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Abstract Background Young women are more likely than older women to present with higher stage breast cancer (BC) and may benefit to a greater extent from downstaging with neoadjuvant systemic treatment (NST). Young age is also associated with greater likelihood of pathologic complete response (pCR). Using a large prospective cohort of young women with BC, we investigated response to neoadjuvant therapy, eligibility for breast conserving surgery (BCS) pre- and post-NST, and surgical treatment. Methods The Young Women's Breast Cancer Study (YWS) is a multi-center cohort of women diagnosed with BC at age ≤40, that enrolled 1302 patients from 2006 to 2016. Disease characteristics and treatment information were obtained through medical record and central pathology review. Surgical recommendation before and after NST, conversion from BCS borderline/ineligible to BCS eligible, surgery, documented reasons for choosing mastectomy (MTX) among BCS eligible women, and final pathologic response were independently reviewed. Results Among 1302 women enrolled in YWS, 801 (62%) presented with unilateral stage I-III breast cancer and 317(40%) received NST. Median age was 36 years old (22-40). Pre-NST, 85/317 (27%) were BCS eligible, 49 (15%) were borderline, and 169 (53%) were not eligible (16 inflammatory breast cancer (IBC), 88 large tumor size /cosmetic, 48 diffuse calcifications, and 83 multicentricity). Among the 218 patients who were BCS ineligible/borderline pre-NST, 82 (38%) became eligible for BCS after NST. 4 patients who were BCS eligible pre-NST became ineligible. Of all patients eligible for BCS post-NST (n=163), 80 (49%) attempted BCS, 74 (93%) of whom were successful, and 83 (51%) chose MTX. Reasons for choosing MTX included: patient preference (38/83 (46%)), BRCA or TP53 mutation (31 (37%)), family history (3 (4%)), unknown (11 (13%)). On final pathology, 75 (24%) patients had pCR. Among patients who achieved a pCR, 48 (64%) underwent MTX, fewer than half (21/48 (44%)) were for anatomic indications (IBC, large tumor at diagnosis, diffuse calcifications, multicentric disease). Conclusion While NST doubled the proportion of young women eligible for BCS, nearly half chose MTX regardless of response to NST, mostly for personal preference or high-risk preventative reasons. These data highlight that surgical decision making among young women with breast cancer is often driven by factors beyond extent of disease and clinical response to therapy. Table 1.Clinical-pathologic characteristicsCharacteristicsNumber%Pre NST surgical recommendation BCS eligible8526.8Borderline4915.5BCS ineligible16953.3Unknown144.4Clinical Response Complete20263.7Partial9229.0Stable30.9Progressing72.2Unknown134.1Pathologic Response pCR (No invasive or DCIS)7524No pCR24276Post NST Surgical recommendation BCS eligible16351.4BCS ineligible14445.4Unknown103.2Attempted surgery BCS8025.2MTX23674.1Unknown20.6Final Surgery BCS7423.3MTX24176unknown20.6 Citation Format: Kim HJ, Dominici L, Rosenberg S, Pak LM, Poorvu PD, Ruddy K, Tamimi R, Schapira L, Come S, Peppercorn J, Borges V, Warner E, Vardeh H, Collins L, King T, Partridge A. Surgical treatment after neoadjuvant systemic therapy in young women with breast cancer: Results from a prospective cohort study [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 GS6-01.

Abstract Background: Synchronous bilateral breast cancer is rare, with reported incidence from 0.3-12%; the incidence and pattern of bilateral breast cancer among younger women is unknown. Here we report the incidence and phenotypes of bilateral breast cancer in women ≤40 years of age enrolled in the Young Women's Study (YWS) cohort. Methods: The YWS is a multi-center, prospective cohort study that enrolled women with newly diagnosed breast cancer at age ≤40 years from 2006-2016. Those with synchronous bilateral breast cancer (in-situ and/or invasive) formed our study cohort. Disease characteristics and treatment were obtained by medical record review. Central pathology review was performed to capture histologic features and categorize the tumor phenotype as either luminal A (hormone receptor (HR)+, HER2-, grade 1 or 2), luminal B (HR+, HER2+, or HER2- and grade 3), HER2-type (HR-, HER2+), or triple negative (TNC; HR/HER2-). Tumor phenotypes of bilateral breast cancers were compared and evaluated for concordance. Results: Among 1302 patients enrolled in the YWS, 20 (1.5%) patients presented with bilateral disease, with median age of diagnosis of 38 years (range 18-40). The majority of patients (13 (65%)) presented with unilateral symptoms and contralateral disease was identified on subsequent imaging. 