Vachon, Celine M.

Abstract Background: Women with benign breast disease (BBD) are at increased risk of breast cancer (BC). Classic studies based on film-based mammographic screening and pathology diagnosis of surgical biopsies conducted in the 1980s established a hierarchy of increasing BC risk: non-proliferative (NP) BBD, proliferative BBD without atypia (PDWA) and atypical hyperplasia (AH). Given changes in epidemiological BC risk factors and introduction of percutaneous core needle biopsy (CNB) in mid-1990s, and later, digital mammography, we hypothesized that the patient characteristics and relative frequency of BBD diagnoses have changed over time. Accordingly, we performed a longitudinal analysis of the frequency of patient characteristics and BBD diagnoses in the Mayo BBD cohort. Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had a BBD biopsy between 1/1/67 and 12/31/13 were identified. Breast pathologists reviewed biopsies masked to diagnoses of incident BC diagnosed in follow-up. Demographic characteristics and BC events were obtained by query of institutional data sources and participant surveys. Trends were evaluated for the following eras: 1: pre-mammogram (1967-1981), 2: pre-CNB (1982-1992), 3: CNB Transition (1993-2001), and 4: CNB (2002-2013). Demographics were formally compared across eras using chi-square tests for categorical variables and analyses of variance (ANOVAs) for continuous variables. Results: From 1967-2013, the cohort includes 19,582 unique women with BBD. The frequency of CNB increased from eras 1-4: 0.04%, 0.6%, 51.3 %, and 88.9%, respectively. Mean age at BBD diagnosis was younger in era 1 (48.0 years) vs eras 2-4 (53.2, 52.0, and 51.8, respectively, p<0.001). The percentage of biopsies diagnosed as PDWA increased from era 1-4 (25.7%, 34.3%, 35.2%, 46.2%, p<0.001), as did the percentage with AH (2.4%, 5.1%, 8.6%, 12.3%, p<0.001). Over eras 1-4, the percentages of women with a strong family history of BC increased (9.9%, 12.7%, 17.1%, and 29.0%, p<0.001) as did mean BMI (24.8, 26.4, 27.4, and 28.6, p<0.001). With a median follow-up of 10.9 years, 1,719 breast cancers have developed, with increasing proportion of noninvasive (DCIS-only) disease across eras 1-4: 15.0%, 21.1%, 21.2%, and 33.2%, p< 0.001. Conclusions: Analysis of this large, single institution BBD cohort for the 46 year period 1967-2013 demonstrates that BC risk factors among BBD patients has changed over time, with subjects demonstrating increasing age, BMI, and family history, and that the percentages of BBD classified as PDWA and AH have increased. Impact on BC risk will be further investigated. Citation Format: Amy Degnim, Karthik Ghosh, Jodi M Carter, Robert A Vierkant, Matthew R Jensen, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Teresa M Allers, Denise L Gehling, Mindy J Kern, Laura M Pacheco-Spann, Celine M Vachon, Derek C Radisky, Daniel W Visscher, Mark E Sherman. Benign breast disease: Temporal trends from 1967 to 2013 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-11.

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10−23; financial concerns: p = 4.8 × 10−40) and mental health (age: p = 3.5 × 10−7; financial concerns: p = 2.0 × 10−69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10−8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10−8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p < 10−6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.

