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Background: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. Results: Alcohol use was positively associated with PD (Ptrend = 0.01), unassociated with DA (Ptrend = 0.23), and inversely associated with NDA (Ptrend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend = 0.0008), unassociated with DA (Ptrend = 0.93), and positively associated with NDA (Ptrend Conclusions: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. Impact: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health.

Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.

Background: High percent density (PD) is common and is among the strongest risk factors for breast cancer. The prevalence of heterogeneously dense or extremely dense breasts is between 40% to 60% of screening age women, and is estimated to account for up to one third of all breast cancer (BC) diagnoses. PD decreases with age, body mass index (BMI), number of children, and menopause; and increases with age at menarche, age at first birth, and family history of breast cancer. Of particular interest are modifiable exposures believed to alter PD, such as the use of menopausal hormone therapy (MHT), tamoxifen and alcohol that could provide opportunities for women to reduce their BC risk. The dense area (DA) of the breast appears radiopaque on a mammogram and contains greater proportions of collagen, epithelial and stromal cells compared to the nondense area (NDA), which largely consists of fatty tissue. Recent studies have shown that NDA is inversely associated with BC risk, independently of DA, suggesting that normal breast fat may play a protective role. The underlying mechanisms through which mammographic density (MD) phenotypes are associated with BC risk are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric (GE). MD measurements were obtained using Cumulus an average of 2.9 years after the survey date. Machine-specific effects were estimated using linear regression, adjusted for known biologically plausible correlates of MD, and combined using random effects meta-analysis methods. Results: Alcohol use was positively associated with PD (ptrend=0.01), unassociated with DA (ptrend=0.23), and inversely associated with NDA (ptrend=0.02) in models adjusted for age, BMI, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (ptrend=0.0008), unassociated with DA (ptrend=0.93), and positively associated with NDA (ptrend Conclusions: This study provides the strongest evidence to date that association of alcohol and tobacco use with PD result from their associations with NDA rather than DA. Impact: Alcohol consumption, and less consistently tobacco use, have been shown to increase risk of breast cancer. These findings indicate that PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health. Citation Format: Russell B McBride, Kezhen Fei, Joseph H Rothstein, Stacey E Alexeeff, Xiaoyu Song, Lori C Sakoda, Valerie McGuire, Ninah Achacoso, Luana Acton, Rhea Y Liang, Jafi A Lipson, Martin J Yaffe, Daniel L Rubin, Alice S Whittemore, Laurel A Habel, Weiva Sieh. Alcohol and tobacco use in relation to mammographic density in 23,456 women [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 P2-08-01.

Background. Physicians are mandated to offer treatment choices to breast cancer patients yet not all patients may want the responsibility that entails. Prior studies show that breast cancer patients who are not given enough responsibility for treatment decision-making have poorer treatment knowledge and report worse quality of care. In contrast, few studies explore potential adverse consequences for breast cancer patients who feel they are given too much responsibility for treatment decision-making. Methods. We sought to describe and compare women by degree of responsibility they felt they had for making decisions about their breast cancer treatment. Our sample includes women with early-stage breast cancer treated surgically at 8 NYC hospitals, recruited for an RCT of patient assistance to improve receipt of adjuvant treatment. In multivariable analyses, we explored the association between treatment decision-making responsibility and a) baseline knowledge of benefit of surgical and adjuvant treatments discussed with doctor and b) regret of treatment decisions after 6 months. Results. Of 368 women aged 28-89y enrolled at baseline, 72% reported a “reasonable amount,” 21% “too much,” and 7% “not enough” responsibility for treatment decision-making. The majority in the first group were White (53%), earned >$150,000/year (33%), completed college (53%), had no health literacy problems (50%), and had a great deal of self-efficacy (61%). In contrast, the majority with “not enough” responsibility were Black (42%), earned Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5497. doi:1538-7445.AM2012-5497

Abstract #5098 Background: It has been well-established that survival following breast conservation surgery(BCS) vs. mastectomy(MT) is equivalent. Therefore women with early-stage breast cancer should given a choice between BCS and MT. It has recently been recognized that women who have a choice of surgery type have better short term health status. Some studies suggest that there is treatment variation according to socioeconomic status and race. But little is known about whether there is a variance in a feeling of choice based on ethnicity/race and socioeconomic status. Do these factors affect women's sense of choice in her surgical treatment? Methods: Women with a newly diagnosed Stage I/II breast cancer were identified from pathology databases of 6 participating NYC hospitals, including 3 municipal, 2 tertiary, and one community hospital. Patients were surveyed an average of 6 months after surgical treatment. Bivariate, logistic and factor analyses were conducted on the 258 participants. IRB approval was obtained at all 6 institutions. Results: Despite high rates(88%) of reported discussion of surgery types, only 55% of women felt they had a choice of surgical treatment. Women who felt they had a choice were more likely to be younger(55 vs. 61; p=0.0009), more knowledgeable about equivalent survival outcomes(24% vs. 12%, p+0.0170), and shared decision making(Cronbach α=0.79) with their physician(92% vs. 88%, p=0.0066). When taking into account the patient's stage of cancer, there was no difference in the feeling of choice based on race/ethnicity, income level, or education level. This feeling of having a choice in the surgical procedure performed was not related to type of surgery: 57% of women with mastectomy felt they had a choice, while 56% of breast conservation surgery patients felt they had a choice. Conclusions: There is a difference between mentioning treatment options during preoperative evaluations and counseling of women with newly diagnosed early-stage breast cancer, and shared decision-making. Shared-decision making is associated with a greater sense of choice, which can affect health status and may influence patients satisfaction with overall treatment. Surgeons should involve women in discussion of treatment options, regardless of education or race, as this can influence patient's sense of choice, which in turn, can affect health status. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5098.

Background: Despite the existence of effective adjuvant treatment for early stage breast cancer, women do not always receive it, particularly, minority women. Primary treatment for breast cancer, surgery and varying combinations of radio-, chemo- and hormonal therapy, is delivered by different specialists and is often fragmented. Underuse of post-surgical adjuvant treatment occurs more commonly among women who do not see a medical oncologist despite surgeons’ referral request. To reduce underuse of adjuvant treatment due to failed connections, we tracked and fedback to surgeons information about whether their newly diagnosed breast cancer patients connected with an oncologist. Methods: We compared oncology referral rates and underuse among pre-intervention (N=677) and intervention (N=300) patients undergoing breast cancer surgery at 6 NYC hospitals. All surgeons consented to the intervention. Each surgeon chose an office person to verify eligibility and identify patient’s oncology referrals. Patients identified upcoming oncology appointment sites and times. Following scheduled visits, oncologists were called to verify patients’ connection & these data were fedback to surgeons & their office staff. Six months later, we abstracted in- & outpatient charts. We compared rates of: completed oncology consultations and underuse of radiotherapy after breast conserving surgery, of chemotherapy for ER negative and hormonal therapy for ER positive tumors >1cm between pre- and intervention women with newly diagnosed early-stage breast cancer. Results: There was a significant increase in oncology consultations completed (83% to 97%; p Conclusions: A tracking and feedback registry which closes the referral loop between surgeons and oncologists appears to improve rates of medical oncology consultation, reduces rates of adjuvant treatment underuse and eliminates the racial disparity in treatment.