the EMA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-04.

Awareness of ovarian cancer symptoms and risk factors in a young ethnically diverse British population.

Ovarian cancer does not cause many symptoms in the early stages, which is why the majority of cases are of advanced disease. Increasing awareness of ovarian cancer symptoms may lead to earlier diagnosis and improved outcomes. Participants in Britain completed the Ovarian Cancer Awareness Measure by online survey (n= 459). Our participants were 75% female, 25% male and a young (27.89 ± 11.44 years) ethnically diverse population (40.3% White, 29.3% Asian and 18.0% Black). Individuals recalled 1.24 ± 1.30 symptoms, and recognised 5.96 ± 2.4 symptoms. We found higher levels of recall and recognition compared to previous research possibly due to using an online survey. Recognition was lowest for difficulty eating (39.4%) and persistently feeling full (38.7%). Males had slightly lower symptom recall and recognition than females. Participants incorrectly recalled an irregular menstrual cycle (22.4%) as an ovarian cancer symptom and 67% answered the age of incidence question incorrectly. Suggesting that participants incorrectly associate ovarian cancer as a disease of pre-menopausal women. Individuals recalled 1.47 ± 1.20 risk factors, and recognised 6.1± 2.4 risk factors. Family history of ovarian cancer was recalled by 59% of participants. Recognition was lowest for in vitro fertilisation treatment (23.0%) and talcum powder in the genital area (23.0%). The generic cancer risk factors of alcohol (9.3%) and poor diet (8.8%) were recalled as specific ovarian cancer risk factors. 57.9% of participants incorrectly answered that there is an ovarian cancer screening programme. Suggesting confusion between ovarian and cervical cancer as participants also recalled cervical cancer risk factors of sexually transmitted diseases (6.3%) and human papillomavirus (1.5%). 29.7% of female participants would seek help for an ovarian cancer symptom within 1-2 days. Help seeking was higher in the Black and Asian ethnicities (44.4% and 45.0%; p= 0.018). Awareness of ovarian cancer symptoms is low. Ovarian cancer awareness campaigns should include common misconceptions identified in this research.

Intention matters: Success rate of bilateral salpingo-oophorectomy at the time of vaginal hysterectomy for pelvic organ prolapse

ObjectiveThe objective of this study was to determine the incidence of successful bilateral salpingo-oophorectomy at the time of vaginal hysterectomy for pelvic organ prolapse and to evaluate associated factors and success rate over time. Study designThis was a retrospective chart review of all women who underwent vaginal hysterectomy for pelvic organ prolapse who were consented for bilateral salpingo-oophorectomy “if possible” and “including extraordinary measures” between 2014 and 2019 at a tertiary medical center. Baseline demographic data along with prolapse stage, operative findings, operative time, and complications were recorded. Univariate analysis using the Pearson’s chi-square test, the student’s t-test or Mann Whitney U test when appropriate and multivariable logistic regression was performed to determine predictors of successful vaginal bilateral salpingo-oophorectomy. ResultsA total of 453 eligible patients were included. 420 patients (92.7 %) were consented for bilateral salpingo-oophorectomy “if possible” and 33 patients (7.3 %) were consented for “including extraordinary measures”. The success rate of vaginal bilateral salpingo-oophorectomy in all patients was 57.9 % (n = 262). Of the patients consented for extraordinary measures, the success rate was 93.9 % (n = 31), compared to a success rate of 55 % (n = 231) in the “if possible” group. A concurrent posterior repair was found to have higher odds of successful bilateral salpingo-oophorectomy (adjOR 1.75 [95 % CI = 1.17–2.61]). Successful bilateral salpingo-oophorectomy extended operative time by 14 min (154 min vs 140 min, p < 0.001). Compared to patients in the unsuccessful group, the successful group had a higher proportion of the following indications: a family history of ovarian cancer, personal breast cancer history or patient request for definitive removal. ConclusionWhen the pre-operative intention to perform bilateral salpingo-oophorectomy at the time of vaginal hysterectomy for pelvic organ prolapse is high, the success rate is nearly 40% higher when compared to an opportunistic procedure. This suggests that success is closely linked to the surgeon’s determination to complete this procedure vaginally.

Human-Centered Design Study to Inform Traceback Cascade Genetic Testing Programs at Three Integrated Health Systems

Introduction: A traceback genetic testing program for ovarian cancer has the potential to identify individuals with hereditary breast and ovarian cancer and their relatives. Successful implementation depends on understanding and addressing the experiences, barriers, and preferences of the people served. Methods: We conducted a remote, human-centered design research study of people with ovarian, fallopian tube, or peritoneal cancer (probands) and people with a family history of ovarian cancer (relatives) at three integrated health systems between May and September 2021. Participants completed activities to elicit their preferences about ovarian cancer genetic testing messaging and to design their ideal experience receiving an invitation to participate in genetic testing. Interview data were analyzed using a rapid thematic analysis approach. Results: We interviewed 70 participants and identified five preferred experiences for a traceback program. Participants strongly prefer discussing genetic testing with their doctor but are comfortable discussing with other clinicians. The most highly preferred experience for both probands and relatives was to discuss with a knowledgeable clinician who could answer questions, followed by directed (sent directly to specific people) or passive (shared in a public area) communication. Repeated contact was acceptable for reminders. Conclusion: Participants were open to receiving information about traceback genetic testing and recognized its value. Participants preferred discussing genetic testing with a trusted clinician. Directed communication was preferable to passive communication. Other valued information included how genetic tests help their family and the cost of genetic testing. These findings are informing traceback cascade genetic testing programs at all three sites.