tbuckley/cabot-search huggingface dataset:
Attitudes and engagement about cascade genetic testing in a population-based cohort of women diagnosed with cancer.
Authors: Steven Jay Katz, Kevin C Ward, Ann S. Hamilton, Paul Abrahamse, Rachel Hodan, Allison W. Kurian, Lauren P. Wallner, Sarah T. Hawley
Journal: Journal of Clinical Oncology (2024)

10589 Background: Cascade testing in families with hereditary cancer syndromes is challenging because patients are responsible for engaging their relatives about test results and clinical support is limited. There are concerns that patient engagement with relatives may not be well matched to the clinical relevance of their test results, with particular concern about variants of uncertain significance (VUS). Methods: We selected patients from the Georgia California Genetic Linkage Initiative, which identified all patients diagnosed with cancer 2013-19 in the 2 states who linked to a germline genetic test. We surveyed 2100 women diagnosed with breast, ovarian or uterine cancer in 2018-19 in Georgia and California who reported "a pathogenic variant (PV) that increases the risk of cancer" on testing about 4 years after diagnosis. We also surveyed a comparable sample of 1300 women diagnosed during the same period who reported a VUS-only result. The expected response rate from the cohorts is 55% (N=1900). We present preliminary results on patient attitudes about cascade family testing and report of engagement with genetic counselors and relatives about test results. Results: The 2 cohorts were comparable in age (mean 54 vs 58 for VUS, p&lt;.001) and education (college graduate or more 52% vs 53% for VUS p=.971). The Table shows that for patients who reported a PV, belief in the utility of testing in relatives (test results useful for family; wanted family members tested) was high. A substantial proportion reported that a genetic counselor encouraged them to talk to relatives and talked directly with relatives about testing. PV carriers informed most first-degree relatives about their test results. Patients who reported VUS only were less likely to endorse the utility of testing in relatives; less likely to report that a genetic counselor encouraged family engagement or engaged family directly about testing; and were less likely to have informed relatives about their test results. Conclusions: Compared to patients with VUS-only test results, women with PVs on germline genetic testing after diagnosis of cancer had more positive attitudes about the utility of testing of family members and greater engagement with clinicians and family members about test results. These findings suggest that engagement with family about genetic testing after cancer diagnosis matches the clinical relevance of the results. [Table: see text]
A targeted panel of actionable high-risk hereditary cancer predisposition genes to identify patients with pathogenic/likely pathogenic variants (PVs) irrespective of meeting established NCCN testing criteria.
Authors: Sarah S. Lee, Jingwen Zhang, Mia Mackall, Sara L. Bristow, Meenakshi Malhotra, Adam ElNaggar, Vivienne Souter, Minetta C. Liu, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2024)

10596 Background: Current germline cancer testing guidelines are limited to patients who meet specific personal and family cancer history (PH, FH) criteria. Our objective was to determine if differences in PV rates exist based on meeting National Comprehensive Cancer Network (NCCN) testing criteria in patients who underwent testing for known actionable genes. Methods: 29 genes with actionable NCCN management guidelines were evaluated. Consecutive patients (N=195,615) aged 18 to 100 years had hereditary cancer testing at a commercial laboratory at the ordering clinician’s discretion that included at least the 29 genes between June 2020 and August 2023. Per clinician-reported patient features (e.g. FH, PH, age), patients were categorized as meeting or not meeting current NCCN testing criteria for breast/ovarian/pancreatic (BOP v2.2024), and colorectal cancer (v1.2023). PV rates were calculated for all genes associated with breast, endometrial, ovarian, prostate, pancreatic, and colorectal cancer risk. Results: PVs were reported in 6634/105,194 (6.3%) patients that met the testing criteria and 5134/90,421 (5.7%) that did not. Of patients with a PV, 5134/11,768 (43.6%) did not meet NCCN testing criteria. When comparing patients with PVs based on NCCN testing criteria, patients were similar in age (median [Q1, Q3], 43.6 [35.0, 56.1] v 42.5 [34.7, 56.6] years) and sex (female 91.5% v 91.3%). While PH and FH were comparable, a PH of cancer (31.5% v 36.1%, OR=0.81, 95% CI 0.75-0.88, p&lt;0.001) and/or a FH of cancer (83.9% v 97.1%, OR=0.16, 95% CI [0.13-0.18], p&lt;0.001) were slightly lower in patients who did not meet criteria compared to those who met testing criteria. On evaluating results in genes associated with individual cancer types, similar PV rates between the groups were observed (Table). Among all patients with PVs, the most common genes were CHEK2, BRCA1, BRCA2, and ATM. Most patients had only 1 PV reported (met: 96.5%, not met: 97.5%). Conclusions: In this cohort of patients who underwent germline testing, approximately 40% of patients with PVs in this study did not meet existing NCCN testing criteria. PV rates were similar between patients that met criteria and those that did not. Broadening existing testing criteria may reduce the number of patients who would otherwise be missed, thereby allowing for treatment decision-making and cascade testing of family members. [Table: see text]
Prevalence of pathogenic genetic variants in patients with gastric cancer ascertained through multi-gene panel testing.
