Pruthi, Sandhya

Abstract Endocrine therapy is underutilized to reduce breast cancer incidence among women at increased risk. Polygenic risk scores (PRSs) assessing 77 breast cancer genetic susceptibility loci personalizes risk estimates. We examined effect of personalized PRS breast cancer risk prediction on intention to take and endocrine therapy uptake among women at increased risk. Eligible participants had a 10-year breast cancer risk ≥5% by Tyrer–Cuzick model [International Breast Cancer Intervention Study (IBIS)] or ≥3.0 % 5-year Gail Model risk with no breast cancer history or hereditary breast cancer syndrome. Breast cancer risk was estimated, endocrine therapy options were discussed, and endocrine therapy intent was assessed at baseline. After genotyping, PRS-updated breast cancer risk estimates, endocrine therapy options, and intent to take endocrine therapy were reassessed; endocrine therapy uptake was assessed during follow-up. From March 2016 to October 2017, 151 patients were enrolled [median (range) age, 56.1 (36.0–76.4 years)]. Median 10-year and lifetime IBIS risks were 7.9% and 25.3%. Inclusion of PRS increased lifetime IBIS breast cancer risk estimates for 81 patients (53.6%) and reduced risk for 70 (46.4%). Of participants with increased breast cancer risk by PRS, 39 (41.9%) had greater intent to take endocrine therapy; of those with decreased breast cancer risk by PRS, 28 (46.7%) had less intent to take endocrine therapy (P < 0.001). On multivariable regression, increased breast cancer risk by PRS was associated with greater intent to take endocrine therapy (P < 0.001). Endocrine therapy uptake was greater among participants with increased breast cancer risk by PRS (53.4%) than with decreased risk (20.9%; P < 0.001). PRS testing influenced intent to take and endocrine therapy uptake. Assessing PRS effect on endocrine therapy adherence is needed. Prevention Relevance: Counseling women at increased breast cancer risk using polygenic risk score (PRS) risk estimates can significantly impact preventive endocrine therapy uptake. Further development of PRS testing to personalize breast cancer risk assessments and endocrine therapy counselling may serve to potentially reduce the incidence of breast cancer in the future.

Abstract Background: Several studies have suggested that vitamin D may have antiproliferative and anticarcinogenic properties and a protective effect against breast cancer. Alaskan Natives have demonstrated high rates of vitamin D deficiency, particularly in young individuals. Hence, high breast density has been associated with increased breast cancer risk. Therefore, we examined the association between serum vitamin D levels and mammographic breast density in a population of Alaskan Native women. Methods: Patients seen in the Mayo Clinic-Alaska Native Medical Center telemedicine program from December 2014 to December 2017 were offered to enroll in the study. Consent was obtained by a study coordinator in Minnesota using a telemedicine platform. Participants were asked to complete the Breast Cancer Risk Questionnaire, which includes questions on hormonal, lifestyle factors and family history. Serum vitamin D levels (25-hydroxyvitamin D2 and D3) were obtained and later correlated with mammographic breast density (percent density). Data were summarized with frequencies and percentages or medians and interquartile ranges (IQR), as appropriate. Pearson correlation was used to estimate the association between breast density and vitamin D levels. Results: 33 women were included; median age was 53 years (IQR 45-58), 70% self-identified as American Indian/Alaskan Native, 12% as White, 6% as Native Hawaiian/Pacific islander and 12% as other. Median BMI was 31 kg/m² (IQR 26.4-34.3), menarche was at age 12 or older for 23 (70%) of the participants and 20 women were postmenopausal at the time enrollment. 10 participants had a hysterectomy, of whom 60% also had oophorectomy. 76% reported history of hormonal birth control use and 23% postmenopausal hormonal supplementation. Median number of pregnancies was 3 (IQR 2-5), and 20 women reported breastfeeding. Fifteen women were current or former smokers (>100 cigarettes) and 19 reported none or low alcohol consumption. Median serum vitamin D level was 39 ng/mL (IQR 30-52) and 9 (27%) women had low vitamin D levels. In regard to breast density, median percentage (average of images) was 15% (IQR 7.5-24.9) with a median dense area of 21.8 cm² (IQR 16.4-34.2). Median time from blood draw to mammogram was 110 days (IQR 41-172) and 19 (58%) participants were taking vitamin D supplementation at the time of study enrollment; doses ranged from 400 to 50,000 units. No correlation was identified between breast density and serum vitamin D levels (correlation=0.02). Conclusion: In this cohort, no association between serum vitamin D levels and breast density was observed. More than half of the participants were on vitamin D supplementation and this could have obscured our observations. Larger studies controlling for vitamin supplementation are needed, as this association could potentially impact breast cancer rates in populations at risk for vitamin D deficiency. Citation Format: Narjust Duma, Ivana Croghan, Sarah Jenkins, Loni Neal, Karthik Ghosh, Sandhya Pruthi. Assessing vitamin D and mammographic breast density in a population of Alaskan Native women [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C088.