Background MBL is a precursor to chronic lymphocytic leukemia (CLL) and is subclassified into low-count (LC) MBL (absolute B-cell count&lt;0.5x109/L) and high-count (HC) MBL (absolute B-cell count between 0.5 and 5x109/L). We previously reported that a polygenic risk score (PRS) based on a weighted average of 41 CLL-susceptibility variants was associated with risk of both MBL and CLL among a cohort of individuals from CLL families. Here we evaluate this PRS in an independent cohort of MBL and CLL individuals of European ancestry (EA), all of whom were ascertained agnostic to CLL family-history status. We also evaluate the PRS by MBL subtype (LC/HC), and in African American (AA) CLL cases and controls. Methods We genotyped 535 EA MBLs (139 HC-MBL, 396 LC-MBLs), 735 CLLs (640 EA, 95 AA), and 2,866 controls (2,631 EA, 235 AA) from the Mayo Clinic CLL Resource, Duke University, and Weill Cornell Medical College. We computed the CLL-PRS for each individual and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals, adjusting for age and sex. To assess discriminatory accuracy, we computed the c-statistic. Among EA individuals, we calculated a trend test among LC-MBL, HC-MBL, and CLL risk using the P-value for heterogeneity from a polytomous logistic regression analysis. Moreover, we plotted a boxplot for the PRS among controls, LC-MBL, HC-MBL, and EA CLL, as well as for AA CLL cases and controls, and tested the statistical difference using the Kruskal Wallis test and Mann-Whitney test, respectively. Results We found a significant association of PRS with overall MBL risk (OR=1.87, P=1.1x10-28) with good discrimination (c-statistic=0.72). Significant associations were also found for LC-MBL (OR=1.75, P=7.5x10-19, c-statistic=0.72), HC-MBL (OR=2.22, P=1.4x10-17, c-statistic=0.74), and CLL of EA (OR=2.60, P=1.2x10-62, c-statistic=0.78), with a significant difference among these cohorts (Figure 1.A) and a significant positive trend across these cohorts (Pheterogeneity=8.4x10-6). Although we observed a 33% increased risk of CLL in AA (c-statistic=0.57), the PRS was borderline significant (P=0.07, Figure 1.B). Conclusion The CLL-PRS is a strong prediction-tool for risk of CLL and MBL among individuals of EA. Future studies are needed to improve the PRS for AAs including performing GWAS of AA in order to identify CLL-susceptibility SNPs that are more representative within known CLL loci and to discover novel CLL loci that are unique for AAs. Disclosures Parikh: GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Genentech: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding; Verastem Oncology: Honoraria. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Brander:Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; NCCN: Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Other; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding. Cerhan:NanoString: Research Funding; BMS/Celgene: Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees. Furman:Acerta: Consultancy; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Speakers Bureau; Loxo Oncology: Consultancy; Oncotarget: Consultancy. Shanafelt:Mayo Clinic: Patents & Royalties: and other intellectual property; Genentech, Pharmacyclics LLC, an AbbVie Company, AbbVie, GlaxoSmithKline, and Merck: Research Funding.

Abstract Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj &gt; 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus &lt;20 years at first pregnancy [0.79 (0.72–0.86)]; &gt;0–&lt;5 years versus ≥10 years since last full-term birth [1.31 (1.11–1.55)]; ever versus never use of oral contraceptives [0.91 (0.87–0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen–progestin therapy [0.61 (0.54–0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02–1.21) for current versus never smoking. Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Abstract High alcohol intake and breast density increase breast cancer (BC) risk, but their interrelationship is unknown. We examined whether volumetric density modifies and/or mediates the alcohol-BC association. BC cases (n = 2233) diagnosed from 2006 to 2013 in the San Francisco Bay area had screening mammograms 6 or more months before diagnosis; controls (n = 4562) were matched on age, mammogram date, race or ethnicity, facility, and mammography machine. Logistic regression was used to estimate alcohol-BC associations adjusted for age, body mass index, and menopause; interaction terms assessed modification. Percent mediation was quantified as the ratio of log (odds ratios [ORs]) from models with and without density measures. Alcohol consumption was associated with increased BC risk (2-sided Ptrend = .004), as were volumetric percent density (OR = 1.45 per SD, 95% confidence interval [CI] = 1.36 to 1.56) and dense volume (OR = 1.30, 95% CI = 1.24 to 1.37). Breast density did not modify the alcohol-BC association (2-sided P &gt; .10 for all). Dense volume mediated 25.0% (95% CI = 5.5% to 44.4%) of the alcohol-BC association (2-sided P = .01), suggesting alcohol may partially increase BC risk by increasing fibroglandular tissue.