Authors: Ophir Gilad, Emma Keel, Emily M. Russell, Sarah M. Nielsen Young, Brandie Heald, Ed Esplin, W. Michael Korn, Maegan Roberts, Carol A. Burke, Sonia S. Kupfer
Journal: Journal of Clinical Oncology (2024)

10578 Background: Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. The role of pathogenic/likely pathogenic variants (PVs) in cancer predisposition genes is not well understood. We aimed to assess the prevalence of PVs in GC patients undergoing germline genetic testing (GGT) via multi-gene panel testing (MGPT) at a large commercial laboratory. Methods: Retrospective review of MGPT (&gt;10 genes) in GC patients at a large commercial laboratory (Invitae Corp.) from March 2015 to July 2023 was performed. GC included diffuse type, intestinal type or unspecified type, as provided by ordering clinicians. Association of patient characteristics with positive GGT results was assessed with logistic regression with a significance threshold of p &lt; 0.05. Results: 3,706 GC patients underwent GGT(Table). Overall, 495 (13.4%) patients were found to carry ≥1 PV, including 29 patients with 2 PVs and 3 patients with 3 PVs. GGT was negative in 1,890 (51.0%) patients, 1,199 (32.4%) had a variant of uncertain significance-only and 121 (3.3%) carried a single PV in a gene associated with autosomal recessive inheritance. PVs were identified in 38 genes; 77.7% (385/495) were in a gene previously associated with GC, primarily the homologous recombination repair genes ( BRCA1, BRCA2, PALB2and ATM, 34.9%), the Hereditary Diffuse Gastric Cancer genes ( CDH1and CTNNA1, 19.6%) and mismatch repair genes ( MLH1, MSH2, MSH6, PMS2and EPCAM, 17.4%). Males were more likely to carry a PV than females (OR 1.4, 95% CI 1.1-1.7) and having a personal history of another cancer increased the odds of carrying a PV (OR 1.3, 95% CI 1.0-1.7). Age, number of genes tested and histology were not significantly associated with PV. Conclusions: In this large study of GGT in GC patients, the prevalence of PVs in cancer associated genes was 13.4%, higher than previous estimates of 3-5%. PVs were predominantly in genes associated with GC. Male sex and history of other cancers were associated with a PV. Limitations include incomplete histologic data, varying panel size, and ascertainment bias as patients may have had additional personal/family history that prompted GGT. These results support consideration of GGT in all GC patients as prevalence of PVs is similar to other cancer types for which guidelines recommend universal genetic testing.[Table: see text]
Metabolomics signatures of air pollution mixtures and lung cancer risk: A large-scale metabolome-wide association study in the Cancer Prevention Study cohorts.