Abstract Background: Studies demonstrate breast cancer risk reduction of 50-65% with the use of endocrine therapy (ET) and yet drug uptake and adherence in this setting is suboptimal even among high risk women. A Polygenic Risk Score (PRS) comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP)) can provide a personalized risk assessment and potentially influence ET adherence. We assessed ET adherence at 1 year comparing women whose risk estimate increased due to PRS versus women whose risk estimate decreased due to PRS. The effect of ET use on quality of life (hot flashes, night sweats, vaginal dryness, weight gain, joint pain) was evaluated. Methods: Eligible women required either a 5 year Gail Model risk of ≥3% or 10 year IBIS ( International Breast Intervention Study or Tyrer-Cuzick model) of ≥5%. Women with a history of breast cancer (BC) or hereditary BC syndrome were excluded. High risk women were counseled at baseline using their Gail and IBIS risk scores and ET options were discussed including benefits and risks. Participants completed a self-reported questionnaire at baseline to assess their understanding of breast cancer risk and decision to take preventive ET. Blood samples were obtained and genotyped for 77 SNPs, and the odds ratio from the SNPs were used to modify the IBIS and Gail risk estimates. The BC -PRS risk estimate information was shared with study participants that reflected the IBIS and Gail risk estimates for 5 year, 10 year, & lifetime BC risk with and without the PRS. Follow up questionnaires at year 1 were administered to assess drug adherence and ET usage on quality of life. Results: 151 women were enrolled at Mayo Clinic Rochester and CancerCare Manitoba from 2016 to 2017. The median age was 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian and 64.7% had>1 family member with BC. Median 5yr, 10yr, & lifetime IBIS- PRS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). At year 1 (n=112 women) 46 % of those with an increase in risk when considering the BC-PRS score and 16 % with a decrease in risk were taking ET ( p< 0.001). Types of ET taken: tamoxifen-18, raloxifene- 3, exemestane -14 and missing-1. Women taking ET reported weight gain ( 19.4% vs 6.7%, p=0.04) and more joint pain ( 27.8 % vs 12%, p=0.04) when compared to women not taking ET. Conclusion: In high risk women, BC-PRS risk estimates in addition to standard BC risk calculators had a significant impact on preventive ET adherence. ET use was associated with weight gain and joint pain. Citation Format: Sandhya Pruthi, Julian O Kim, Daniel Schaid, Andrew Cooke, Christina Kim, Benjamin Goldenberg, Jason Sinnwell, Debjani Grenier, Fergus Couch, Celine Vachon. Impact of the breast cancer polygenic risk score on preventive endocrine therapy adherence and endocrine therapy usage on quality of life - The Genetic Risk Estimate (GENRE) trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-03.

