Citations

Abstract Physical activity (PA) is associated with improvement in breast cancer treatment-related symptoms and survival, yet most breast cancer survivors do not meet national PA guidelines. This study aimed to identify characteristics of participants that were associated with an increased likelihood of meeting PA guidelines. Adults with breast cancer seen at Mayo Clinic (Rochester, MN) were surveyed regarding their PA participation, and those who self-reported at least 150 minutes of moderate and/or strenuous aerobic PA weekly on average were considered to be “meeting guidelines”. Three thousand participants returned PA data. Younger age, completion of the survey 7-12 years after diagnosis, absence of recurrence, no bilateral mastectomy, absence of metastatic disease, and lower BMI at the time of survey completion were associated with PA participation (P < .05 in univariate and multivariate analyses). Findings were similar when a threshold of 90 minutes was applied. These results may inform the development of targeted PA-facilitating interventions.

Abstract Women who have had breast cancer in the past are at increased risk of developing a second primary cancer (SPC), including second primary breast cancer (SPBC) or a second primary non-breast cancer (SPNBC). In the Multiethnic Cohort (MEC) Study, we conducted a prospective cohort analysis in 3,223 female breast cancer survivors from five racial/ethnic populations (White, African American, Japanese American, Latino, and Native Hawaiian) to assess the association of rare pathogenic variants (PV) in 37 known cancer predisposition genes with risk of SPC. A total of 719 (22.3%) women developed SPC, of which, 323 (10.0%) were SPBC. Germline PVs in BRCA1 (HR, 2.28; 95% CI, 1.11–4.65) and ERCC2 (HR, 3.51; 95% CI, 1.29–9.54) were significantly enriched in women with SPC. In the subtype analysis for SPBC, a significant association of ERCC2 PVs (HR, 5.09; 95% CI, 1.58–16.4) and a suggestive association of BRCA2 PVs (HR, 2.24; 95% CI, 0.91–5.55) were observed. There was also a higher risk of SPNBC in carriers of BRCA1 PVs (HR, 2.98; 95% CI, 1.21–7.36). These results provide evidence that germline PVs in BRCA1, BRCA2, and ERCC2 contribute to the development of SPC in breast cancer survivors. These findings also suggest that compromised DNA repair mechanisms could be a predisposition factor for SPC in patients with breast cancer, supporting the need for closer monitoring of SPC in women carrying PVs in these genes. Significance: This multiethnic study links germline pathogenic variants in BRCA1, BRCA2, and ERCC2 to the development of second primary cancer in breast cancer survivors, providing biological insights and biomarkers to guide patient monitoring.

Abstract Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory. Experimental Design: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. Results: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. Conclusions: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with low overall survival rates and high molecular heterogeneity; therefore, few targeted therapies are available. The luminal androgen receptor (LAR) is the most consistently identified TNBC subtype, but the clinical utility has yet to be established. Here, we constructed a novel genomic classifier, LAR-Sig, that distinguishes the LAR subtype from other TNBC subtypes and provide evidence that it is a clinically distinct disease. A meta-analysis of seven TNBC datasets (n = 1086 samples) from neoadjuvant clinical trials demonstrated that LAR patients have significantly reduced response (pCR) rates than non-LAR TNBC patients (odds ratio = 2.11, 95% CI: 1.33, 2.89). Moreover, deconvolution of the tumor microenvironment confirmed an enrichment of luminal epithelium corresponding with a decrease in basal and myoepithelium in LAR TNBC tumors. Increased immunosuppression in LAR patients may lead to a decreased presence of cycling T-cells and plasma cells. While, an increased presence of myofibroblast-like cancer-associated cells may impede drug delivery and treatment. In summary, the lower levels of tumor infiltrating lymphocytes (TILs), reduced immune activity in the micro-environment, and lower pCR rates after NAC, suggest that new therapeutic strategies for the LAR TNBC subtype need to be developed.