Authors: Sabrina S Chow, Ying Wang, Jeremy A Sarnat, Ryan Diver, Emily L Deubler, Stephanie M Eick, Douglas I Walker, Ziyin Tang, Aparna H. Kesarwala, Michelle Turner, Donghai Liang
Journal: Journal of Clinical Oncology (2024)

10571 Background: Despite the well-established link between air pollution exposure and lung carcinogenesis, the underlying mechanism remains underexplored. While metabolomics has provided valuable molecular insights, existing air pollution metabolomics studies only assess biological changes to single air pollutants, without examining the join effects of air pollutant mixtures. We sought to identify metabolic signatures mediating the association between ambient air pollution mixtures and lung cancer risk. Methods: A total of 603 matched lung cancer case-control pairs were selected from the Cancer Prevention Study cohorts. Controls were matched to cases on age at blood draw, sex, race/ethnicity, and blood draw date. Plasma metabolomics was conducted using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Air pollution mixtures include carbon monoxide, nitrogen dioxide, particulate matter, sulfur dioxide, and ozone, matched to subjects’ residential address at blood draw. We conducted an untargeted metabolome-wide association study with multivariable-adjusted linear and conditional logistic regression models to assess associations between metabolites and individual air pollutants and lung cancer risk, respectively, adjusting for individual and lifestyle-related covariates. We used a meet-in-the-middle (MITM) approach to identify potential mediators. Quantile g-computation was used to examine the effects of air pollution mixtures on metabolome perturbations to analyze the collective effects of multiple air pollutants concurrently. Results: Among 1,138 extracted metabolic features, 162 were significantly associated with the combined mixture (false discovery rate &lt; 0.2). Using MITM, no metabolites were associated with both air pollution mixture and lung cancer risk at FDR &lt; 0.2. At raw p &lt; 0.05, 16 metabolites were identified as potential mediators of the air pollution mixture and lung cancer risk. These metabolites, including 4-hydroxyphenylacetylglutamine, glutamate, and 3-aminoisobutyrate, were also significantly associated with the mixture at FDR &lt; 0.2. Conclusions: Findings from this analysis demonstrate the feasibility of considering multiple air pollutants as mixtures when conducting air pollution-related metabolomics investigations. Future exploration of the underlying biological mechanisms will be critical for validating pathways that participate in air pollution carcinogenicity. As lung cancer cases in never smokers continue to increase, it is pertinent to study air pollution and other environmental risk factors on cancer incidence.
Adverse childhood experiences and cancer: A systematic review and meta-analysis.
Authors: Anna Mavromanoli, Claudia Sikorski, Danial Behzad, Karishma Manji, Catherine Kreatsoulas
Journal: Journal of Clinical Oncology (2024)

10565 Background: Cancer is one of the leading causes of morbidity and mortality globally, with increasing incidence rates. The major governing cancer societies identify cancer risk factors into five broad groups (infectious disease, environmental/chemical pollutants, genetics, behavioral and ultraviolet radiation). However, little attention has been dedicated to understanding the potential primordial risk of the early psychosocial environment. Life course epidemiology is a framework that considers how the harmful effects of adverse childhood experiences (ACEs) contribute to the development of disease later in life. It is postulated that such stressful events that occur during a critical period of development likely trigger increased inflammatory responses, which could ultimately contribute to the manifestation of chronic diseases such as cancer. While there are studies that have reported an association between ACEs and cancer, this relationship has yet to be systematically analyzed. The objectives of this study are to a) meta-analyze the pooled association of the presence of at least one ACE, b) the burden of different ACEs, and c) specific ACE types, and their association with cancer in adulthood. Methods: This systematic review compiled studies from PubMed, EMBASE, Medline, Web of Science, Google Scholar, Biological Psychiatry, and grey literature up to Mar 16, 2023, and was registered on PROSPERO. Observational studies with a comparator group that assessed ACEs that occurred prior to age 18, and diagnosed cancer ≥21 years of age were included. Two review authors independently screened articles, extracted data, assessed risk of bias using QUIPS, and conducted GRADE assessment. Pooled odds ratios (ORs) were calculated using multilevel linear random-effects models. Results: Of the total 39,658 articles, our search identified 26 studies, of which 23 studies (356,519 participants, 9 countries) were eligible for meta-analysis. The occurrence of ≥1 ACE(s) was associated with cancer (OR=1.16, 95% CI: 1.08-1.24, I2 = 58.7%), compared to participants with no ACEs. As the number of ACEs increased, the odds of cancer increased (≥4 ACEs compared to no ACEs OR=1.30, 1.04-1.62, p-trend = 0.0003). Specific ACE types did explain a significant amount of heterogeneity (F = 2.02, p = 0.04). Parental or sibling death (OR=1.88, 1.29-2.73), household mental illness (OR=1.36, 1.14-1.61), sexual abuse (OR=1.20, 1.04-1.37), and physical abuse (OR=1.18, 1.05-1.34) had the largest associations with cancer. Conclusions: Our findings confirm ACEs as important risk factors for cancer in adulthood. These findings have important clinical and public health implications to develop primary and secondary prevention and treatment strategies. Also, further research is warranted to explore this relationship on the epigenetic level, and among specific cancers.