Abstract Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Abstract Background: Clinical use of breast cancer risk prediction requires simplified models. We evaluate a simplified version of the validated Rosner–Colditz model and add percent mammographic density (MD) and polygenic risk score (PRS), to assess performance from ages 45–74. We validate using the Mayo Mammography Health Study (MMHS). Methods: We derived the model in the Nurses' Health Study (NHS) based on: MD, 77 SNP PRS and a questionnaire score (QS; lifestyle and reproductive factors). A total of 2,799 invasive breast cancer cases were diagnosed from 1990–2000. MD (using Cumulus software) and PRS were assessed in a nested case–control study. We assess model performance using this case–control dataset and evaluate 10-year absolute breast cancer risk. The prospective MMHS validation dataset includes 21.8% of women age &lt;50, and 434 incident cases identified over 10 years of follow-up. Results: In the NHS, MD has the highest odds ratio (OR) for 10-year risk prediction: ORper SD = 1.48 [95% confidence interval (CI): 1.31–1.68], followed by PRS, ORper SD = 1.37 (95% CI: 1.21–1.55) and QS, ORper SD = 1.25 (95% CI: 1.11–1.41). In MMHS, the AUC adjusted for age + MD + QS 0.650; for age + MD + QS + PRS 0.687, and the NRI was 6% in cases and 16% in controls. Conclusion: A simplified assessment of QS, MD, and PRS performs consistently to discriminate those at high 10-year breast cancer risk. Impact: This simplified model provides accurate estimation of 10-year risk of invasive breast cancer that can be used in a clinical setting to identify women who may benefit from chemopreventive intervention. See related commentary by Tehranifar et al., p. 587

Abstract Purpose: Among a Latina population in a low resource healthcare setting, to test the effectiveness of bilingual (Spanish/English) written and interpersonal educational interventions in increasing breast density (BD) awareness, knowledge, and conversations with healthcare providers, which are goals of BD notification mandates. Procedures: This randomized trial was conducted at a Federally Qualified Health Center (FQHC) in an urban community of the Southwest U.S. Women ages 40- 74 presenting for screening mammography were recruited and randomized 1:1:1 to usual care (mailed letter with mammogram and BD results), enhanced care (letter plus BD educational brochure), or interpersonal care (letter, brochure, and telephonic promotora education). The baseline survey was administered in person at enrollment prior to the mammogram. Follow-up surveys were by phone or mail after the mammography results letter was mailed and promotora delivery was complete (median days from baseline to follow-up survey = 97 days). Differences between groups at baseline or follow-up were assessed with chi-square tests. Logistic regression using generalized estimating equations to account for repeated data was used to assess differences by time (baseline to follow-up) within group, including a time-by-group interaction. Results: Between October 2016 and October 2019, 1377 women were enrolled. Of these, 1085 (79%) self-identified Latinas completed baseline and follow-up surveys. Median age was 47 years. Most (91%) reported speaking mostly Spanish, and 69.1% had less than a high school degree. At baseline, only 20.9% reported having heard of BD, and only 30.5% of those knew their personal BD category. At follow-up, women in the interpersonal group were more likely to report seeing their BD results in the notification letter compared to the usual care and enhanced groups (70.4% vs. 52.9% and 54.3%, p &lt; 0.001) and to report having spoken with a provider about their BD (27.3% vs. 14.2% and 15.7%, p &lt; 0.001). They also reported higher mean understanding of BD (7.7 on a 0-10 scale vs. 6.3 and 6.6, p &lt; 0.001). There were no significant differences on these outcomes between the usual care and enhanced groups. All groups saw significant improvement in correct responses from baseline to follow-up for questions on the ability of BD to mask tumors on a mammogram and BD as a breast cancer risk factor (p &lt; 0.001 all groups), but the degree of improvement in masking knowledge was significantly higher for the interpersonal vs usual care group [OR for a correct response in follow-up vs baseline: 6.4 (interpersonal) vs 3.7 (usual care), p=0.01]. Conclusion: Among a Latina population in a FQHC, telephonic promotora education was more effective than written notification alone or a mailed brochure on key goals of notification mandates. Adding a brochure does not appear to be more effective than sending a letter alone on key outcomes, but the interpersonal nature of promotora education may prompt attention to mailed information and provide an opportunity for questions. Citation Format: Jennifer L. Ridgeway, Sarah M. Jenkins, Deborah J. Rhodes, Bhavika K. Patel, Edna Ramos, Bijan Borah, Karthik Ghosh, Vera J. Suman, Aaron Norman, Davinder Singh, Celine M. Vachon. Evaluating educational interventions to increase breast density awareness among Latinas: A randomized clinical trial in a Federally Qualified Health Center [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-245.