Abstract Biallelic mutations in Fanconi anemia complementation group genes disrupt DNA repair and result in the complex Fanconi anemia phenotype. In addition, germ line mutations in the BRCA2/FANCD1 Fanconi anemia complementation group gene have also been implicated in predisposition to a number of cancers including pancreatic cancer. The recent identification of FANCC and FANCG mutations in resected pancreatic tumors selected for loss of heterozygosity on chromosome 9, some of which were present in the germ line DNA, suggests that inactivation of these and other Fanconi complementation group genes may contribute to pancreatic cancer. To further assess the relevance of FANCC and FANCG mutations to pancreatic cancer we conducted a mutation screen of these genes in DNA from blood of 421 sequentially collected pancreatic cancer cases diagnosed at the Mayo Clinic. Two truncating FANCC mutations but no truncating FANCG mutations were identified in young onset (<55 years) pancreatic cancer cases with no family history of pancreatic cancer. Both mutations were associated with loss of heterozygosity of the wild-type allele in corresponding pancreatic tumors. In addition, no truncating mutations were identified in germ line DNA from blood of 658 control individuals undergoing routine colonoscopy. Taken together these data support the assertion that inherited mutations in FANCC can predispose to pancreatic cancer.

Abstract The influence of germ line BRCA2 unclassified variants (UCV), including missense mutations and in-frame deletions and insertions on BRCA2 function and on cancer risk, has not been defined although these mutations account for 43% of all identified BRCA2 sequence alterations. To investigate the effects of UCVs on BRCA2 function, we compared mutant and wild-type forms of BRCA2 using assays of cellular survival and viability, homologous recombination repair, and genome instability. We confirm that the effects of known deleterious mutations can be distinguished from neutral polymorphisms and wild-type BRCA2 in these assays, and we characterize the influence of a series of UCVs on BRCA2 function. We also describe how the results from the assays can be combined with data from analysis of cosegregation of the UCVs with cancer, co-occurrence of the UCVs with other deleterious mutations, and interspecies sequence variation in a comprehensive framework in an effort to better distinguish between disease predisposing and neutral UCVs. This combined approach represents a useful means of addressing the functional significance and cancer relevance of UCVs in BRCA2.

Abstract Introduction: Patients at extremes of age may be particularly vulnerable to poor physical and mental health after treatment for breast cancer; we examined factors associated with poor health in older breast cancer survivors. Methods: The Mayo Clinic Breast Disease Registry (MCBDR) is a prospective longitudinal cohort study that enrolls Mayo Clinic Rochester patients diagnosed with stage 0-4 breast cancer (BC). In 2020, we mailed a survey to 1,273 MCBDR participants aged 77+. Three PROMIS-10 items were used to assess overall health, mental health, and physical function. Self-reported comorbidities were also collected. Multivariate logistic regression analysis was used to identify significant (p<0.05) predictors of overall health, mental health, and physical function. Independent variables included demographics, clinical characteristics, and comorbidities. Results: 848/1273 MCBDR participants (67%) responded, 842 reporting their overall health. Median age at survey return was 82 years (range 77-100), and the median time since cancer diagnosis was 12 years. Excellent or very good overall health, mental health, and physical function were reported by 48%, 63.5%, and 77.1%, respectively. Older age was associated with poorer self-reported overall health, as were heart disease, diabetes, and lung disease, reported by 18%, 14%, and 7%, respectively (p<0.05 for all; see Table). Only heart disease was statistically significantly associated with poorer mental health (p=0.03). Physical function was reportedly better in survivors without a history of diabetes, stroke, or lung disease (p<0.05 for all), and in those who were closer to their cancer diagnosis (p=0.03). Tumor characteristics were not associated with overall health, mental health, or physical function. Conclusions: Comorbidities are common and impact self-reported overall health, mental health, and physical function in older breast cancer survivors. Table: Multivariate logistic regression model for overall health Overall health self-reported as excellent or very good No Yes Total p-value (N=437) (N=405) (N=842) Age at survey (years) <.001 Mean (SD) 82.8 (4.22) 81.7 (3.85) 82.3 (4.08) Median (range) 82.0 (77.0, 96.0) 81.0 (77.0, 100.0) 82.0 (77.0, 100.0) Years from cancer diagnosis to survey 0.708 Mean (SD) 12.1 (5.16) 11.8 (5.47) 11.9 (5.31) Median (range) 12.2 (3.1, 36.9) 11.5 (3.1, 36.4) 12.0 (3.1, 36.9) T stage T2 or higher, n (%) 0.276 No 357 (81.7%) 337 (83.2%) 694 (82.4%) Yes 80 (18.3%) 68 (16.8%) 148 (17.6%) N stage N1 or higher, n (%) 0.185 No 376 (86.0%) 339 (83.7%) 715 (84.9%) Yes 61 (14.0%) 66 (16.3%) 127 (15.1%) M stage M1, n (%) 0.313 No 434 (99.3%) 404 (99.8%) 838 (99.5%) Yes 3 (0.7%) 1 (0.2%) 4 (0.5%) Race, n (%) 0.460 Non-White 13 (3.0%) 8 (2.0%) 21 (2.5%) White 424 (97.0%) 397 (98.0%) 821 (97.5%) Heart disease, n (%) <.001 No 334 (76.4%) 353 (87.2%) 687 (81.6%) Yes 103 (23.6%) 52 (12.8%) 155 (18.4%) High blood pressure, n (%) 0.376 No 168 (38.4%) 188 (46.4%) 356 (42.3%) Yes 269 (61.6%) 217 (53.6%) 486 (57.7%) Stroke, n (%) 0.195 No 407 (93.1%) 392 (96.8%) 799 (94.9%) Yes 30 (6.9%) 13 (3.2%) 43 (5.1%) Diabetes, n (%) <.001 No 355 (81.2%) 370 (91.4%) 725 (86.1%) Yes 82 (18.8%) 35 (8.6%) 117 (13.9%) Lung disease, n (%) 0.023 No 394 (90.2%) 386 (95.3%) 780 (92.6%) Yes 43 (9.8%) 19 (4.7%) 62 (7.4%) Liver disease, n (%) 0.345 No 425 (97.3%) 401 (99.0%) 826 (98.1%) Yes 12 (2.7%) 4 (1.0%) 16 (1.9%) Kidney disease, n (%) 0.240 No 408 (93.4%) 392 (96.8%) 800 (95.0%) Yes 29 (6.6%) 13 (3.2%) 42 (5.0%) Citation Format: Dhauna Karam, Robert A. Vierkant, Shawna Ehlers, Rachel A. Freedman, Nicole Larson, Charles L. Loprinzi, Fergus Couch, Janet Olson, Kathryn J. Ruddy. Physical function, mental health, and overall health of older breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5262.

