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Simple Summary: Uterine serous carcinomas (USC) represent a rare and aggressive subtype of uterine cancer. Patients often receive adjuvant therapy including chemotherapy and/or radiation after surgery, which has limited efficacy in preventing high rates of recurrence. Understanding the tumor microenvironment in USC is paramount to developing new targeted therapies at the time of progression. This study evaluated the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in 53 patients with USC. In this cohort, the median TMB was 1.35 mutations/megabase (mt/Mb); patients with TMB greater than the median had improved survival outcomes. The median GIS was 31, and a higher GIS was not associated with improved survival. We characterized immune cell populations and found that increased immune populations were not associated with a better prognosis. Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0–52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS. [ABSTRACT FROM AUTHOR]

Background: Although several hereditary cancer predisposition genes have been implicated in pancreatic ductal adenocarcinoma (PDAC) susceptibility, gene-specific risks are not well defined and are potentially biased because of the design of previous studies. More precise and unbiased risk estimates can result in screening and prevention better tailored to genetic findings.Methods: This is a retrospective analysis of 676 667 individuals, 2445 of whom had a personal diagnosis of PDAC, who received multigene panel testing between 2013 and 2020 from a single laboratory. Clinical data were obtained from test requisition forms. Multivariable logistic regression models determined the increased risk of PDAC because of pathogenic variants (PVs) in various genes as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable odds ratios were adjusted for age, personal and/or family cancer history, and ancestry.Results: Overall, 11.1% of patients with PDAC had a PV. Statistically significantly elevated PDAC risk (2-sided P < .05) was observed for CDK2NA (p16INK4a) (OR = 8.69, 95% CI = 4.69 to 16.12), ATM (OR = 3.44, 95% CI = 2.58 to 4.60), MSH2 (OR = 3.17, 95% CI = 1.70 to 5.91), PALB2 (OR = 3.09, 95% CI = 2.02 to 4.74), BRCA2 (OR = 2.55, 95% CI = 1.99 to 3.27), and BRCA1 (OR = 1.62, 95% CI = 1.07 to 2.43).Conclusions: This study provides PDAC risk estimates for 6 genes commonly included in multigene panel testing for hereditary cancer risk. These estimates are lower than those from previous studies, possibly because of adjustment for family history, and support current recommendations for germline testing in all PDAC patients, regardless of a personal or family history of cancer. [ABSTRACT FROM AUTHOR]

The clinical predictions, spectrum, and frequency of BRCA1 and BRCA2 mutations in an ethnically diverse high-risk clinic population and the performance of the BRCAPRO statistical model in predicting the likelihood of a mutation are evaluated. The result supported the use of BRCAPRO and genetic testing for BRCA1 and BRCA2 mutations in the management of high-risk African American families.

Cancer risk assessment and genetic counseling for hereditary breast and ovarian cancer (HBOC) are a communication process to inform and prepare patients for genetic test results and the related medical management. An increasing number of healthcare providers are active in the delivery of cancer risk assessment and testing, which can have enormous benefits for enhanced patient care. However, genetics professionals remain key in the multidisciplinary care of at‐risk patients and their families, given their training in facilitating patients' understanding of the role of genetics in cancer development, the potential psychological, social, and medical implications associated with cancer risk assessment and genetic testing. A collaborative partnership of non‐genetics and genetics experts is the ideal approach to address the growing number of patients at risk for hereditary breast and ovarian cancer. The goal of this practice resource is to provide allied health professionals an understanding of the key components of risk assessment for HBOC as well as the use of risk models and published guidelines for medical management. We also highlight what patient types are appropriate for genetic testing, what are the most appropriate test(s) to consider, and when to refer individuals to a genetics professional. This practice resource is intended to serve as a resource for allied health professionals in determining their approach to delivering comprehensive care for families and individuals facing HBOC. The cancer risk and prevalence figures in this document are based on cisgender women and men; the risks for transgender or non‐binary individuals have not been studied and therefore remain poorly understood. [ABSTRACT FROM AUTHOR]

