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While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.

Background Although it has been well-documented that obesity is associated with decreased risk of premenopausal breast cancer and increased risk of postmenopausal breast cancer, it is unclear whether these associations differ among breast cancer subtypes defined by the tumor protein expression status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Methods We evaluated the associations of body mass index (BMI) at age 18 years and recent BMI in relation to risk of breast cancer overall and ER/PR/HER2-defined subtypes, in 6320 women (3934 case-patient participants, 2386 control participants) aged 35–64 years, who participated in one of three population-based case-control studies. We estimated multivariable-adjusted odd ratios (ORs) and corresponding 95% confidence intervals (CIs) using polychotomous unconditional logistic regression methods for case-control comparisons in premenopausal women and postmenopausal women. Results BMI at age 18 years was inversely associated with risk of breast cancer, particularly among premenopausal women (≥ 25 vs. < 20 kg/m 2 , OR = 0.72, 95% CI = 0.53–0.96; per 5 kg/m 2 increase, OR = 0.83, 95% CI = 0.73–0.95). This inverse association did not differ across ER/PR/HER2-defined subtypes or by race (white women, African-American women). Recent BMI was not associated with risk of premenopausal breast cancer after adjustment for BMI at age 18 years; nevertheless, the analysis for the joint effects of BMI at age 18 years and recent BMI showed that premenopausal women in the highest categories of the two BMI measures (≥ 25 kg/m 2 at age 18 years and ≥ 30 kg/m 2 for recent BMI) had 46% lower risk of breast cancer than premenopausal women in the lowest categories of the two BMI measures (< 20 kg/m 2 at age 18 years and < 25 kg/m 2 for recent BMI; OR = 0.54, 95% CI = 0.38–0.78). Neither measure of BMI was statistically significantly associated with risk of postmenopausal breast cancer. Conclusion Our findings indicate that high BMI near the end of adolescence decreases risk of all ER/PR/HER2-defined subtypes of premenopausal breast cancer and also suggest that this benefit could be maximized among premenopausal women who consistently have high BMI during their premenopausal years.

Background There is sparse clinical information on the racial and ethnic distribution of results of multigene panel testing among individuals at high risk for hereditary cancer. Methods We evaluated the results of multigene panel testing across eight clinical sites across the state of Michigan for individuals seen for genetic counseling from May 13, 2013 to October 31, 2019 at the Karmanos Cancer Institute's cancer genetics clinic. We estimated the prevalence of pathogenic variants and variants of uncertain significance (VUS) from genes other than BRCA1/2 among individuals of non‐Hispanic White (NHW), Black or African American (AA), Ashkenazi Jewish (AJ), Arab, Hispanic, and other ancestry. Results The racial and ethnic distribution of 2419 individuals who had panel testing included 68.8% NHW, 22.1% AA, 2.3% Arab, 2.2% AJ, 1.0% Hispanic, and 3.6% other. Of these, 11.2% had pathogenic variants and 17.5% had VUS. After multivariable analyses, compared to NHW, AA were less likely to have pathogenic variants (OR 95% CI, 0.38, 0.24–0.59, p < 0.001). Both AA and Arabs were more likely to have VUS (OR 95% CI, 1.53, 1.18–1.98, p = 0.001 and OR 95% CI, 2.28, 1.17–4.43, p = 0.015, respectively). There were no significant differences for other groups. The most common pathogenic variants were CHEK2 (n = 65), MUTYH (n = 45), ATM (n = 28), and MSH2 (n = 22); the most common pathogenic variants by race and ethnicity were CHEK2 (NHW), MSH2 and MUTYH (AA), MSH2 (Arab), MSH6 and CHEK2 (AJ), and MLH1 (Hispanic); the most common pathogenic variants by primary cancer site were CHEK2 (breast), MSH2 (colon), BRIP1 and MUTYH (ovarian), and MSH2 and MSH6 (endometrial). Conclusions Understanding the racial and ethnic distribution of pathogenic variants in multi‐gene panels has the potential to lead to better identification of individuals at risk for hereditary cancer. Racial and ethnicity variations were described in patients undergoing multi‐gene panel testing. In addition, common pathogenic variants based on race/ethnicity as well as cancer type was described. This descriptive study allows for informed decisions in counseling of patients.

