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PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

To determine the relationship between characteristics of employment and future hospitalization in older adults.We conducted a survey of adults aged 65 years or older participating in the Mayo Clinic Biobank. Using a frequency-matched, case-control design, we compared patients who were hospitalized within 5 years of biobank enrollment (cases) with those who were not hospitalized (controls). We assessed the duration of work, age at first job, number of jobs, disability, retirement, and reasons for leaving work. We performed logistic regression analysis to assess the association of these factors with hospitalization, accounting for age, sex, comorbid conditions, and education level.Among 3536 participants (1600 cases and 1936 controls; median age, 68.5 years; interquartile range, 63.4-73.9 years), cases were older, more likely to be male, and had lower education levels. Comorbid illnesses had the largest association with hospitalization (odds ratio [OR], 4.09; 95% CI, 3.37-4.97 [highest vs lowest quartile]). On adjusted analyses, odds of hospitalization increased with the presence of disability (OR, 1.31; 95% CI, 1.01-1.69) and decreased with having 1 or 2 lifetime jobs vs no employment (OR, 0.77; 95% CI, 0.60-1.00). The length of work, furlough, age of retirement, childcare issues, and reasons for leaving a job were not associated with hospitalization.This study reports an association between disability during work and hospitalization. On the basis of our findings, it may be important to obtain a more detailed work history from patients because it may provide further insight into their future health.

Monoclonal B-cell lymphocytosis (MBL) is a common hematological premalignant condition that is understudied in screening cohorts. MBL can be classified into low-count (LC) and high-count (HC) types based on the size of the B-cell clone. Using the Mayo Clinic Biobank, we screened for MBL and evaluated its association with future hematologic malignancy and overall survival (OS). We had a two-stage study design including discovery and validation cohorts. We screened for MBL using an eight-color flow-cytometry assay. Medical records were abstracted for hematological cancers and death. We used Cox regression to evaluate associations and estimate hazard ratios and 95% confidence intervals (CIs), adjusting for age and sex. We identified 1712 (17%) individuals with MBL (95% LC-MBL), and the median follow-up time for OS was 34.4 months with 621 individuals who died. We did not observe an association with OS among individuals with LC-MBL (P = .78) but did among HC-MBL (hazard ratio, 1.8; 95% CI, 1.1-3.1; P = .03). Among the discovery cohort with a median of 10.0 years follow-up, 31 individuals developed hematological cancers with two-thirds being lymphoid malignancies. MBL was associated with 3.6-fold risk of hematological cancer compared to controls (95% CI, 1.7-7.7; P < .001) and 7.7-fold increased risk for lymphoid malignancies (95% CI:3.1-19.2; P < .001). LC-MBL was associated with 4.3-fold risk of lymphoid malignancies (95% CI, 1.4-12.7; P = .009); HC-MBL had a 74-fold increased risk (95% CI, 22-246; P < .001). In this large screening cohort, we observed similar survival among individuals with and without LC-MBL, yet individuals with LC-MBL have a fourfold increased risk of lymphoid malignancies. Accumulating evidence indicates that there are clinical consequences to LC-MBL, a condition that affects 8 to 10 million adults in the United States.

