Vachon, Celine M.

Abstract Background: High mammographic breast density is a strong, well-established breast cancer risk factor. A recent study found increased expression of stem cell markers in the areas of high breast density, but, whether stem cells may explain high breast cancer risk due to high breast density is unknown. We investigated the association between breast density and the risk of breast cancer by the status of stem cell markers CD44, CD24, and ALDH1A1 in the tumor. Methods: We included 223 postmenopausal women with primary invasive or in-situ breast cancer and 399 age-matched controls from Mayo Clinic Mammography Study. Percent breast density, absolute dense area and non-dense area were assessed using computer-assisted thresholding technique. Immunohistochemical analysis of the markers was performed on tumor tissue microarrays according to a standard protocol with commercial antibodies. Cases with positive staining (≥1% positively stained cells) on one or more cores were considered marker-positive. We used polychotomous logistic regression to quantify the associations of breast density measures with breast cancer risk by the status of each of the markers. Heterogeneity tests were conducted to compare the differences in associations by marker-defined tumor subtypes. Results: Of the 223 cancers in the study, 182 (82%) were positive for CD44, 83 (37%) for CD24 and 52 (23%) for ALDH1A1. Associations of percent density were not significantly different across any of the marker-defined subtypes (density 51%+ vs. 11-25%: OR=2.83, 95% CI 1.49-5.37 for CD44+ vs. OR=1.87, 95% CI 0.47-7.51 for CD44-, p-heterogeneity=0.66; OR=2.80, 95% CI 1.27-6.18 for CD24+ vs. OR=2.44, 95% CI 1.14-5.22 for CD24-, p-heterogeneity=0.61; OR=3.04, 95% CI 1.14-8.10 for ALDH1A1+ vs. OR=2.57. 95% CI 1.30-5.08 for ALDH1A1-, p-heterogeneity=0.94). Positive associations of absolute dense area and inverse associations of non-dense area with breast cancer risk were similar across marker-defined subtypes. Similar associations of breast density measures with breast cancer were seen when cancer subtypes were defined using combined marker expression status (none, one positive marker, or two and more positive markers). Conclusions: We found no evidence of differential associations of breast density measures with breast cancer risk by the status of stem cell markers. However, our power was limited and further studies in larger study populations are warranted to confirm these associations in a larger sample. Citation Format: Lusine Yaghjyan, Ashwini Esnakula, Christopher Scott, Akemi Wijayabahu, Matthew Jensen, Celine Vachon. Associations of mammographic breast density with breast stem cell marker-defined breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 592.

Abstract Genome-wide association studies (GWAS) conducted among populations of European ancestry (EA) have identified 23 common single nucleotide polymorphisms (SNPs) associated with multiple myeloma (MM) risk. We hypothesize that the combination of these SNPs in a polygenic risk score (PRS) is likely to be a strong risk factor for MM. However, it is unclear whether the genetic variation associated with MM susceptibility also predisposes to monoclonal gammopathy of undetermined significance (MGUS). Thus, we calculated a PRS and evaluated the association with risk of MM and its precursor, MGUS. We pooled genotype data for 2434 MM and 3446 controls from ten MM GWAS of individuals of EA within the Interlymph Consortium, for 23 MM risk SNPs identified by prior GWAS. An additional 754 MGUS cases were ascertained from Mayo Clinic and MD Anderson clinical practices. To calculate the PRS, we used the risk estimates corresponding to the 23 SNP associations from the largest published MM GWAS. The log of the odds ratio (OR) for each SNP was multiplied by the respective number of risk alleles and summed to generate a PRS for each individual. The PRS was examined continuously, per one standard deviation (SD), and as quintiles, based on the PRS distribution in the controls. Associations of PRS with MM and MGUS risk were examined separately, using multivariable logistic regression assuming an additive model to assess ORs and 95% confidence intervals adjusted for age, sex, and site. We also evaluated age and sex stratified models. The distribution of sex within MM cases, MGUS cases and controls were each ~60% male and ~40% female. The median age was 61, 66, and 66 years for MM cases, MGUS cases and controls, respectively. PRS ranged from 1.52-4.91, with a median PRS of 3.21 for MM cases, 3.19 for MGUS cases, and 3.05 for controls. PRS was significantly associated with MM risk when assessed continuously (OR=1.19 per SD, p=2.2x10-16) and categorically; compared with the middle quintile (Q3), individuals in the highest quintile (Q5) had a 66% increased MM risk (OR=1.66, p=2.3x10-9) and those in the lowest quintile (Q1) had a 38% decreased MM risk (OR=0.62, p=1.3x10-6). PRS was also significantly associated with MGUS risk (OR=1.19 per SD, p=1.7x10-11); individuals with the highest PRS (Q5) had a 77% increased risk (OR=1.77, p=4.0x10-4) and those with lowest PRS (Q1) had 30% decreased risk (OR=0.70, p=0.04), compared with Q3. When stratified by age and sex, similar associations and trends were found. Using an independent sample of MM / MGUS cases and controls, we showed that a PRS constructed from 23 common genetic variants for MM risk is associated with risk of both MM and MGUS, regardless of age or sex. A future direction of this work is testing associations with PRS and clinical characteristics of the MM cases, as well as differences between MGUS cases that progress and those that do not. Our results suggest that common genetic variation may predispose to MGUS as the precursor to MM. Citation Format: Alyssa I. Clay-Gilmour, Michelle A. Hildebrandt, Nicola J. Camp, Elad Ziv, Elizabeth E. Brown, Jonathan N. Hofmann, John J. Spinelli, Graham G. Giles, Parveen Bhatti, Wendy Cozen, Xifeng Wu, Dennis P. Robinson, Aaron D. Norman, Jason P. Sinnwell, Shaji K. Kumar, S Vincent Rajkumar, Susan L. Slager, Celine M. Vachon. Associations between a polygenic risk score and risk of multiple myeloma and its precursor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2686.

Abstract Background: Mammographic breast density declines during menopause. We assessed changes in volumetric breast density across the menopausal transition and factors that influence these changes. Methods: Women without a history of breast cancer, who had full field digital mammograms during both pre- and postmenopausal periods, at least 2 years apart, were sampled from four facilities within the San Francisco Mammography Registry from 2007 to 2013. Dense breast volume (DV) was assessed using Volpara on mammograms across the time period. Annualized change in DV from pre- to postmenopause was estimated using linear mixed models adjusted for covariates and per-woman random effects. Multiplicative interactions were evaluated between premenopausal risk factors and time to determine whether these covariates modified the annualized changes. Results: Among the 2,586 eligible women, 1,802 had one premenopausal and one postmenopausal mammogram, 628 had an additional perimenopausal mammogram, and 156 had two perimenopausal mammograms. Women experienced an annualized decrease in DV [−2.2 cm3 (95% confidence interval, −2.7 to −1.7)] over the menopausal transition. Declines were greater among women with a premenopausal DV above the median (54 cm3) versus below (DV, −3.5 cm3 vs. −1.0 cm3; P < 0.0001). Other breast cancer risk factors, including race, body mass index, family history, alcohol, and postmenopausal hormone therapy, had no effect on change in DV over the menopausal transition. Conclusions: High premenopausal DV was a strong predictor of greater reductions in DV across the menopausal transition. Impact: We found that few factors other than premenopausal density influence changes in DV across the menopausal transition, limiting targeted prevention efforts.