Background The study was conducted to evaluate racial differences in referral and uptake of genetic counseling (GC) in a clinic‐based population of women with breast cancer. Methods Medical records of 150 breast cancer patients at the Karmanos Cancer Institute were reviewed to determine eligibility for GC according to National Comprehensive Cancer Network guidelines, GC referral rates, and appointment completion rates. Logistic regression was used to assess the relationship between demographic and clinical factors and GC eligibility and referral. Results The mean age at diagnosis was 57.1 (SD 12.6) and 66% of the women were Black. There were 91 women (60.7%) eligible for GC and of those, 54 (61.4%) were referred. After multivariable analyses, factors associated with reduced eligibility were older age at diagnosis (OR = 0.91, 95% CI [0.87,0.95]) and Black race (OR = 0.37, 95% CI [0.15, 0.96]). After additional multivariable analysis, eligibility was associated with an increased likelihood of referral (OR = 5.97, 95% CI [2.29, 15.56]), however, Medicare versus private insurance was associated with a lower likelihood for referral (OR = 0.32, 95% CI [0.12–0.80]. Of those referred, 49 (76.6%) completed an appointment, and 47 had genetic testing. Women with Medicare were also less likely to complete an appointment. Race had no impact on referral or appointment completion. Conclusions There were no racial differences in GC referral or appointment completion in a clinic‐based sample of women with breast cancer. Further interventions are needed to promote increased referral and appointment completion for women with breast cancer who are eligible for GC. There were no racial differences in GC referral or appointment completion in a clinic‐based sample of women with breast cancer. Further interventions are needed to promote increased referral and appointment completion for women with breast cancer who are eligible for GC.

Background Many of the 3.8 million breast cancer survivors in the United States experience long‐term side effects of cancer therapy including peripheral neuropathy (PN). We assessed the prevalence and predictors of PN among women with breast cancer followed in the Women's Health Initiative's Life and Longevity After Cancer survivorship cohort. Methods The study population included 2420 women with local (79%) or regional (21%) stage disease. Presence of PN was based on the reports of “nerve problems and/or tingling sensations” after treatment and PN severity was assessed using the Functional Assessment of Cancer Therapy‐Gynecologic Oncology Group/Neurotoxicity instrument. Logistic regression analysis was used to evaluate the socio‐demographic and clinical factors associated with PN prevalence and severity. Results Initial breast cancer treatment included surgery‐only (21%), surgery and radiation (53%), or surgery and chemotherapy (±radiation) (26%). Overall, 17% of women reported PN occurring within days (30%), months (46%), or years (24%) after treatment and 74% reported ongoing symptoms at a median of 6.5 years since diagnosis. PN was reported by a larger proportion of chemotherapy recipients (33%) compared to those who had surgery alone (12%) or surgery+radiation (11%) (p < 0.0001). PN was reported more commonly by women treated with paclitaxel (52%) and docetaxel (39%), versus other chemotherapy (17%) (p < 0.0001). In multivariable analyses, treatment type (chemotherapy vs. none; OR, 95% CI: 3.31, 2.4–4.6), chemotherapy type (taxane vs. no‐taxane; 4.74, 3.1–7.3), and taxane type (paclitaxel vs. docetaxel; 1.59, 1.0–2.5) were associated with higher odds of PN. Conclusion PN is an important long‐term consequence of taxane‐based chemotherapy in breast cancer survivors.

Purpose: To evaluate the association between statins and breast cancer stage and mortality in the Women's Health Initiative. Methods: The study population included 128,675 postmenopausal women aged 50–79 years, out of which there were 7,883 newly diagnosed cases of in situ (19 %), local (61 %)-, regional (19 %)- and distant (1 %)-stage breast cancer and 401 deaths due to breast cancer after an average of 11.5 (SD = 3.7) years of follow-up. Stage was coded using SEER criteria and was stratified into early (in situ and local)- versus late (regional and distant)-stage disease. Information on statins and other risk factors were collected by self- and interviewer-administered questionnaires. Cause of death was based on medical record review. Multivariable-adjusted hazards ratios (HR) and 95 % confidence intervals (CIs) evaluating the relationship between statin use (at baseline only and in a time-dependent manner) and diagnosis of late-stage breast cancer and breast cancer-specific mortality were computed from Cox proportional hazards analyses after adjusting for appropriate confounders. Results: Statins were used by 10,474 women (8 %) at baseline. In the multivariable-adjusted time-dependent model, use of lipophilic statins was associated with a reduction in diagnosis of late-stage breast cancer (HR 0.80, 95 % CI 0.64–0.98, p = 0.035) which was also significant among women with estrogen receptor-positive disease (HR 0.72, 95 % CI 0.56–0.93, p = 0.012). Breast cancer mortality was marginally lower in statin users compared with nonusers (HR 0.59, 95 % CI 0.32–1.06, p = 0.075). Conclusions: Prior statin use is associated with lower breast cancer stage at diagnosis.