COVID-19 is a multi-system disorder with high variability in clinical outcomes among patients who are admitted to hospital. Although some cytokines such as interleukin (IL)-6 are believed to be associated with severity, there are no early biomarkers that can reliably predict patients who are more likely to have adverse outcomes. Thus, it is crucial to discover predictive markers of serious complications.In this retrospective cohort study, we analysed samples from 455 participants with COVID-19 who had had a positive SARS-CoV-2 RT-PCR result between April 14, 2020, and Dec 1, 2020 and who had visited one of three Mayo Clinic sites in the USA (Minnesota, Arizona, or Florida) in the same period. These participants were assigned to three subgroups depending on disease severity as defined by the WHO ordinal scale of clinical improvement (outpatient, severe, or critical). Our control cohort comprised of 182 anonymised age-matched and sex-matched plasma samples that were available from the Mayo Clinic Biorepository and banked before the COVID-19 pandemic. We did a deep profiling of circulatory cytokines and other proteins, lipids, and metabolites from both cohorts. Most patient samples were collected before, or around the time of, hospital admission, representing ideal samples for predictive biomarker discovery. We used proximity extension assays to quantify cytokines and circulatory proteins and tandem mass spectrometry to measure lipids and metabolites. Biomarker discovery was done by applying an AutoGluon-tabular classifier to a multiomics dataset, producing a stacked ensemble of cutting-edge machine learning algorithms. Global proteomics and glycoproteomics on a subset of patient samples with matched pre-COVID-19 plasma samples was also done.We quantified 1463 cytokines and circulatory proteins, along with 902 lipids and 1018 metabolites. By developing a machine-learning-based prediction model, a set of 102 biomarkers, which predicted severe and clinical COVID-19 outcomes better than the traditional set of cytokines, were discovered. These predictive biomarkers included several novel cytokines and other proteins, lipids, and metabolites. For example, altered amounts of C-type lectin domain family 6 member A (CLEC6A), ether phosphatidylethanolamine (P-18:1/18:1), and 2-hydroxydecanoate, as reported here, have not previously been associated with severity in COVID-19. Patient samples with matched pre-COVID-19 plasma samples showed similar trends in muti-omics signatures along with differences in glycoproteomics profile.A multiomic molecular signature in the plasma of patients with COVID-19 before being admitted to hospital can be exploited to predict a more severe course of disease. Machine learning approaches can be applied to highly complex and multidimensional profiling data to reveal novel signatures of clinical use. The absence of validation in an independent cohort remains a major limitation of the study.Eric and Wendy Schmidt.

Although the benefits of surveillance mammography for older breast cancer survivors have not been quantified prospectively, it is unlikely that mammography provides substantial benefit (and possible that mammography is harmful) to women with limited life expectancy and a low risk for in-breast cancer events.We identified 1268 women aged 77 and older with a history of Stage I-III breast cancer, who did not undergo bilateral mastectomy, were diagnosed with cancer at least three years prior to study entry, and who had consented to be surveyed as part of the Mayo Clinic Breast Disease Registry. We mailed them a one-time survey asking about their experiences with surveillance mammography. Women with metastatic disease were excluded. The primary endpoint was whether or not women reported at least one mammogram since breast cancer surgery.Eight hundred forty-six of 1268 (67%) returned the survey, 734 of whom were eligible for analysis. The median age at the time of survey was 82, and the median time since cancer diagnosis was 12 years. Ninety-three percent reported having had at least one mammogram since their initial breast cancer surgery. Seventy-nine percent reported that they had surveillance mammography annually over the prior three years, including 76% of the 491 aged 80+ and 64% of the 189 aged 85 + .Most older breast cancer survivors who have residual breast tissue are undergoing annual mammograms. Additional educational materials may be beneficial for patients and clinicians to better individualize plans for surveillance mammography in older breast cancer survivors.

Purpose: Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer–related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence.Experimental Design: Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors.Results: Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up.Conclusion: An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain. Clin Cancer Res; 16(3); 995–1007

Summary results for all SNPs at the 4q24 locus associated with breast cancer risk at P

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

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Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7].Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer.Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.

Figure S1: BCRA2 p.Y3035S Pedigrees. Figure S2: Western blot of ectopically expressed full-length wildtype and mutant hBRCA2 protein in VC8 DR-GFP cells subjected to HDR assay. Figure S3: Purification of wildtype and mutant BRCA2 from human cells. Figure S4: Position of BRCA2 DNA binding domain (DBD) variants on a ribbon diagram of the murine DBD crystal structure.

Table S1: Description of the BCAC studies contributing to COGS. Table S2: Predicted effects of BRCA1 and BRCA2 variants included in the iCOGS array on protein function. Table S3: Frequency of BRCA1 and BRCA2 variants from iCOGS in breast cancer cases and controls. Table S4: Family studies of Y3035S showing scores for each family by constant relative risk and 75% penetrance. Supplementary References.