Population attributable fraction of reproductive factors in triple negative breast cancer by race.
Authors: Rachel Jaber Chehayeb, Nicole Odzer, Roberta A Albany, Amanda I. Phipps, Allison Meisner, Lajos Pusztai
Journal: Journal of Clinical Oncology (2024)

10522 Background: Age-adjusted incidence rates of triple negative breast cancer (TNBC) are higher in African American (AA) women than in non-Hispanic White (White) women. The disproportionate incidence of TNBC in AA women partially drives the 40% higher mortality rate from breast cancer in AA women compared to White women. Several studies have identified lack of breastfeeding and younger age at first birth as risk factors for TNBC. There are large differences in breastfeeding uptake and duration in the US: only 44% of AA women breastfeed for 6 months or longer, compared to 60% of White women. To quantify the contribution of differences in breastfeeding patterns and younger age at first birth to disparities in incidence of TNBC, we calculate the population-attributable fraction (PAF), which is the proportion of the incidence of a disease that may be attributable to a particular exposure. Methods: A systematic review was performed to identify relevant case-control studies. Pooled odds ratios (ORs) for breastfeeding for &lt; 6 months and age at first birth &lt; 25 years were calculated from data extracted from studies using a common effect model. PAF was calculated using the Levin formula. Risk factor population prevalences were extracted from national surveys. Pooled ORs were used as estimates of relative risk (RR). A combined PAF was calculated using the polychoric correlation coefficient between breastfeeding duration and age at first birth to account for contributions of multiple risk factors. Results: Using race specific ORs, the PAF of breastfeeding for &lt; 6 months was 12% (95% confidence interval (CI) 5-20%) among White women and 15% (95% CI 3-26%) among AA women. The PAF of having a child before age 25 was not significantly different from zero for White women (2% (CI -6-11%)) but was significantly different from zero for AA women (21% (CI 5-25%)). The combined PAF was 27% for AA women and 17% for all women in the US. Extrapolating to the US population, we estimated that 4,850 annual cases of TNBC (2,421 among White women and 1,533 among AA women) could be attributed to breastfeeding for &lt; 6 months and age at first birth &lt; 25 years. Conclusions: Given the protective role of breastfeeding against TNBC, policy changes aimed at supporting breastfeeding, addressing structural barriers, and promoting a culture shift could reduce racial disparities in TNBC incidence in the US. [Table: see text]
An emulated target trial assessing the impact of physical activity on 14-year cancer risk: Insights from the Cancer Prevention Study-II.