Abstract BACKGROUND: The American Cancer Society recommends at least 150 minutes of moderate and/or strenuous exercise and muscle-strengthening activities each week for adults. Exercise has been associated with decreased breast cancer mortality and adverse symptoms. This study’s purpose is to understand prevalence and predictors of inadequate aerobic exercise in patients recently diagnosed with breast cancer to inform interventions to increase exercise participation. METHODS: Patients seen at least once at Mayo Clinic Rochester were prospectively enrolled within one year of an initial breast cancer diagnosis in the Mayo Clinic Breast Disease Registry after providing informed consent. This analysis includes those who completed a baseline survey with self-reported exercise data using the Godin Leisure-Time Exercise Questionnaire. This longitudinal cohort study was approved by the Mayo Clinic institutional review board. RESULTS: 1,738 participants reported their usual weekly quantity of moderate and strenuous exercise an average of 95 days (SD 71 days, range 0-365) after diagnosis. Table 1 displays participant characteristics overall and by whether participants reported at least 150 minutes of moderate and/or strenuous activity weekly (“met guidelines”) or not (“did not meet guidelines”). Overall, 39% of participants met guidelines, including 56% of those aged 18-39 years, 40% of those aged 40-69 years, and 27% of those aged 70+ years. CONCLUSION: Older age was associated with less likelihood of meeting exercise guidelines (all age groups vs 70+, p < 0.05). A more diverse cohort will be needed to evaluate differences by gender and race/ethnicity. There did not appear to be any obvious impact on exercise level by time since diagnosis (during the first year after diagnosis) or educational status, though substantial missing data limit conclusions related to the latter. Additional research is needed to assess exercise levels later in survivorship and the impact of various treatment modalities on exercise habits Table 1. Patient and tumor characteristics Citation Format: Paulina S. Marell, Janet E. Olson, Joerg Herrmann, Nicole L. Larson, Nathan K. LeBrasseur, Stacy D. D'Andre, Andrea L. Cheville, Toure Barksdale, Charles L. Loprinzi, Fergus J. Couch, Kathryn J. Ruddy. Factors associated with exercise participation in patients with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5868.