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

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Supplementary Table 2. Associations (95% Confidence Interval (CI) in brackets) between all 77 breast cancer susceptibility variants and percent dense area, dense area, and non-dense area

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Supplementary Table 3. Associations (95% Confidence Interval (CI) in brackets) between breast cancer susceptibility variants and the mammographic measures with adjustment for case-control status

Supplementary Table 1. Mean (95% Confidence Interval (CI)) mammographic density measurements by covariate distribution

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Background Larger within‐patient variability of lipid levels has been associated with increased risk of cardiovascular disease (CVD); however, measures of lipid variability require ≥3 measurements and are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record–based population cohort and assessed associations with incident CVD. Methods and Results We identified all individuals ≥40 years of age who resided in Olmsted County, MN, on January 1, 2006 (index date), without prior CVD, defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention, or CVD death. Patients with ≥3 measurements of total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, or triglycerides during the 5 years before the index date were retained. Lipid variability was calculated using variability independent of the mean. Patients were followed through December 31, 2020 for incident CVD. We identified 19 652 individuals (mean age 61 years; 55% female), who were CVD‐free and had variability independent of the mean calculated for at least 1 lipid type. After adjustment, those with highest total cholesterol variability had a 20% increased risk of CVD (Q5 versus Q1 hazard ratio, 1.20 [95% CI, 1.06–1.37]). Results were similar for low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Conclusions In a large electronic health record–based population cohort, high variability in total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol was associated with an increased risk of CVD, independent of traditional risk factors, suggesting it may be a possible risk marker and target for intervention. Lipid variability can be calculated in the electronic health record environment, but more research is needed to determine its clinical utility.

Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death in epilepsy (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the United States do not mandate the use of electrocardiography (ECG) in diagnostic evaluation of seizures or epilepsy.The purpose of this study was to determine the frequency of ECG use and of QT prolongation, and whether QT prolongation predicts mortality in patients with seizures.We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to July 31, 2015, with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by the presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period.Optimal cutoff QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 patients (57.4%). After patients with confounding ECG findings were excluded, primary prolonged QT intervals were seen in 223 cases (1.4%), similar to the general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.76-2.05) for prolonged optimal cutoff QT, maintained after adjustments for age, Charlson comorbidity index, and sex (HR 1.48; 95% CI 1.37-1.59).Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cutoff QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy.