1501 Background: Despite BC risk reduction of 50-65% by preventive endocrine therapy (ET), very few at-risk women choose to take them. A woman’s perceived BC risk correlates with uptake of ET. A PRS comprised of 77 BC genetic susceptibility loci (Single Nucleotide Polymorphisms (SNP) improves the accuracy of risk prediction for BC. We examined the impact of the addition of individualized PRS BC risk prediction to standard risk calculator estimates on intent to take BC prevention medication. Methods: Eligible women had ≥5% 10 yr BC Tyrer-Cuzick risk (IBIS) or 5 year Gail score ≥3%, with no history of BC or hereditary BC syndrome. Standard BC risk estimates (IBIS or Gail) were incorporated into the counselling on BC preventive ET. A self-reported questionnaire at baseline quantified intention to take ET and explored factors associated with this decision. Blood samples were obtained and genotyped for 77 SNPs, individualized PRS were calculated then incorporated into IBIS and Gail predictions for 5 yr, 10 yr, & lifetime BC risk. At a second visit, PRS risk & prevention recommendations were revisited. Post visit questionnaires assessed change in intent to take ET. Multivariable linear regression was performed to assess impact of baseline variables on change in intent to take medication. Results: From 2016 to 2017, 151 women in Canada & USA were enrolled, median age: 56.1 (range 36-76.4), 35.6% were premenopausal, 98.7% were Caucasian. Median 5yr, 10yr, & lifetime IBIS risk estimates were 3.8% (2.0-11.5), 7.9% (5.0-23.1), and 25.3% (5.5 to 92.2). PRS increased BC risk estimates in 84 (55.6%) and reduced BC risk estimates in 67 (44%) women. After PRS risk counselling, intention to take ET significantly changed (p<0.001): 41.9% of those with increased PRS were more inclined, and 46.7% of women with decreased PRS were less inclined to take ET. On multivariable regression, increase in PRS (p<0.0001) and less concern about ET side effects (p<0.0001) were associated with greater intent to take ET. Conclusions: In high risk women, PRS significantly changed BC risk estimates & intent to take preventive ET. Further assessments of the impact of PRS scores on compliance with ET are warranted. Clinical trial information: NCT02517593.

Abstract Background: Chemotherapy can damage the ovaries and cause amenorrhea, a surrogate for infertility. Young women often wish to understand and minimize their risk of chemotherapy-related amenorrhea (CRA). However, the incidence of CRA with regimens that do not include either an anthracycline or cyclophosphamide is poorly studied. For patients with HER-2 positive disease, these anthracycline and cyclophosphamide-sparing regimens (e.g., docetaxel-carboplatin) are common (in combination with Her-2 directed therapy) in both the neoadjuvant and adjuvant settings. Methods: Women diagnosed with breast cancer under age 50 and within the past 10 years were recruited through a Dr. Susan Love Research Foundation Army of Women e-mail blast. Those who provided their contact information were mailed a consent form and medical record authorization form. Participants then received a web-based survey that inquired about receipt of and type of chemotherapy (including date of last dose) and date of last menstrual period (LMP). Patient-reported LMP was compared to date of final chemotherapy dose to determine if the LMP occurred before (defined as “CRA”) or after the last chemotherapy dose. When available, medical record data was used in place of survey data regarding type of chemotherapy used. Exclusion criteria included: LMP prior to diagnosis date, receipt of multiple chemotherapy regimens or no chemotherapy regimens, receipt of ovarian suppression medications (which interfere with interpretation of menstrual data), surgical menopause prior to or at the same time as diagnosis, a cancer diagnosis more than 10 years prior, incomplete menstrual data on the survey, report of an unknown chemotherapy regimen, and no date available for the last chemotherapy dose without an LMP within a month prior to survey completion. Fisher Exact test was used to compare CRA rates between regimens. Rates after two anthracycline-sparing regimens (taxane/cyclophosphamide; taxane/carboplatin) were compared to rates after anthracycline/cyclophosphamide/taxane. Results: 273 women consented to participate in this study, 258 of whom filled out the web survey. 151 of them were eligible for this analysis with a median age at diagnosis of 41 (range 24-49) and a median time from last chemotherapy dose to survey of 62.5 months (range 2-138). CRA occurred in 51.2% of the 86 participants who received an anthracycline, cyclophosphamide, and a taxane, in 41.9% of the 43 participants who received only a taxane and cyclophosphamide (p=0.35), and in 13.3% of the 15 participants who received carboplatin with a taxane (p=0.01). When the 11 patients who were &lt;12 months since last chemotherapy were excluded, CRA rates changed minimally. Age did not differ by regimen, but median time since chemotherapy was shorter in the taxane/carboplatin group (35 months vs. 68 months). Trastuzumab with or without pertuzumab was administered in 100% of patients who received carboplatin/taxane, in 23.3% of patients who received taxane and cyclophosphamide, and in 22.1% of patients who received anthracycline/cyclophosphamide/taxane. Conclusions: This study suggests that carboplatin/taxane may be substantially less gonadotoxic than cyclophosphamide-based (neo)adjuvant regimens. Further research is necessary to confirm these findings. Citation Format: Gast KC, Cathcart-Rake EJ, Norman A, Eshragi L, Obidegwu N, Yost K, Nichols HB, Rosenberg S, Su HI, Stewart E, Couch F, Vachon C, Ruddy KJ. Regimen-specific rates of chemotherapy-related amenorrhea in breast cancer survivors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-12-10.