Purpose Pre‐existing comorbidities play an important role in choice of cancer treatment. We retrospectively evaluated the relationship between pre‐existing comorbidities and receipt of local and systemic therapy in a cohort of Black women with Stage I–III breast cancer. Methods The study population for analysis included 1169 women with Stage I–III disease enrolled in the Detroit Research on Cancer Survivors (ROCS) cohort. Information on comorbidities, socio‐demographic, and clinical variables were obtained from self‐reported questionnaires and the cancer registry. Comorbidities were analyzed individually, and comorbidity burden was categorized as low (0–1), moderate (2–3) or high (≥4). We used logistic regression analysis to evaluate factors associated with receipt of local treatment (surgery ± radiation; N = 1156), hormonal (N = 848), and chemotherapy (N = 680). Adjusted models included variables selected a priori that were significant predictors in univariate analysis. Results Receipt of treatment was categorized into local (82.6%), hormonal (73.7%), and/or chemotherapy (79.9%). Prior history of arthritis and depression were both associated with a lower likelihood to receive local treatment, [odds ratio (OR), 95% confidence interval (CI), 0.66, 0.47–0.93, and 0.53, 0.36–0.78], respectively. Obesity was associated with higher likelihood of receiving hormonal therapy (OR: 1.64, 95% CI: 1.19, 2.26), and heart failure a lower likelihood (OR: 0.46, 95% CI: 0.23, 0.90). Older age (Ptrend <0.01) and increasing co‐morbidity burden (Ptrend = 0.02) were associated with lower likelihood of receiving chemotherapy. Conclusion History of prior co‐morbidities has a potentially detrimental influence on receipt of recommended cancer‐directed treatment among women with Stage I–III breast cancer.

Background Epidemiological studies of chemotherapy‐induced peripheral neuropathy (CIPN) have predominantly focused on non‐Hispanic White patients, despite the observation that African Americans are more likely to experience CIPN. To address this health disparities gap, we sought to identify non‐genetic risk factors and comorbidities associated with CIPN in African American cancer survivors using the Detroit Research on Cancer Survivors study. Methods Logistic regression was used to evaluate relationships between presence of self‐reported CIPN and relevant clinical characteristics in 1045 chemotherapy‐treated African American cancer survivors. Linear regression was used to evaluate risk factors for CIPN and quality of life outcomes that reflect physical, social, emotional, and functional domains of health. Results Patients with CIPN were more likely to report hypertension (OR = 1.28, 95% CI: 0.98–1.67, p = 0.07), hypercholesterolemia (OR = 1.32, 95% CI: 1.001–1.73, p = 0.05), history of depression (OR = 1.62, 95% CI: 1.18–2.25, p = 0.003), and diabetes (OR = 1.33, 95% CI: 0.98–1.82, p = 0.06) after adjustment for age at diagnosis, sex, and cancer site. BMI (OR = 1.02 kg/m2, 95% CI: 1.006–1.04 kg/m2, p = 0.008) was also positively associated with CIPN. In addition, CIPN status was significantly associated with quality of life (FACT‐G total: β = −8.60, 95% CI: −10.88, −6.32) p < 0.0001) and mood (PROMIS® Anxiety: β = 4.18, 95% CI: 2.92–5.45, p < 0.0001; PROMIS® Depression: β = 2.69, 95% CI: 1.53–3.84, p < 0.0001) after adjustment for age at diagnosis, sex, cancer site, and comorbidities. Neither alcohol consumption (OR = 0.88, 95% CI: 0.68–1.14, p = 0.32) nor tobacco use (ever smoked: OR = 1.04, 95% CI: 0.80–1.35, p = 0.76; currently smoke: OR = 1.28, 95% CI: 0.90–1.82, p = 0.18) was associated with increased CIPN risk. Conclusion Risk factor profiles in African Americans are not entirely consistent with those previously reported for non‐Hispanic White patients. Neglecting to understand the correlates of common chemotherapy‐induced toxicities for this patient population may further contribute to the health disparities these individuals face in receiving adequate healthcare. Although African Americans have an increased susceptibility to developing chemotherapy‐induced peripheral neuropathy, epidemiological studies have predominantly focused on non‐Hispanic Whites. Our study demonstrates that risk factor profiles in African Americans are not entirely consistent with those previously reported for non‐Hispanic Whites, and that neglecting to understand the correlates of common chemotherapy‐induced toxicities for this patient population may further contribute to the health disparities these individuals face in receiving adequate healthcare.

