Publications by authors named "Susan M Domchek"
Article Synopsis
- - Pathogenic variants in certain genes increase the risk of developing breast, ovarian, pancreatic, and prostate cancer due to their role in DNA repair.
- - Targeted treatments like PARP inhibitors have been developed based on the biology of these genes and are approved for various cancers linked to these genetic mutations.
- - The discussion includes how PARP inhibitors work, potential resistance, their use in cancers beyond the traditional ones, and new agents being researched.
Traditional approaches for evaluating the impact of scientific research - mainly scholarship (i.e., publications, presentations) and grant funding - fail to capture the full extent of contributions that come from larger scientific initiatives.
View Article and Find Full Text PDFPurpose: Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited.
Methods: Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.
Purpose: To determine the relationship between germline pathogenic variants (PVs) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).
Methods: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls, and between DCIS and infiltrating ductal carcinoma (IDC) cases from a clinical-testing cohort (n=9,887), a population-based cohort (n=3,876) and the UK Biobank (n=2421). The risk of contralateral breast cancer for DCIS cases with PVs was estimated in the population-based cohort.
Article Synopsis
- Women with BRCA1 and BRCA2 pathogenic variants may experience surgical menopause after RRSO, with previous studies showing increased depressive and anxiety symptoms at 6 and 12 months post-surgery.
- A controlled study tracking 59 women undergoing RRSO and 91 comparison women found that, at 24 months, depressive and anxiety symptoms were not significantly elevated and did not differ between the two groups. However, symptoms at 12 months strongly predicted outcomes at 24 months.
- The study concluded that while symptoms don't seem to escalate after 24 months, persistent symptoms observed at 12 months can indicate ongoing issues, with no significant impact from Menopausal Hormone Therapy on mental health.
Objective: To measure vasomotor symptoms and menopause-related quality of life up to 24 months after RRSO, and the effects of Menopausal Hormone Therapy (MHT).
Methods: Prospective observational study of 104 premenopausal women at elevated risk of ovarian cancer planning RRSO and age-matched comparators (n = 102) who retained their ovaries. Vasomotor symptoms and quality of life were measured using the Menopause-specific QoL Intervention (MENQOL-I) scale.
Article Synopsis
- Pathogenic variants (PVs) in certain genes like BRCA1 and BRCA2 increase breast cancer risk, but it's unclear how risk varies based on the type and location of these variants.
- This study analyzed breast cancer risks associated with different PV types and locations using data from 12 US studies and clinical cohorts involving over 64,000 women.
- Results showed that women with specific exon PTVs had higher breast cancer risks, lower rates of ER-negative breast cancer, and were diagnosed at younger ages compared to those with other variants, with these patterns observed across multiple cohorts.
Article Synopsis
- The study investigates the relationship between hormonal contraceptive use and breast cancer risk in both unaffected women and mutation carriers.
- Out of the participants, it was found that hormonal contraceptive use was linked to a higher breast cancer risk in mutation carriers, particularly with longer duration of use.
- The findings suggest that decisions regarding hormonal contraceptive use for women with genetic mutations should consider individual risk factors and benefits.
Article Synopsis
- - Ovarian cancer is a major health concern for women, mainly due to the lack of effective screening methods, prompting this study to explore new diagnostic approaches. - Researchers analyzed cell-free DNA and protein biomarkers in 591 women to develop a machine learning model that achieved over 99% specificity and variable sensitivity across cancer stages for detecting ovarian cancer. - The results suggest that combining cfDNA fragmentome analysis with protein biomarkers significantly improves the detection and differentiation of ovarian cancers from benign masses, paving the way for better noninvasive screening methods.
Article Synopsis
- Clinical genetic testing helps find cancer risks by identifying gene changes, but some of these changes are confusing because we don't know what they mean (called VUS).
- Researchers studied a huge number of breast cancer patients and healthy people to understand these confusing gene changes better.
- They found that their method of analyzing data closely matches what other experts say about which gene changes are harmless or harmful, giving more information about 785 unclear changes.
Development of a Breast Cancer Risk Prediction Model Integrating Monogenic, Polygenic, and Epidemiologic Risk.
Cancer Epidemiol Biomarkers Prev
November 2024
Article Synopsis
- - The study aimed to enhance breast cancer risk modeling by integrating pathogenic variants (PVs) in specific genes, a polygenic risk score (PRS), and an epidemiologic risk score (ERS) using data from over 23,000 breast cancer cases and controls.
- - The results showed that postmenopausal women with no PVs but high ERS had a 4.4-fold increase in breast cancer risk, while some CHEK2 PV carriers had a predicted lifetime risk below 20%, indicating potential over-screening in certain groups.
- - The findings suggest that combining these risk factors can improve risk assessment and possibly lead to more tailored screening and prevention strategies for breast cancer.
The co-occurrence of germline and somatic oncogenic alterations is frequently observed in breast cancer, but their combined biologic and clinical significance has not been evaluated. To assess the role of germline-somatic interactions on outcomes in routine practice, we developed an integrated clinicogenomic pipeline to analyze the genomes of over 4,500 patients with breast cancer. We find that germline (g) -associated tumors are enriched for loss-of-function mutations and manifest poor outcomes on standard-of-care, front-line CDK4/6 inhibitor (CDK4/6i) combinations.
View Article and Find Full Text PDFArticle Synopsis
- - Half of all BRCA1 and BRCA2 gene mutation carriers are male, yet their increased cancer risks—especially for prostate, pancreatic, and breast cancers—are often overlooked compared to females.
- - Current research shows a growing number of FDA-approved targeted therapies for cancers linked to BRCA1/2 mutations, and there are new clinical trials that focus on male carriers, highlighting the need for better screening and risk-reduction options.
- - Despite these advancements, fewer males are getting genetic testing compared to females, and healthcare providers need to prioritize offering these tests to men to improve early detection and treatment for male carriers.
Purpose: Germline genetic testing (GT) is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC), but the traditional clinical genetics infrastructure is limited in addressing the unique needs of this population. We describe the integration of point of care (POC) GT into routine clinical practice for all patients with PDAC at an academic medical center.
Methods: We developed a clinical POC workflow that leverages electronic health record (EHR) tools and behavioral nudges to enhance the sustainability and scalability of our previously described research-based POC model.
Background: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management.
Patients And Methods: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing.
Article Synopsis
- BRCA1 and BRCA2 gene mutation carriers may have a higher risk of gastric cancer, but the reasons behind this link are not well understood.
- A study of 100 BRCA1/2 carriers showed that the prevalence of the gastric cancer risk factors H. pylori infection and gastric intestinal metaplasia (GIM) was low, with only 1% infected with H. pylori and 7% having GIM.
- The findings suggest that while the prevalence of these risk factors is similar to the general population, understanding their presence can inform future strategies for managing gastric cancer risks in BRCA1/2 carriers.
Rapid advances in technology and therapeutics, along with better methods to discern who is at risk for cancer by genetic testing and other means, has enabled the development of cancer interception. Targeted therapies and "immuno-interception" may eliminate premalignant lesions and require clinical trial and treatment paradigms altogether distinct from current approaches.
View Article and Find Full Text PDFPurpose: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline , high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment.
Methods: Data were collected before random assignment, and at 6, 12, 18, and 24 months.
Unlabelled: Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all variants.
View Article and Find Full Text PDFGermline Genetic Testing for Hereditary Breast and Ovarian Cancer: Current Concepts in Risk Evaluation.
Cold Spring Harb Perspect Med
August 2024
Article Synopsis
Purpose: Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts).
Patients And Methods: In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab.