Simon, Michael S.

Abstract Purpose: The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period. Methods: The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group. Results: The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and <1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38-4.28) and AJ more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61-6.58).Conclusion: These results suggest the continued need for genetic testing and variant reclassification for individuals of all race and ethnic groups.

Purpose: Women whose mammographic breast density declines within 12–18 months of initiating tamoxifen for chemoprevention or adjuvant treatment show improved therapeutic responses compared with those whose density is unchanged. We tested whether measuring changes in sound speed (a surrogate of breast density) using ultrasound tomography (UST) could enable rapid identification of favorable responses to tamoxifen. Methods: We evaluated serial density measures at baseline and at 1 to 3, 4 to 6, and 12+ months among 74 women (aged 30–70 years) following initiation of tamoxifen for clinical indications, including an elevated risk of breast cancer (20%) and diagnoses of in situ (39%) or invasive (40%) breast carcinoma, enrolled at Karmanos Cancer Institute and Henry Ford Health System (Detroit, MI, USA). For comparison, we evaluated an untreated group with screen negative mammography and frequency-matched on age, race, and menopausal status (n = 150), at baseline and 12 months. Paired t-tests were used to assess differences in UST sound speed over time and between tamoxifen-treated and untreated patients. Results: Sound speed declined steadily over the 12 month period among patients receiving tamoxifen (mean (SD): −3.0 (8.2) m/s; p = 0.001), whereas density remained unchanged in the untreated group (mean (SD): 0.4 (7.1) m/s; p = 0.75 (relative change between groups: p = 0.0009)). In the tamoxifen group, we observed significant sound speed reductions as early as 4–6 months after tamoxifen initiation (mean (SD): −2.1 (6.8) m/s; p = 0.008). Sound speed reductions were greatest among premenopausal patients (P-interaction = 0.0002) and those in the middle and upper tertiles of baseline sound speed (P-interaction = 0.002). Conclusions: UST can image rapid declines in sound speed following initiation of tamoxifen. Given that sound speed and mammographic density are correlated, we propose that UST breast imaging may capture early responses to tamoxifen, which in turn may have utility in predicting therapeutic efficacy.

AbstractBackgroundThere is sparse clinical information on the racial and ethnic distribution of results of multigene panel testing among individuals at high risk for hereditary cancer.MethodsWe evaluated the results of multigene panel testing across eight clinical sites across the state of Michigan for individuals seen for genetic counseling from May 13, 2013 to October 31, 2019 at the Karmanos Cancer Institute's cancer genetics clinic. We estimated the prevalence of pathogenic variants and variants of uncertain significance (VUS) from genes other than BRCA1/2 among individuals of non‐Hispanic White (NHW), Black or African American (AA), Ashkenazi Jewish (AJ), Arab, Hispanic, and other ancestry.ResultsThe racial and ethnic distribution of 2419 individuals who had panel testing included 68.8% NHW, 22.1% AA, 2.3% Arab, 2.2% AJ, 1.0% Hispanic, and 3.6% other. Of these, 11.2% had pathogenic variants and 17.5% had VUS. After multivariable analyses, compared to NHW, AA were less likely to have pathogenic variants (OR 95% CI, 0.38, 0.24–0.59, p < 0.001). Both AA and Arabs were more likely to have VUS (OR 95% CI, 1.53, 1.18–1.98, p = 0.001 and OR 95% CI, 2.28, 1.17–4.43, p = 0.015, respectively). There were no significant differences for other groups. The most common pathogenic variants were CHEK2 (n = 65), MUTYH (n = 45), ATM (n = 28), and MSH2 (n = 22); the most common pathogenic variants by race and ethnicity were CHEK2 (NHW), MSH2 and MUTYH (AA), MSH2 (Arab), MSH6 and CHEK2 (AJ), and MLH1 (Hispanic); the most common pathogenic variants by primary cancer site were CHEK2 (breast), MSH2 (colon), BRIP1 and MUTYH (ovarian), and MSH2 and MSH6 (endometrial).ConclusionsUnderstanding the racial and ethnic distribution of pathogenic variants in multi‐gene panels has the potential to lead to better identification of individuals at risk for hereditary cancer.

Abstract Background: Tamoxifen therapy has been shown to have greater therapeutic benefit among women whose breast density declines subsequent to treatment than among women whose density does not decline. Although limited data suggests that endocrine symptoms after tamoxifen initiation may be associated with improved breast cancer outcomes, it is unknown whether these symptoms are associated with reductions in breast density. We therefore evaluated endocrine symptoms and change in breast density in a 12-month longitudinal study of women undergoing tamoxifen therapy for clinical indications. Methods: Cohort members (N=74) were aged 30-74 years in the Ultrasound Study of Tamoxifen at Karmanos Cancer Institute and Henry Ford Health Systems (Detroit, MI). Endocrine symptoms and breast density were both assessed prior to tamoxifen initiation (T0) and at 1-3 months (T1), 4-6 months (T2), and approximately 12 months (T3) post-tamoxifen initiation. Treatment-associated endocrine symptoms included treatment-emergent or increasing vasomotor and/or joint symptoms. Endocrine symptom severity was also assessed with a Likert scale for symptom frequency and categorized as no symptoms (score=0), low/moderate symptoms (score=1-5), and high symptoms (score=6+). Sound speed (m/s), a surrogate of volumetric breast density, was measured with whole breast ultrasound tomography. Change in breast density was calculated as density at T1-T3 minus density at T0. We used multivariable linear regression to estimate mean change in density by endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline sound speed. Generalized estimating equations were used to account for within-subject correlations over time. Results: Women with treatment-associated endocrine symptoms had an overall greater mean reduction in breast density compared with women without symptoms (mean change [95% CI]: -1.97 m/s [-3.80, -0.13]; -0.27 m/s [- 3.50, 2.95], respectively; p=0.22). Longitudinal trends in breast density significantly differed for women with versus without treatment-associated endocrine symptoms (p-interaction=0.02). Significant declines in breast density over time were observed among women with treatment-associated endocrine symptoms (p-trend=0.005), but not among women without symptoms (p-trend=0.16). Similar trends in breast density decline were observed among women with higher symptom severity (p-trends for no symptoms=0.53; low/moderate symptoms=0.04; high symptoms=0.008). Conclusions: These findings suggest that treatment-associated endocrine symptoms may be associated with a significant decline in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations can predict clinical outcome, and if confirmed, both treatment-associated endocrine symptoms and observed reductions in breast density may be useful for patients and providers to improve adherence. Citation Format: Cody Ramin, Ruth Pfeiffer, Shaoqi Fan, Maeve Mullooly, Roni T. Falk, Mark A. Sak, Michael S. Simon, David H. Gorski, Haythem Ali, Peter Littrup, Nebojsa Duric, Mark E. Sherman, Gretchen L. Gierach. Treatment-associated endocrine symptoms and change in ultrasound tomography measures of breast density after tamoxifen therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5805.

e13540 Background: The identification of pathogenic variants and variants of unknown significance (VUS) in multi-gene cancer predisposition testing raises new questions regarding cancer risk and management. We evaluated the personal and family cancer patterns and variation by race and ethnicity, among individuals positive for pathogenic variants in non-BRCA1/ 2 cancer predisposing genes. Methods: The Karmanos Cancer Institute (KCI) Cancer Genetics database was queried from May 13, 2013 through December 31, 2018. There were 3,544 unrelated individuals evaluated for hereditary cancer predisposition of whom 1,868 had 18-gene panel testing at 6 sites across Michigan. Data was collected on personal and family cancer history including ages at diagnosis utilizing a 3-generation pedigree, self-identified race and ethnicity and results of genetic testing. We describe the prevalence of pathogenic variants by proband cancer diagnosis, family history, race, and ethnicity. Results: The race/ethnic distribution of the tested cohort included 67.5% non-Hispanic White (NHW), 24.4% African American (AA), 2.1% Arab, 1.8% Ashkenazi Jewish (AJ), 1.0% Hispanic, and 3.4% other. The distribution of cancer diagnoses included 40.6% breast, 5.5% ovarian, 4.1% colon, 3.5% endometrial, 2.0% pancreas and 39.7% unaffected. Pathogenic variants were seen in 151 (8.1%) individuals and VUS in 309 (16.5%). The five most common pathogenic variants were CHEK2 (40), MUTYH (22), ATM (20), and PALB2 (18). The most common pathogenic variants by race and ethnicity were CHEK2 (NHW), RAD51C (AA), PALB2 (Arab), CHEK2, MSH6 (AJ), and none in Hispanics. Variants associated with the four most common cancer types were breast ( CHEK2 ), ovarian ( CHEK2, MUTYH, BRIP1), colon ( ATM), and endometrial ( MSH6, PALB2). Of 40 individuals with CHEK2 variants, 92.5% were NHW, and 34 (85%), 31 (78%), 10 (25%), 1 (2.5%) had family history of breast cancer, breast cancer before age 50, ovarian, and colon cancer, respectively. Of 20 with ATM variants, 95% were NHW, 13 had family history data and 10 (76.9%), 8 (61.5%), 2 (15.4%), 1 (7.7%) had family history of breast, breast cancer before age 50, ovarian, and colon cancer, respectively. Conclusions: Pathogenic variants seen using multigene panel testing differ by race, ethnicity and personal/family history of cancer. This data will inform genetic counseling strategies in regards to cancer risk and management. Data on additional genes updated through 2019 will be presented.