Abstract Background: Medical financial hardship, encompassing material, behavioral, and psychologic domains, is becoming an increasingly common consequence of illness in cancer patients. Identifying at-risk patients is the first step to develop proactive approaches to mitigate this problem. To try and address this need, Mayo Clinic Breast Disease Registry (MCBDR) is prospectively collecting data about financial concerns in addition to the usual sociodemographic and clinical information. Methods: We used data from Mayo Clinic Breast Disease Registry, a prospective cohort of consenting patients seen at Mayo Clinic Rochester within one year of initial breast cancer diagnosis. Participants completed baseline and annual follow-up surveys rating 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 evaluated for predictors of worsening financial concerns. Results: 1,957 participants responded to financial concern questions on a baseline and at least one follow-up survey between 2015 and 2020. Mean age was 58.5 years (SD 12.5), and mean time between diagnosis and the most recent follow-up was 25.6 months (SD 16.2). 357 (18.2%) reported worsening financial concerns. Only lower baseline financial status was associated with a greater likelihood of worsening financial concerns (see Table). Conclusions: 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. Funding: Breast Cancer Research Foundation (CLL) and NR015259 (KJR). Patient and tumor characteristics, compared by whether financial status worsened over time Full Cohort (n=1957) Worsening, ≥ 1-point change (n=357) Stable/Improved (n=1600) p value Full Cohort (n=1957) Worsening, ≥ 1-point change (n=357) Stable/Improved (n=1600) p value Age at diagnosis II or III 502 (25.7%) 98 (27.5%) 404 (25.3%) 0.239 ≤ 50 546 (27.9%) 105 (29.4%) 441 (27.6%) IV 67 (3.4%) 17 (4.8%) 50 (3.1%) 0.086 51-64 757 (38.7%) 136 (38.1%) 621 (38.8%) 0.562 Unknown 351 (17.9%) 65 (18.2%) 286 (17.9%) 0.536 ≥65 654 (33.4%) 116 (32.5%) 538 (33.6%) 0.506 ER and/or PR positive Race No/Unknown 482 (24.6%) 92 (25.8%) 390 (24.4%) White 1863 (95.2%) 337 (94.4%) 1526 (95.4%) Yes 1475 (75.4%) 265 (74.2%) 1210 (75.6%) 0.580 Non-white 24 (1.2%) 5 (1.4%) 19 (1.2%) 0.729 Her2 positive Other/Unknown/Choose not to respond 70 (3.6%) 15 (4.2%) 55 (3.4%) 0.478 No/Unknown 1746 (89.2%) 314 (88.0%) 1432 (89.5%) Educational status Yes 176 (9.0%) 37 (10.4%) 139 (8.7%) 0.321 Less than bachelor’s degree 880 (45.0%) 168 (47.1%) 712 (44.5%) Borderline 35 (1.8%) 6 (1.7%) 29 (1.8%) 0.898 Bachelor's degree or higher 1065 (54.4%) 187 (52.4%) 878 (54.9%) 0.384 Radiation Unknown 12 (0.6%) 2 (0.6%) 10 (0.6%) 0.832 No/Unknown 781 (39.9%) 140 (39.2%) 641 (40.1%) Financial status near time of diagnosis Yes 1176 (60.1%) 217 (60.8%) 959 (59.9%) 0.768 Pay bills, money for special things 1412 (72.2%) 244 (68.3%) 1168 (73.0%) Chemotherapy/targeted therapy Pay bills, no money for special things 367 (18.8%) 80 (22.4%) 287 (17.9%) 0.046 No/Unknown 1264 (64.6%) 221 (61.9%) 1043 (65.2%) Pay bills by making cuts 102 (5.2%) 19 (5.3%) 83 (5.2%) 0.729 Yes 693 (35.4%) 136 (38.1%) 557 (34.8%) 0.241 Unable to pay bills 56 (2.9%) 10 (2.8%) 46 (2.9%) 0.911 Hormone/endocrine therapy Unknown 20 (1.0%) 4 (1.1%) 16 (1.0%) 0.750 No/Unknown 710 (36.3%) 141 (39.5%) 569 (35.6%) Employment status at time of diagnosis Yes 1247 (63.7%) 216 (60.5%) 1031 (64.4%) 0.163 Employed full-time 462 (23.6%) 83 (23.2%) 379 (23.7%) Surgery type Employed part-time/unemployed/retired 525 (26.8%) 92 (25.8%) 433 (27.1%) 0.856 Lumpectomy 846 (43.2%) 145 (40.6%) 701 (43.8%) Not available 970 (49.6%) 182 (51.0%) 788 (49.3%) 0.716 Mastectomy 903 (46.1%) 165 (46.2%) 738 (46.1%) 0.535 Stage at time of diagnosis None/Unknown 208 (10.6%) 47 (13.2%) 161 (10.1%) 0.069 0 or I 1037 (53.0%) 177 (49.6%) 860 (53.8%) Citation Format: Michael H. Storandt, Urshila Durani, Daniela Stan, Nicole Larson, Charles Loprinzi, Fergus Couch, Janet E. Olson, Nandita Khera, Kathryn J. Ruddy. Financial hardship in breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1012.