Background Alcohol consumption is associated with increased risk of breast cancer; however, its association with subsequent risk of breast cancer death is unclear. Methods We followed 4523 women with complete information on relevant risk factors for mortality; these women were 35 to 64 years of age when diagnosed with incident invasive breast cancer between 1994 and 1998. During follow up (median, 8.6 years), 1055 women died; 824 died from breast cancer. The information on alcohol consumption before diagnosis was collected shortly after breast cancer diagnosis (average: 5.1 months) during an in-person interview which used a structured questionnaire. Multivariable Cox proportional hazards regression models provided hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific mortality, mortality due to causes other than breast cancer, and all-cause mortality associated with alcohol consumption from age 15 years until breast cancer diagnosis and during recent periods of time prior to breast cancer diagnosis. Results Average weekly alcohol consumption from age 15 years until breast cancer diagnosis was inversely associated with breast cancer-specific mortality ( P trend  = 0.01). Compared to non-drinkers, women in the highest average weekly alcohol consumption category (≥7 drinks/week) had 25% lower risk of breast cancer-specific mortality (HR = 0.75, 95% CI = 0.56–1.00). Breast cancer mortality risk was also reduced among women in the highest average weekly alcohol consumption category in two recent time periods (5-year period ending 2-years prior to breast cancer diagnosis, HR = 0.74, 95% CI = 0.57–0.95; 2-year period immediately prior to breast cancer diagnosis: HR = 0.73, 95% CI = 0.56–0.95). Furthermore, analyses of average weekly alcohol consumption by beverage type from age 15 years until breast cancer diagnosis suggested that wine consumption was inversely associated with breast cancer-specific mortality risk (wine P trend  = 0.06, beer P trend  = 0.24, liquor P trend  = 0.74). No association with any of these alcohol consumption variables was observed for mortality risk due to causes other than breast cancer. Conclusions Overall, we found no evidence that alcohol consumption before breast cancer diagnosis increases subsequent risk of death from breast cancer.

Background This study aimed to identify predictors of nonadherence to breast cancer screening guidelines in an urban screening clinic among high‐ and average‐risk women in the United States. Methods We reviewed records of 6090 women who received ≥2 screening mammograms over 2 years at the Karmanos Cancer Institute to examine how breast cancer risk and breast density were associated with guideline‐concordant screening. Incongruent screening was defined as receiving supplemental imaging between screening mammograms for average‐risk women, and as not receiving recommended supplemental imaging for high‐risk women. We used t‐tests and chi‐square tests to examine bivariate associations with guideline‐congruent screening, and probit regression to regress guideline‐congruence unto breast cancer risk, breast density, and their interaction, controlling for age and race. Results Incongruent screening was more likely among high‐ versus average‐risk women (97.7% vs. 0.9%, p < 0.01). Among average‐risk women, incongruent screening was more likely among those with dense versus nondense breasts (2.0% vs. 0.1%, p < 0.01). Among high‐risk women, incongruent screening was more likely among those with nondense versus dense breasts (99.5% vs. 95.2%, p < 0.01). The significant main effects of density and high‐risk on increased incongruent screening were qualified by a density by high‐risk interaction, showing a weaker association between risk and incongruent screening among women with dense breasts (simple slope = 3.71, p < 0.01) versus nondense breasts (simple slope = 5.79, p < 0.01). Age and race were not associated with incongruent screening. Conclusions Lack of adherence to evidence‐based screening guidelines has led to underutilization of supplementary imaging for high‐risk women and potential overutilization for women with dense breasts without other risk factors.