Abstract Purpose: The evidence on associations of mammographic breast density with breast cancer risk by combination of tumor aggressiveness features is limited. We examined associations of breast density phenotypes with risk of aggressive breast tumor features by menopausal status, and current postmenopausal hormone therapy. Methods: This study included 2,635 invasive breast cancer cases and 4,059 controls from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses Health Study, Nurses Health Study II, and San Francisco Mammography Registry. Percent breast density, absolute dense and non-dense areas were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density measures with risk of breast tumor aggressiveness (defined as presence of 2 or more of the following tumor characteristics: size ≥2cm, grade 2 or 3, or positive nodes), stratified by menopausal status and current hormone therapy (i.e., premenopausal, postmenopausal/estrogen therapy, postmenopausal/combined therapy, and postmenopausal/no hormones). We also evaluated differences in the strength of associations across categories. In a secondary analysis, we examined these associations while excluding cases with mammogram date within 2 years of diagnosis. Results: Positive associations of percent density and dense area and inverse associations of non-dense area with breast cancer risk were stronger in aggressive vs. non-aggressive tumors (OR=2.62, 95%CI 2.08-3.31 vs. OR=1.94, 95%CI 1.62-2.33 for percent density≥51% vs. 11-25%, p-heterogeneity=0.001; OR=1.89, 95%CI 1.54-2.31 vs. OR=1.65, 95%CI 1.41-1.93 for dense area 4th vs. 2nd quartile, p-heterogeneity=0.015; OR=0.56, 95%CI 0.44-0.72 vs. OR=0.71, 95%CI 0.59-0.86 for non-dense area 4th vs 2nd quartile, p-heterogeneity=0.007, respectively). These patterns were similar across all menopausal and hormone therapy groups (P-interactions=0.62, 0.76, and 0.23, for percent density, dense area and non-dense area, respectively). Excluding cases diagnosed within 2 years of mammography resulted in similar findings. Conclusion: Mammographic density phenotypes were more strongly associated with aggressive cancer (having two or more of the following: size ≥2cm, grade 2 or 3, or positive nodes) vs. non-aggressive types of breast cancer across categories of menopause and hormone therapy types. Citation Format: Lusine Yaghjyan, Rulla Tamimi, Kimberly Bertrand, Christopher G. Scott, Matthew R. Jensen, Shane Pankratz, Kathleen Brandt, Daniel Visscher, Aaron Norman, Fergus Cough, John Shepherd, Bo Fan, Yunn-Yi Chen, Lin Ma, Andrew H. Beck, Steven R. Cummings, Karla Kerlikowske, Celine Vachon. Interaction of mammographic breast density with menopausal status and postmenopausal hormone use in relation to the risk of aggressive breast cancer subtypes. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B27.