Introduction: Breast cancer treatments can impair fertility via direct gonadotoxicity (chemotherapy) as well as by introducing delays in childbearing that allow natural ovarian aging. Guidelines strongly recommend fertility counseling and consideration of fertility preservation techniques for premenopausal women who have not completed their desired childbearing at the time of cancer diagnosis. Prior studies have identified high rates of fertility concern but relatively low rates of fertility counseling and use of fertility preservation techniques. We sought to investigate rates of fertility counseling, use of fertility preservation techniques, and how fertility concerns impact cancer treatment decisions in a modern cohort of patients with breast cancer at a large academic medical center in the United States. Methods: All patients seen at Mayo Clinic Rochester with a new diagnosis (within the year prior) of stage 0-4 breast cancer were invited (by mail or in person) to participate in the Mayo Clinic Breast Registry. After informed consent, participants were asked to complete a baseline survey and annual follow-up surveys. On baseline and one-year surveys, patients were queried about desire for future children and fertility concerns. Nurse chart abstraction was used to collect information about tumor subtype, stage, and treatments received. We examined survey data from women diagnosed under the age of 50 who expressed an interest in having future biological children on either the baseline or year 1 survey between February 2015 and October 2020. Descriptive statistics were used to summarize the degree of fertility concern in this population, the impact of that concern on cancer treatment decisions, and steps taken to preserve fertility. Results: Between February 2015 and October 2020, 865 women under age 50 at diagnosis consented to the registry. Of these women, 627 completed a baseline and/or 1-year survey and 100 answered either “yes” or “unsure” to the question: “At the present time, do you wish to have any more biological children in the future?” on one or both surveys. Among the 100 women expressing interest in future child-bearing, 92% were white, 27% had node-positive and one had distant metastatic disease at diagnosis. The age at diagnosis ranged from 19 to 49 years, with a mean age of 33.8 years. Of the 75 who reported a desire for future children at baseline, 28% felt “somewhat concerned” about their future fertility and 40% felt “very concerned.” Of the 70 who reported a desire for future children on the year 1 survey, 17% felt “somewhat concerned” and 59% felt “very concerned.” For those “very concerned” about future fertility at year 1, 65% reported that this concern had a major impact on their treatment decisions. Often, that treatment modification entailed using endocrine therapy for less than 5 years; 52% of those who specified the type of treatment modification they had made indicated this option. Of note, six women who reported no desire for future biological children at baseline were “unsure” at year 1. At year 1, 93% of women recalled a discussion about fertility with their doctor prior to starting treatment, and 49% had taken steps to preserve fertility (32.5% with embryo cryopreservation, 20% with oocyte cryopreservation and 65% with a GnRH agonist; some selected multiple options). Conclusion: We found a reassuringly high rate of patient-reported fertility counseling and use of reproductive endocrinology technologies to preserve fertility in women who reported a desire for additional children at or soon after diagnosis with breast cancer. Consistent with prior studies, fertility concerns frequently impacted breast cancer treatment decisions. It is important to err on the side of inclusivity when providing fertility counseling because desire for fertility can change over time. Citation Format: Samantha Mannion, Alexandra Higgins, Elizabeth A Stewart, Zaraq Khan, Chandra Shenoy, Nicole Larson, Hazel B Nichols, H Irene Su, Ann H Partridge, Fergus J Couch, Janet E Olson, Kathryn Ruddy. Prevalence and impact of fertility concerns in young women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-02.

Funding Source: Institutional funds at Mayo Clinic. Background: While alopecia is a common and distressing acute side effect of chemotherapy, chronic hair thinning is also reported by some survivors during endocrine therapy. The purpose of the current study was to evaluate real world experiences of late/long-term alopecia among breast cancer survivors. Methods: Breast cancer survivors participating in the ongoing prospective Mayo Clinic Breast Disease Registry (MCBDR) were mailed a survey six years after diagnosis, between June and November 2020. Respondents were asked to report how bothered they are by hair thinning and hair loss over the last year on a scale from 0 “not at all” to 4 “extremely”. They were also asked whether they used any hair thickening or regrowth products. Results: 552/899 survivors responded (response rate 61%); 403 survivors’ responses were available for analysis. Respondents’ median age was 66 years, and median time since diagnosis was 78 months. Seventy patients (17%) were diagnosed with stage 0 breast cancer, 195 (48%) were diagnosed with stage 1 cancer, 104 (26%) with stage 2, 25 (6%) with stage 3; 6 (1%) had been diagnosed with metastatic or recurrent disease at the time of this survey. 139 (34%) patients had received chemotherapy. Of the patients who received chemotherapy, 82 (59%) had received doxorubicin and cyclophosphamide, 41 (29%) received docetaxel and cyclophosphamide, 77 (55%) received paclitaxel, and 27 (19%) received carboplatin. 258 (64%) received endocrine therapy. Of these patients who received endocrine therapy, 131 (51%) received Tamoxifen and 186 (72%) received aromatase inhibitors. 309 survivors (77%) were 55 years or older. 189 (47%) of all patients reported that they were bothered by chronic hair loss, and 225 (56%) reported that they were bothered by hair thinning; 71 (18%) reported use of thickening/regrowth products. There did not appear to be differences in chronic hair loss or thinning by receipt of chemotherapy: 64 patients (46%) who received chemotherapy reported hair loss and 79 (56%) reported hair thinning, compared with 123 patients (46%) who did not receive chemotherapy and reported hair loss and 142 (54%) who reported hair thinning. Hair thinning or loss did not appear to differ based upon age (Table 1). Symptoms did not appear to be more common amongst current or previous endocrine therapy recipients, with 113 (44%) of that subset bothered by hair loss and 128 (50%) by hair thinning. Conclusion: Hair loss and thinning are frequently reported as bothersome symptoms by long-term breast cancer survivors. Future investigations into treatments for chronic hair thinning during and after cancer therapy are needed. Table 1.< 5555+Bothered by hair loss (n)%Bothered by hair thinning (n)%Bothered by hair loss (n)%Bothered by hair thinning (n)%Not at all5761%4649%15751%13142%Slightly1920%2426%8728%9731%Moderately77%910%3110%4113%BOTHERED BY HAIR LOSS (N)%BOTHERED BY HAIR THINNING (N)%BOTHERED BY HAIR LOSS (N)%BOTHERED BY HAIR THINNING (N)%Quite a bit77%1112%227%268%Extremely44%33%93%103%Missing00%11%31%41% Citation Format: Elizabeth Cathcart-Rake, Charles L Loprinzi, Janet E Olson, Fergus Couch, Brittany Dulmage, Maryam Lustberg, Nicole Larson, Kathryn J Ruddy. Alopecia among breast cancer survivors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-17.

PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

Medical financial hardship, encompassing material, behavioral, and psychologic domains, has been shown to impair quality of life during and after cancer therapy. We sought to evaluate the change in financial concerns in breast cancer survivors over time and identify those at risk of worsening financial concerns.In Mayo Clinic Breast Disease Registry (MCBDR), a prospective cohort of consenting patients seen at Mayo Clinic Rochester within 1 year of their initial breast cancer diagnosis, consenting participants were asked to complete baseline and annual follow-up surveys that included an item on which respondents were asked to report their financial concerns on a linear analogue scale from 0 ("none") to 10 ("constant concerns"). We compared patient-reported financial concern at baseline to that on each patient's most recent survey, with worsening concerns defined as a 1+-point increase. Logistic regression analysis evaluated for possible predictors of worsening financial concerns.One-thousand nine-hundred fifty-seven participants responded to financial concern questions on the baseline and at least one follow-up survey between 2015 and 2020. Three-hundred fifty-seven (18.2%) reported worsening financial concerns. Only baseline financial situation of "enough to pay the bills, but little spare money to buy extra or special things," was associated with a greater likelihood of worsening financial concerns.More than one in seven breast cancer survivors develop worsening financial concerns within 5 years of diagnosis, and those with less financial security at baseline appear to be most vulnerable.Financial concerns may worsen over time for breast cancer survivors, and therefore, oncology providers must continue to assess the financial well-being of survivors over time.

PURPOSE The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years. METHODS A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs. RESULTS The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1, BRCA2, and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)–negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2, PALB2, BRCA2, and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1, BRCA2, and PALB2. CONCLUSION This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening.

Irritable bowel syndrome (IBS) is a pain disorder classified by bowel habits, disregarding other factors that may influence the clinical course. The aim of this study was to determine if IBS patients can be clustered based on clinical, dietary, lifestyle, and psychosocial factors.Between 2013 and 2020, the Mayo Clinic Biobank surveyed and received 40,291 responses to a questionnaire incorporating Rome III criteria. Factors associated with IBS were determined and latent class analysis, a model-based clustering, was performed on IBS cases.We identified 4021 IBS patients (mean 64 years; 75% women) and 12,063 controls. Using 26 variables separating cases from controls, the optimal clustering revealed 7 latent clusters. These were characterized by perceived health impairment (moderate or severe), psychoneurological factors, and bowel dysfunction (diarrhea or constipation predominance). Health impairment clusters demonstrated more pain, with the severe cluster also having more psychiatric comorbidities. The next 3 clusters had unique enrichment of psychiatric, neurological, or both comorbidities. The bowel dysfunction clusters demonstrated less abdominal pain, with diarrhea cluster most likely to report pain improvement with defecation. The constipation cluster had the highest exercise score and consumption of fruits, vegetables, and alcohol. The distribution of clusters remained similar when Rome IV criteria were applied. Physiologic tests were available on a limited subset (6%), and there were no significant differences between clusters.In this cohort of older IBS patients, 7 distinct clusters were identified demonstrating varying degrees of gastrointestinal symptoms, comorbidities, dietary, and lifestyle factors. Further research is required to assess whether these unique clusters could be used to direct clinical trials and individualize patient management.