PURPOSE: Prior estimates of breast cancer risk in women with Lynch syndrome (LS) range from population risk to 18-fold increased risk with reported differences by gene. Here, breast cancer rates were determined in a large cohort of women with pathogenic variants (PVs) in a mismatch repair (MMR) gene detected through multigene panel testing and compared with rates in the US population and women undergoing panel testing. METHODS: MMR gene PV carriers were identified among women tested for suspicion of LS or hereditary breast and ovarian cancer (HBOC) who met inclusion criteria. Standardized incidence ratios (SIRs) and 95% CIs of breast cancer were calculated compared with age-matched incidence in the general US female population and with women negative for PVs stratified by the test indication. RESULTS: In total, 0.8% of women (30,362 of 441,966 women) carried MMR gene PVs. PVs in PMS2 (37.5%) and MSH6 (29.3%) were more common than in MLH1 (13.7%) and MSH2/EPCAM (19.4%). Women with PVs in PMS2 and MSH6 were tested more frequently for HBOC, whereas those with PVs in MLH1 and MSH2/EPCAM were tested more frequently for LS. Breast cancer rates in women with LS were lower than those in the general female population (SIR, 0.88; 95% CI, 0.81 to 0.96) and did not differ compared with women with negative panel testing for HBOC (SIR, 0.90; 95% CI, 0.82 to 0.99) or LS (SIR, 1.02; 95% CI, 0.78 to 1.30). CONCLUSION: In this large cohort of women with LS identified through panel testing, there was no evidence for increased risk of breast cancer compared with the general US population or women undergoing panel testing. These findings support average-risk breast cancer screening in women with LS. [ABSTRACT FROM AUTHOR]

Background: Women diagnosed as having a high risk for breast cancer (HR-BC) often seek different health behaviors (HBs) such as complementary and alternative medicine (CAM), diet, and exercise to improve their health and cancer outcome. Methods: Women already enrolled in a multimodality screening study for patients at HR-BC (gene mutation carrier or >20% cumulative lifetime risk) were given a questionnaire to evaluate their use of CAM therapies, diet, and exercise before and after a diagnosis of HR-BC. Patients were also asked to complete the Short-Form 36, State-Trait Anxiety Inventory, and Beck Depression Inventory. Results: A total of 134 (67%) subjects completed the survey from the original cohort. General characteristics included a median age of 46 years (range = 24-73 years), majority were White (91%), BRCA1/2 gene mutation carrier (49%), and prior diagnosis of breast and/or ovarian cancer (30%). Almost all of the patients reported a lifetime prevalence of any HB (97%) and CAM utilization (91%). Subjects also had a high lifetime utilization of exercise (83%), herbs and supplements(72%), and diet programs (58%). All of these HBs declined in utilization after diagnosis of HR-BC by as much as 30%. After diagnosis of a HR-BC, a personal history of breast and/or ovarian cancer was significantly correlated with increased use of CAM (odds ratio [OR] = 5.9, P <.01), herbs and supplements (OR = 4.3, P <.01), and diet program (OR = 4.4, P <.01) in multivariate analysis. Conclusions: HBs such as CAM, diet, and exercise are highly prevalent among women with HR-BC, and the utilization of HB decreases significantly after diagnosis of HR-BC. [ABSTRACT FROM AUTHOR]

Measures the accuracy of BRCAPRO in calculating breast cancer (BRCA) gene mutation probability as an important component of pretest counseling. Measurement on the performance of several cancer risk counselors; Discrimination between BRCA gene mutation carriers a nd BRCA noncarriers; Usability of BRCAPRO in calculating BRCA gene mutation.

To define the prevalence and relative contributions of BRCA1 and BRCA2 mutations among African American families with breast cancer, we analyzed 28 DNA samples from patients identified through two oncology clinics. The entire coding regions of BRCA1 and BRCA2 were screened by protein truncation test, heteroduplex analysis, or single-stranded conformation polymorphism followed by DNA sequencing of variant bands. Deleterious protein-truncating BRCA1 and BRCA2 mutations were identified in five patients or 18% of the entire cohort. Only 8% (1 of 13) of women with a family history of breast cancer, but no ovarian cancer, had mutations. The mutation rates were higher for women from families with a history of breast cancer and at least one ovarian cancer (three of six, 50%). One woman with a family history of undocumented cancers was also found to carry a deleterious mutation in BRCA2. The spectrum of mutations was unique in that one novel BRCA1 mutation (1625del5) and three novel BRCA2 mutations (1536del4, 6696delTC, and 7795delCT) were identified. No recurrent mutations were identified in this cohort, although one BRCA2 (2816insA) mutation had been previously reported. In addition, two BRCA1 and four BRCA2 missense mutations of unknown significance were identified, one of which was novel. Taken together with our previous report on recurrent mutations seen in unrelated families, we conclude that African Americans have a unique mutation spectrum in BRCA1 and BRCA2 genes, but recurrent mutations are likely to be more widely dispersed and therefore not readily identifiable in this population. [ABSTRACT FROM AUTHOR]

Identification of the genes BRCA1 and BRCA2 offers individuals at high risk for breast, ovarian, colon, or prostate cancer the opportunity to learn if they are genetically predisposed to these diseases. The department of Medicine at the University of Chicago Medical Center has a program that provides genetic testing for people with a family history of these cancers. However, African Americans do not participate in genetic testing at the same rate European Americans do. Thus, focus groups were conducted to learn more about the factors influencing the participation of African Americans in genetic testing. The findings indicated that several factors influence their participation, including perceptions about cancer survivability and lack of awareness about the role of genetic testing. The article discusses these factors and provides specific recommendations for improving African Americans' access and response to genetic testing. [ABSTRACT FROM AUTHOR]

Presents a correction to the article "Prevalence of BRCA1 and BRCA2 Mutations Among Clinic-Based African American Families With Breast Cancer," previously published in the journal "Human Genetics."