Authors: Valeria Elahy, Marjorie McCullough, Alpa Patel, Erika Rees-Punia, Anita R Peoples, Ying Wang
Journal: Journal of Clinical Oncology (2024)

10541 Background: The American Cancer Society, along with the World Cancer Research Fund/American Institute of Cancer Research, recommends a weekly regimen of physical activity (at least 75 minutes of vigorous or 150 minutes of moderate-intensity aerobic physical activity) for cancer prevention. The positive impact of physical activity on reducing cancer risk is well-known; however, the causal link between physical activity and cancer risk reduction is not established, primarily due to the observational nature of the current evidence. Given the ethical considerations involved in assigning physical activity levels below the recommended minimum, coupled with the impracticality of conducting decades-long trials due to the latency period of cancer development, there is a need for an innovative approach beyond traditional observational and randomized trial methodologies. This highlights the importance of applying alternative strategies like emulated target trials to produce evidence of the causal effect of physical activity on cancer risk that would otherwise be difficult to obtain. This study aims to estimate the causal effect of adherence to recommended physical activity levels on the 14-year total cancer and obesity-related cancer risk using an emulated target trial framework. Methods: Data from 79,668 participants who were non-current smokers and without prevalent cancer diagnosis at pre-baseline in the Cancer Prevention Study-II were analyzed. This study estimated the effect of different physical activity levels (&lt;7.5, 7.5-&lt;15, and ≥15 MET-hrs/wk) on 14-year cancer risks using a parametric g-formula. Models adjusted for confounders include age, sex, education, years since quitting smoking, family history of cancer, physical activity, body mass index, alcohol consumption, diet quality (measured by the ACS diet score), history of cardiovascular disease, and diabetes. Results: Under no intervention, the estimated 14-year risk for any cancer was 27.9% (95% CI: 27.6%, 28.4%), and for obesity-related cancers, it was 11.2% (95% CI: 11.0%, 11.5%). Compared with no intervention, engaging in 7.5-&lt;15 MET-hrs/wk of physical activity (minimum recommended) was linked with a 0.31% reduction in the risk of any cancer (95% CI: -0.41%, -0.06%) and a 0.19% reduction in the risk of obesity-related cancers (95% CI: -0.37%, -0.04%). Engaging in ≥15 MET-hrs/wk of physical activity (twice the minimum recommended level) was linked with a 1.31% risk reduction for any cancer (95% CI: -1.67%, -1.20%) and a 0.91% risk reduction for obesity-related cancers (95% CI: -1.09%, -0.80%), compared with no intervention. Conclusions: Incremental adherence to physical activity recommendations for cancer prevention could significantly lower the risk of developing cancers, including those related to obesity.
Racial differences in background parenchymal enhancement, a novel marker of breast cancer.
Authors: Mattia Mahmoud, Sarah Ehsan, Elizabeth Mack, Christine E Edmonds, Despina Kontos, Jinbo Chen, Oluwadamilola Motunrayo Fayanju, Anne Marie McCarthy
Journal: Journal of Clinical Oncology (2024)

10528 Background: Breast density is a risk factor for breast cancer that can guide eligibility for supplemental screening including MRI, but Black women are less likely to qualify for supplemental screening due to having less dense breasts on average despite higher rates of breast cancer mortality. Background parenchymal enhancement (BPE), the enhancement of fibroglandular breast tissue on contrast-enhanced MRI, is a novel biomarker that has been shown to be a superior breast cancer risk marker than breast density. Women with high BPE levels have up to a four-fold increased risk of breast cancer, even after adjusting for density, but no studies have examined BPE exclusively among Black women. Methods: We identified Black and white women ages 40-74 with no prior history of breast cancer who had a mammogram and subsequent MRI as part of a screening or diagnostic work-up from 2016-2022 at our institution. BPE was qualitatively defined according to BI-RADS (Breast Imaging Reporting and Data System), with four ordinal levels of increasing enhancement: minimal, mild, moderate, and marked. We conducted a cross-sectional study to perform a logistic regression with race as the exposure and moderate or marked BPE as the outcome, using minimal and mild BPE as the reference group, adjusted for age and BI-RADS density. Results: We included 1027 Black women and 4834 white women in our analysis. Fewer Black women had extremely dense breasts compared to white women (6% vs 13%, p= 0.04), however, there was a larger proportion of high BPE (moderate or marked) in Black women compared to white women (32% vs 28%, p = 0.03) (Table). There was an inverse association between age and BPE levels (p = 0.03), and a positive association between density and BPE levels regardless of race (p&lt; 0.01) (not shown). Black women were 39% more likely to have high BPE levels (95% CI: 1.39 [1.19, 1.63]), adjusted for age and density. Conclusions: Black women have lower density but higher BPE than white women, suggesting that BPE may improve identification of breast cancer risk for Black women. Participants [Table: see text]