Abstract PURPOSE. Increased mammographic percent density (MPD) is a strong independent risk factor for developing breast cancer. Previous studies have shown that tissue sound speed, derived from ultrasound tomography, is a surrogate biomarker of MPD. We examined associations of sound speed and MPD with breast cancer risk in a case-control study. METHOD AND MATERIALS. We evaluated breast cancer risk associated with sound speed and MPD in a case-control study involving 59 participants with recent breast cancer diagnoses (cases, aged 30-70 years) and 150 participants with no history of breast cancer (controls), who were matched to cases on age, race, and menopausal status. The cases and controls were imaged with both ultrasound tomography (UST) and mammography. In cases, breast density was measured pre-treatment in the contralateral breast to avoid potential influences of tumor-related changes on MPD or sound speed. In controls, a randomly selected breast was imaged. The ultrasound tomography images were used to estimate the volume averaged sound speed of the breast, and the Cumulus software package was applied to mammograms to determine MPD. Odds Ratios (ORs) and 95% Confidence Intervals (CIs), adjusted for matching factors, were calculated for the relation of quartiles of MPD and sound speed with breast cancer risk. OR differences were tested using a bootstrap approach. RESULTS. MPD was associated with elevated breast cancer risk compared to controls, consistent with previous studies, although the trend did not reach statistical significance (OR per quartile=1.28, 95%CI: 0.95, 1.73; ptrend=0.10). In contrast, elevated sound speed was significantly associated with increased breast cancer risk in a dose-response fashion (OR per quartile=1.79, 95%CI: 1.30, 2.48; ptrend=0.0004). The OR-trend for sound speed was statistically significantly different from that observed for MPD (p=0.01). DISCUSSION. Our case-control study showed that increasing quartiles of whole breast sound speed were consistently and more strongly associated with increasing breast cancer risk than quartiles of MPD. These results show promise for UST’s role in breast cancer risk stratification. CONCLUSION. Elevated breast density strongly increases breast cancer risk. UST has the potential to provide a more accurate, non-ionizing method for assessing breast density and its associated breast cancer risk. Citation Format: Mark Sak, Neb Duric, Ruth Pfeiffer, Mark Sherman, Peter Littrup, Michael Simon, David Gorski, Teri Albrecht, Haythem Ali, Rachel Brem, Rachel Brem, Sharon Fan, Gretchen Gierach. Tissue sound speed is more strongly associated with breast cancer risk than mammographic percent density: A comparative case-control study [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 P3-08-28.