Background: Although several hereditary cancer predisposition genes have been implicated in pancreatic ductal adenocarcinoma (PDAC) susceptibility, gene-specific risks are not well defined and are potentially biased because of the design of previous studies. More precise and unbiased risk estimates can result in screening and prevention better tailored to genetic findings., Methods: This is a retrospective analysis of 676 667 individuals, 2445 of whom had a personal diagnosis of PDAC, who received multigene panel testing between 2013 and 2020 from a single laboratory. Clinical data were obtained from test requisition forms. Multivariable logistic regression models determined the increased risk of PDAC because of pathogenic variants (PVs) in various genes as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable odds ratios were adjusted for age, personal and/or family cancer history, and ancestry., Results: Overall, 11.1% of patients with PDAC had a PV. Statistically significantly elevated PDAC risk (2-sided P < .05) was observed for CDK2NA (p16INK4a) (OR = 8.69, 95% CI = 4.69 to 16.12), ATM (OR = 3.44, 95% CI = 2.58 to 4.60), MSH2 (OR = 3.17, 95% CI = 1.70 to 5.91), PALB2 (OR = 3.09, 95% CI = 2.02 to 4.74), BRCA2 (OR = 2.55, 95% CI = 1.99 to 3.27), and BRCA1 (OR = 1.62, 95% CI = 1.07 to 2.43)., Conclusions: This study provides PDAC risk estimates for 6 genes commonly included in multigene panel testing for hereditary cancer risk. These estimates are lower than those from previous studies, possibly because of adjustment for family history, and support current recommendations for germline testing in all PDAC patients, regardless of a personal or family history of cancer., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: To evaluate prophylactic salpingo-oophorectomy uptake and timing among BRCA1/2 mutation carriers in a cancer risk assessment program., Methods: Clinical records of female BRCA1/2 mutation carriers who received cancer genetic counseling between 1996 and 2003 were reviewed to determine the completion and the timing of prophylactic salpingo-oophorectomy. Logistic regression models evaluated associations between subject characteristics and surgery. Survival analysis methods were used to estimate the distribution of time to surgery., Results: Among 88 women, 70% underwent prophylactic salpingo-oophorectomy. Prophylactic salpingo-oophorectomy was associated with older age, white race, having children, and a family history of ovarian cancer. Many women waited more than 12 months to undergo surgery and some delayed by several years. Younger age and not having children were associated with delays to surgery., Conclusion: Prophylactic salpingo-ooporectomy is an acceptable risk reduction measure for many BRCA1/2 mutation carriers. Some women make this decision many years after genetic testing. Continued discussion of the risks and benefits of risk reduction options may facilitate the uptake of recommended risk reduction interventions among BRCA mutation carriers.

Purpose: To evaluate the rate of prophylactic contralateral mastectomy in an international cohort of women with hereditary breast cancer and to evaluate the predictors of uptake of preventive surgery., Patients and Methods: Women with a BRCA1 or BRCA2 mutation who had been diagnosed with unilateral breast cancer were followed prospectively for a minimum of 1.5 years. Information was collected on prophylactic surgery, tamoxifen use, and the occurrence of contralateral breast cancer., Results: Nine hundred twenty-seven women were included in the study; of these, 253 women (27.3%) underwent a contralateral prophylactic mastectomy after the initial diagnosis of breast cancer. There were large differences in uptake of contralateral prophylactic mastectomy by country, ranging from 0% in Norway to 49.3% in the United States. Among women from North America, those who had a prophylactic contralateral mastectomy were significantly younger at breast cancer diagnosis (mean age, 39 years) than were those without preventive surgery (mean age, 43 years). Women who initially underwent breast-conserving surgery were less likely to undergo contralateral prophylactic mastectomy than were women who underwent a mastectomy (12% v 40%; P < 10(-4)). Women who had elected for a prophylactic bilateral oophorectomy were more likely to have had their contralateral breast removed than those with intact ovaries (33% v 18%; P < 10(-4))., Conclusion: Age, type of initial breast cancer surgery, and prophylactic oophorectomy are all predictive of prophylactic contralateral mastectomy in women with breast cancer and a BRCA mutation. The acceptance of contralateral preventive mastectomy was much higher in North America than in Europe.