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

Background: Lymphoma patients exposed to chest RT during adolescence/young adulthood are at increased risk for BC; the cumulative incidence exceeds 20% by age 45 and the BC risk is comparable to that in women with BRCA1 mutations. These findings present an urgent yet unmet need to reduce the risk of BC in RT-exposed lymphoma survivors. The risk of BC is 50% lower in chest RT-exposed survivors who also receive ovarian radiation, suggesting a critical role of endogenous estrogens in RT-related breast carcinogenesis, making tamoxifen (a selective estrogen receptor modulator) an attractive risk-reducing option. Tamoxifen administered at 20 mg/d is effective in BC prevention in other high risk populations, but severe adverse events (SAE: venous thromboembolism, endometrial cancer) have limited its broad use. Previous biomarker trials in the general population have shown that LDTam (5mg/d) is not inferior to tamoxifen at 20 mg/d in reducing BC risk, and is associated with a safer AE profile. Mammographic breast density (MBD) is an established biomarker of BC risk; high MBD is associated with a 4-fold higher risk of BC. We hypothesized that LDTam would be effective in reducing BC risk (using MBD as a primary endpoint) in chest RT-exposed lymphoma survivors. We used an investigator-initiated, multi-institutional, randomized phase IIb, double blind, placebo controlled trial (FDA IND 107367) to test this hypothesis. Methods: Female patients from 13 sites were ≥25y at enrollment, with a history of exposure to chest RT at ≥12 Gy by age 40 for their primary cancer, and were off therapy for ≥6 mo. Subjects with a prior history of BC/DCIS, B/L mastectomy, or baseline MBD <25% in both breasts were excluded. Tamoxifen 5mg or identical placebo tablets were provided by Sharp Clinical Services (Allentown, PA) under good manufacturing practice. Subjects were randomized 1:1 in a double-blinded fashion by a Web-based system to receive LDTam or placebo daily for 2y. MBD (in both breasts) was measured centrally on digital scans independently by 3 radiologists at baseline, 1y and 2y. Using an intention-to-treat analysis, the efficacy of LDTam in reducing MBD was compared between the LDTam and placebo arms by applying a linear mixed effects model for bivariate normally distributed data with random intercept and time*treatment arm effects. Correlations between the left and right breasts and within radiologists were accounted for in the model. Treating clinicians and all research staff were blinded to the treatment arm. Results: A total of 72 patients (LDTam: n=34; placebo: n=38) participated in the trial; primary diagnosis: Hodgkin lymphoma (86%); non-Hodgkin lymphoma (10%); other (3%); median age at diagnosis of primary cancer: 21.5y (IQR, 16-28), and at trial enrollment: 43.8y (35-49); median time from diagnosis of primary cancer to study: 17.0y (12-26). Median chest RT dose: 30.3 Gy (21-37.3); 11% had received pelvic radiation; 39% were post-menopausal at study. Participant characteristics were comparable between the two treatment arms, as was the mean baseline MBD (LDTam: 52.6% vs. placebo: 50.4%, p=0.6). The time*treatment arm effect was statistically significant (LDTam vs. placebo: estimate = -1.7, SE = 0.5, p = 0.001), indicating a significantly lower mean fitted MBD for LDTam (43.9%) vs. placebo (47.3%) at 2y (Figure). This represented a 16.5% relative reduction in MBD on the LDTam arm, corresponding to an estimated 33% lower risk of BC (assuming that reductions in MBD have the same benefit in lymphoma survivors as they do in the general population). There were no grade 3 or 4 AEs related to LDTam. Grade 2 AEs did not differ between treatment arms (LDTam: 44.1% vs. placebo: 36.8%, p=0.6). There was no difference in the prevalence of moderate-to-severe patient-reported outcomes between the treatment arms (Table). Conclusion: Low-dose tamoxifen was associated with a significantly steeper decline in MBD in chest RT-exposed lymphoma survivors, when compared with placebo, and was safe and well-tolerated. This is the first trial demonstrating efficacy of a pharmacologic intervention in reducing a biomarker strongly associated with breast cancer risk in lymphoma survivors with a past history of chest radiation. Disclosures Palomares: Covance: Other: Medical monitoring. Henderson:Seattle Genetics: Research Funding. OffLabel Disclosure: The drug is a low-dose tamoxifen, a selective estrogen receptor modulator. Tamoxifen in standard doses is used to reduce the risk of breast cancer in high risk populations. Tamoxifen in standard or low doses have not been tested before for chest-irradiated cancer survivors to reduce the risk of radiation-related breast cancer.

Background: Breast cancer diagnosis and treatment affect quality of life and stress and are associated with fatigue. Meditation interventions are effective strategies for patients with breast cancer but are often limited by poor access, high cost, substantial time commitment, and poor adherence. In this feasibility study, we investigated the use of a portable, wearable, electroencephalographic device for guided meditation practices by breast cancer patients during the period from breast cancer diagnosis until 3 months after surgical treatment. Methods: We enrolled women (age = 20-75 years) who had received a recent diagnosis of breast cancer and planned to undergo surgical treatment. Participants were randomly assigned to perform guided meditation with the device (intervention group) or receive CD-based stress-reduction education (control group). Surveys were used to measure stress, quality of life, and fatigue at baseline, within 4 days before surgery, up to 14 days after surgery, and at 3 months after surgery. Results: In the intervention group, 15 of 17 participants (88.2%) completed the study; in the control group, 13 of 13 participants completed the study (100%). Participants in both groups had less fatigue and stress and improved quality of life at 2 weeks and 3 months after surgery compared with baseline, but there were no significant intergroup differences at any time point. Conclusion: The use of this wearable electroencephalographic device for meditation is a feasible strategy for patients with breast cancer.

PURPOSE To update the ASCO guideline on pharmacologic interventions for breast cancer risk reduction and provide guidance on clinical issues that arise when deciding to use endocrine therapy for breast cancer risk reduction. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS A randomized clinical trial that evaluated the use of anastrozole for reduction of estrogen receptor–positive breast cancers in postmenopausal women at increased risk of developing breast cancer provided the predominant basis for the update. UPDATED RECOMMENDATIONS In postmenopausal women at increased risk, the choice of endocrine therapy now includes anastrozole (1 mg/day) in addition to exemestane (25 mg/day), raloxifene (60 mg/day), or tamoxifen (20 mg/day). The decision regarding choice of endocrine therapy should take into consideration age, baseline comorbidities, and adverse effect profiles. Clinicians should not prescribe anastrozole, exemestane, or raloxifene for breast cancer risk reduction to premenopausal women. Tamoxifen 20 mg/day for 5 years is still considered standard of care for risk reduction in premenopausal women who are at least 35 years old and have completed childbearing. Data on low-dose tamoxifen as an alternative to the standard dose for both pre- and postmenopausal women with intraepithelial neoplasia are discussed in the Clinical Considerations section of this article. Additional information is available at www.asco.org/breast-cancer-guidelines .

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