Mammographic percent density (MPD) is an independent risk factor for developing breast cancer, but its inclusion in clinical risk models provides only modest improvements in individualized risk prediction, and MPD is not typically assessed in younger women because of ionizing radiation concerns. Previous studies have shown that tissue sound speed, derived from whole breast ultrasound tomography (UST), a non-ionizing modality, is a potential surrogate marker of breast density, but prior to this study, sound speed has not been directly linked to breast cancer risk. To that end, we explored the relation of sound speed and MPD with breast cancer risk in a case-control study, including 61 cases with recent breast cancer diagnoses and a comparison group of 165 women, frequency matched to cases on age, race, and menopausal status, and with a recent negative mammogram and no personal history of breast cancer. Multivariable odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the relation of quartiles of MPD and sound speed with breast cancer risk adjusted for matching factors. Elevated MPD was associated with increased breast cancer risk, although the trend did not reach statistical significance (OR per quartile = 1.27, 95% CI: 0.95, 1.70; ptrend = 0.10). In contrast, elevated sound speed was significantly associated with breast cancer risk in a dose–response fashion (OR per quartile = 1.83, 95% CI: 1.32, 2.54; ptrend = 0.0003). The OR trend for sound speed was statistically significantly different from that observed for MPD (p = 0.005). These findings suggest that whole breast sound speed may be more strongly associated with breast cancer risk than MPD and offer future opportunities for refining the magnitude and precision of risk associations in larger, population-based studies, including women younger than usual screening ages.

Abstract Background: Statins are the most widely prescribed cholesterol-lowering drugs in the United States, with approximately 25% of US adults using statins by 2008. The anti-carcinogenic effect of statins may reduce the metastatic potential of cancer cells leading to ‘stage migration’ with statin users more likely diagnosed with early rather than late stage cancer. We evaluated the effects of statins on breast cancer stage migration and breast cancer-specific mortality in the Women’s Health Initiative (WHI) Clinical Trial and Observational Study. Methods: The study population included 128,675 postmenopausal women aged 50 to 79 years, with 7,883 newly-diagnosed pathologically-confirmed cases of in situ (19%), local stage (61%), regional stage (19%) and distant stage (1%) breast cancer and 401 deaths due to breast cancer after an average of 11.5 (SD=3.7) years of follow-up. To reduce the possibility of detection bias, we excluded women who did not report a mammogram within 5 years of study entry, and who had no health insurance or medical care provider (n=28,237). Stage was coded using criteria implemented in the Surveillance, Epidemiology and End Results Program and stratified into early stage (in situ and local) vs. late stage (regional and distant). Information on statin use prior to breast cancer diagnosis was collected at baseline and years one, three, six, and nine years post-baseline. Self- and interviewer-administered questionnaires were used to collect risk factor information. Cause of death was based on medical record review by physician adjudicators. Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) to evaluate the relationship between statin use as a time-dependent exposure and diagnosis of late stage breast cancer and breast cancer-specific mortality adjusting for important confounders. For these models, participants who had early stage breast cancer or who died during follow-up were censored at time of diagnosis or death, respectively. We also evaluated the effect of statins stratified by estrogen receptor (ER) status. Statistical tests were two-sided. Results: Statins were used by 10,474 women (8%) at baseline. In the multivariable-adjusted time-dependent model, statin use was associated with a marginal reduction in risk of late stage breast cancer (HR 0.84, 95% CI: 0.70-1.02, p=0.082) and a reduction in risk of late stage estrogen receptor positive breast cancer (HR 0.79, 95% CI: 0.63-0.99, p=0.044). Statin use was also associated with a marginal reduction in breast cancer-specific mortality although it did not reach statistical significance (HR 0.59, 95% CI: 0.32-1.06, p=0.075). Conclusions: In the WHI, statin use was associated with a modest reduction in risk of late stage estrogen positive breast cancer and a non-significant decrease in breast cancer mortality. We are currently performing sensitivity analyses on these models. Studies using other large data sets with longer follow-up and information on cancer-directed therapy are needed to further evaluate this possible association. Citation Format: Monica P Arun, Pinkal Desai, Amy Lehman, Marilyn L Kwan, JoAnn E Manson, Sayeh Lavasani, Sylvia Wasswertheil-Smoller, Gloria E Sarto, Meryl S LeBoff, Jane Cauley, Michele L Cote, Jennifer Beebe-Dimmer, Allison Jay, Rowan T Chlebowski, Michael S Simon. Statins and breast cancer stage and mortality in the Women's Health Initiative cohort [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-04.