PURPOSE This study assessed the joint association of pathogenic variants (PVs) in breast cancer (BC) predisposition genes and polygenic risk scores (PRS) with BC in the general population. METHODS A total of 26,798 non-Hispanic white BC cases and 26,127 controls from predominately population-based studies in the Cancer Risk Estimates Related to Susceptibility consortium were evaluated for PVs in BRCA1, BRCA2, ATM, CHEK2, PALB2, BARD1, BRIP1, CDH1, and NF1. PRS based on 105 common variants were created using effect estimates from BC genome-wide association studies; the performance of an overall BC PRS and estrogen receptor–specific PRS were evaluated. The odds of BC based on the PVs and PRS were estimated using penalized logistic regression. The results were combined with age-specific incidence rates to estimate 5-year and lifetime absolute risks of BC across percentiles of PRS by PV status and first-degree family history of BC. RESULTS The estimated lifetime risks of BC among general-population noncarriers, based on 10th and 90th percentiles of PRS, were 9.1%-23.9% and 6.7%-18.2% for women with or without first-degree relatives with BC, respectively. Taking PRS into account, more than 95% of BRCA1, BRCA2, and PALB2 carriers had > 20% lifetime risks of BC, whereas, respectively, 52.5% and 69.7% of ATM and CHEK2 carriers without first-degree relatives with BC, and 78.8% and 89.9% of those with a first-degree relative with BC had > 20% risk. CONCLUSION PRS facilitates personalization of BC risk among carriers of PVs in predisposition genes. Incorporating PRS into BC risk estimation may help identify > 30% of CHEK2 and nearly half of ATM carriers below the 20% lifetime risk threshold, suggesting the addition of PRS may prevent overscreening and enable more personalized risk management approaches.

Context Metformin is the first-line drug for treating diabetes but has a high failure rate. Objective To identify demographic and clinical factors available in the electronic health record (EHR) that predict metformin failure. Methods A cohort of patients with at least one abnormal diabetes screening test that initiated metformin was identified at three sites (Arizona, Mississippi, and Minnesota). We identified 22,047 metformin initiators (48% female, mean age of 57 ± 14 years) including 2141 African Americans, 440 Asians, 962 Other/Multi-racials, 1539 Hispanics, and 16,764 Non-Hispanic whites. We defined metformin failure as either the lack of a target hemoglobin A1c ( Results In this large diverse population, we observed a high rate of metformin failure (33%). The XGBoost model that included baseline hemoglobin A1c, age, sex, and race/ethnicity corresponded to high discrimination performance (C-index of 0.731; 95% CI 0.722, 0.740) for risk of metformin failure. Baseline hemoglobin A1c corresponded to the largest feature performance with higher levels associated with metformin failure. The addition of other clinical factors improved model performance (0.745; 95% CI 0.737, 0.754, p Conclusions Baseline hemoglobin A1c was the strongest predictor of metformin failure and additional factors substantially improved performance suggesting that routinely available clinical data could be used to identify patients at high risk of metformin failure who might benefit from closer monitoring and earlier treatment intensification.

The aim of this cross-sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical-linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z-scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A total of 2235 women had no prior history of any cancer, and 76 (3%) of these had a history of raloxifene use. No significant associations between tamoxifen use and cognition, or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders. Similarly, raloxifene use was not significantly associated with cognition, or odds of MCI in women without a history of cancer after adjusting for confounders. We did not find significant associations between the use of either SERM and MRI markers. Use of tamoxifen or raloxifene was not significantly associated with cognition in postmenopausal women.