Abstract Background: This analysis aimed to determine if associations of prediagnostic mammographic percent breast density, absolute dense area, and absolute non-dense area and risk of breast cancer vary according to the subsequent breast tumors biomarker status. Methods: We included 1,154 postmenopausal women diagnosed with breast cancer between June 1, 1989, and June 30, 2004, and 2,078 matched controls from the Nurses' Health Study I and II. Percent breast density, absolute dense and non-dense areas were estimated from digitized film mammograms using computer assisted thresholding techniques. Density measures were modeled as quartiles. Information on estrogen receptor (ESR1 [ER]), progesterone receptor (PGR [PR]), and human epidermal growth factor receptor 2 (ERBB2 [HER2]) status was obtained from pathology reports and medical records, and if missing, from immunostains performed on paraffin sections of tumor tissue microarrays (TMAs). Other biomarkers assessed on TMAs were androgen receptor (AR), cytokines 5/6 (KRT5/KRT6 [CK5/6]), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGFA [VEGF]), and cyclooxygenase 2 (PTGS2 [COX2]). Information on breast cancer risk factors was obtained prospectively from biennial questionnaires before the date of cancer diagnosis for cases and matched controls. Polychotomous logistic regression was used to assess associations of the three breast density measures with tumor subtypes based on the status of selected tissue markers. Results: Breast cancer risk was positively associated with percent density and absolute dense area and inversely associated with absolute non-dense area (p for trend&lt;0.0001 for all). The associations of percent density with breast cancer risk did not statistically significantly differ by the status of any of the markers. However, we found stronger positive associations for absolute dense area and KRT5/KRT6- and EGFR- tumors as compared to respective marker-positive tumors (4th vs. 1st quartile: OR=2.99 for KRT5/KRT6- vs. OR=0.92 for KRT5/KRT6+ tumors, p-heterogeneity &lt;0.001; OR=3.06 for EGFR- vs. OR=1.08 for EGFR+ tumors, p-heterogeneity=0.001). Stronger inverse associations of absolute non-dense area with breast cancer risk were found for ESR1- as compared to ESR1+ tumors, and for AR+, KRT5/KRT6+, and EGFR+ tumors as compared to respective marker-negative tumors (4th vs. 1st quartile: OR=0.21 for ESR1- vs. OR=0.59 for ESR1+ tumors, p-heterogeneity &lt;0.0001; OR=0.22 for AR+ vs. OR=0.42 for AR- tumors, p-heterogeneity=0.04; OR=0.21 for KRT5/KRT6+ vs. OR=1.14 for KRT5/KRT6- tumors, p-heterogeneity&lt;0.01; OR=0.37 for EGFR+ vs. OR=1.11 for EGFR- tumors, p-heterogeneity&lt;0.01). There were no differences in associations of the density measures with breast cancer by status of other markers evaluated. Conclusions: The findings suggest that some mammographic density measures are differentially associated with the risk of subsequent breast tumor subtypes. Citation Format: Lusine Yaghjyan, Andreas Pettersson, Graham Colditz, Laura Collins, Stuart Schnitt, Andrew Beck, Bernard Rosner, Celine Vachon, Rulla Tamimi. Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to the status of selected tissue markers: A case-control study. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PR09.

e20092 Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.

6531 Background: Annual mammography is recommended to screen residual breast tissue for new cancers and recurrent disease after treatment for early stage breast cancer. This study aimed to assess mammography rates over time in breast cancer survivors. Methods: We used administrative claims data from a large U.S. commercial insurance database, OptumLabs, to retrospectively identify privately- and Medicare Advantage-insured women with operable breast cancer who had residual breast tissue after definitive breast surgery between 2006 and 2015. We required coverage for at least 13 months following surgery. For each subsequent 13-month time period, we only included women without a loss of coverage, bilateral mastectomy, metastatic breast cancer diagnosis, or non-breast cancer diagnosis. We calculated the proportion of patients who had a mammogram during each 13-month period following breast surgery. We used multivariable logistic regression to test for factors associated with mammography in the first 13 months. Results: The cohort included 26,011 women followed for a median of 2.9 years (IQR 1.9-4.6) after surgery; 63.1% were less than 65 years of age, and 74.4% were white. In their first year of follow-up, 86% underwent mammography, but by year 7, this decreased to 73%. Fewer than 1% underwent MRI instead of mammography. In multivariable analysis, mammograms were less likely during the first year after surgery among women aged < 50 years (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.6 to 0.8), African Americans (OR, 0.7; 95% CI, 0.7 to 0.8), patients who underwent mastectomy (OR, 0.7; 95% CI, 0.6 to 0.7), and patients residing in the Western part of the country (OR, 0.9; 95% CI, 0.7 to 0.9). Those with 1-2 comorbidities were more likely (OR, 1.1; 95% CI 1.1-1.2) than those with none to have a mammogram during that period. Mammography use did not differ significantly by year of diagnosis (2006-2015). Conclusions: Even in an insured cohort, a substantial proportion of breast cancer survivors do not undergo annual surveillance mammography. Mammography use falls as the time from the early stage breast cancer diagnosis increases. Understanding factors associated with lack of mammographic screening may help improve survivorship care.