Abstract Objective: Breast density notification laws aim to increase women’s awareness and knowledge about breast density (BD). This study’s aim was to compare BD knowledge and awareness in two Hispanic populations: a safety-net clinic serving Latina population in Maricopa County, Arizona (AZ) and a national sample of Hispanic women participating in an online research panel. Materials/Methods: Women ages 40-74 were recruited at the AZ clinic from 2016-2019 at a screening mammography appointment as part of a larger clinical trial (AZ cohort). Surveys were completed in person (English or Spanish) at enrollment to assess awareness of BD, understanding of BD risk, and mammography history. The same questions were asked in a nationally representative online panel survey conducted in 2017. All data from the national survey were weighted to adjust for probability of selection into the panel and post-stratified to match known U.S. Hispanic population distributions (NS cohort). Univariate comparisons between the clinic and the national panel were performed using Rao-Scott chi-square tests. Associations with awareness and correct knowledge were examined with multivariable logistic regression. All summaries and analyses are weighted, and were performed with SAS version 9.4 SURVEY procedures (SAS Institute Inc., Cary, NC). Results: The analysis included 1332 Hispanic women from the AZ clinic and 152 Hispanic women who completed the national survey. The AZ cohort was younger (mean age: 48.5 vs 52.8), had less education (less than high school: 68.7% vs 34.8% less than high school), more likely to prefer Spanish (92.3% vs 53.1%) and less likely to have had a prior mammogram as compared NS cohort (82.8% vs 90.4%) (all p≤ 0.03). NS cohort was more likely to have awareness of BD (32.6% vs 20.7%); correct understanding of the masking effect of BD, (67.8% vs 37.0%,) and breast cancer risk (72.2% vs 32.6%,), compared to the AZ cohort (all p &lt; 0.004). When adjusted for differences in education, age, language, and screening mammography history, BD awareness was similar between the two cohorts (adjusted odds ratio [ORadj] 0.95, p=0.83). Awareness was positively associated with more education, previous mammogram history, and English language. However, differences in BD knowledge remained (ORadj=2.8 [p=0.03] and 7.2 [P&lt;0.001] for knowledge of masking and risk, respectively). Conclusions: There were significant differences in BD awareness and knowledge between a nationally-representative sample of Latinas and Latinas in a low-resource setting. The differences in BD awareness, but not knowledge, could be explained by education, screening history and preferred language. These findings suggest that a one-size-fits-all approach to raising BD awareness and knowledge will not work. To ensure equitable dissemination of health care to Latina women undergoing screening mammography, future work should be aimed at developing effective tools and resources for educating Spanish-speaking women about BD and risk-based screening. Citation Format: Jillian Leaver, Bhavika K. Patel, Jennifer L. Ridgeway, Sarah Jenkins, Vera Suman, Deborah J. Rhodes, Aaron Norman, Karthik Ghosh, Bijan Borah, Carrie Hruska, Edna Ramos, Davinder Singh, Matt Jewett, Carmen Radecki-Breitkof, Celine Vachon. Breast density knowledge and awareness among Latinas in a low-resource setting: A comparison nationally-representative sample of Latinas [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-238.