12 (60%) reported a positive family history of breast cancer and 17 (85%) underwent genetic testing; resulting in the identification of 6 mutation carriers (2 BRCA1, 3 BRCA2, 1 TP53). The majority of patients (15 (75%)) underwent bilateral mastectomy, 1 underwent unilateral mastectomy with contralateral lumpectomy, and 4 underwent bilateral lumpectomy. On pathology, 2 patients had bilateral in-situ disease, 5 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, all had concordant tumor histology (92% ductal, 8% ductal and lobular), 10 (77%) patients had bilateral luminal tumors and when fully characterized 6 were of the same luminal type. Only one patient had bilateral basal-like breast cancer. Patient ID ERPRHer2 amplifiedGradePhenotype1Left++-2Luminal A Right++-3Luminal B3Left++-3Luminal B Right++-3Luminal B6Left++-3Luminal B Right++-3Luminal B9Left++-2Luminal A Right++-2Luminal A10Left+++3Luminal B Right++-2Luminal A12Left+--3Luminal B Right+--2Luminal A13Left---NABasal-like Right++-NALuminal A or B14Left+++2Luminal B Right++-3Luminal B15Left++-3Luminal B Right+++3Luminal B16Left+++3Luminal B Right--+NAHEr2-type17Left---3Basal-like Right---3Basal-like19Left++-2Luminal A Right++-3Luminal B20Left++-1Luminal A Right++-2Luminal A Conclusions: Among a large cohort of young women, only 20 (1.5%) had bilateral disease, and the majority of the invasive tumors were of the luminal phenotype, yet frequently differed by grade or HER2 status; supporting the need for thorough pathologic evaluation of bilateral disease to determine risk and tailor treatment. Overall the low incidence of bilateral disease and preponderance of the luminal phenotype in this population is reassuring. Citation Format: Pak LM, Rosenberg SM, Ruddy KJ, Tamimi RM, Peppercorn J, Schapira L, Borges VF, Come SE, Warner E, Snow C, Collins L, King TA, Partridge AH. Tumor phenotype and concordance in synchronous bilateral breast cancer in young women [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 P6-22-03.

Abstract Background: The 21-gene Recurrence Score (RS) assay is prognostic among women with early-stage estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) and is used to select patients for chemotherapy (CT). Young women (age <40) have represented a minority in studies evaluating gene expression assays, including TAILORx, and additional data in young women are needed. Methods: In the Young Women's Breast Cancer Study, a prospective cohort study of women diagnosed with BC at age <40 enrolling between 2006-2016 (N=1302), we identified those with stage I-III ER+/HER2- BC. Disease and treatment information were obtained through serial surveys and medical record review. The RS was performed on banked specimens for those not tested clinically. Distant recurrence free interval (DRFI), defined as distant recurrence or BC specific death, by risk group was assessed using Cox regression and Kaplan-Meier survival estimates. Outcomes by receipt of CT were explored in the RS 11-25 group, and due to small number of events, reported descriptively. Results: Among eligible women (N=577), 189 (33%) had undergone RS testing and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6 years. Median age at diagnosis was 37, most had N0 BC (300/509, 59%), and the majority had RS 11-25 (306/509, 60%). RS result was significantly associated with DRFI in N0 BC, with hazard ratio (HR) (95% CI) of 0.29 (0.07,1.30) and 0.21 (0.09,0.50) for RS<11 and RS 11-25, respectively, relative to RS>26 (and trended towards significance in N1 BC). Results were similar using conventional RS groups. Among women with N0 BC and RS 11-25, 44% received CT, with two events in the 86 receiving CT (2.3%) and 6 events in the 109 without CT (5.5%); 5/8 (63%) occurred in those with RS 20-25. Table 1 N0N1Total Cohort N%N%N% 3005916332509100Median Age37.137.537.2Tumor Stage T120869694229358T28227784817635T3103159357T4001151Grade I4716855711II16555794926652III8829754618536Not assessed 1 1 PR status by IHC Negative (<1%)2071710398Positive (>=1%)280931469047092Chemotherapy No1414712715430Yes159531519335570Ovarian Suppression No263881499145289Yes37121495711TAILORx RS Groups RS <1133111495411RS 11-2519565885430660RS >=267224613714929Conventional RS Groups RS <1812742543319939RS 18-3012542694221142RS >=31481640259919 Table 2 6-year freedom from distant recurrence or breast cancer deathDRFI HR (95% CI) N0N1N0N1TAILORx RS Groups RS <1194.4%92.3%0.29 (0.07,1.30)0.21 (0.03,1.61)RS 11-2596.9%85.2%0.21 (0.09, 0.50)0.55 (0.27,1.12)RS >=2685.1%71.3%RefRefConventional RS Groups RS <1897.5%85.9%0.19 (0.06,0.59)0.31 (0.13,0.74)RS 18-3093.1%87.3%0.39 (0.16,1.00)0.32 (0.14,0.73)RS >=3186.4%62.8%RefRef Conclusions: The RS is prognostic among young women with node-negative and node-positive BC, and is a valuable tool for risk stratification. Disease outcomes among young women with N0 disease and RS 11-25, a minority of whom received CT, are very good. Evaluation of the effect of ovarian suppression/CT-induced amenorrhea by RS/treatment strata is ongoing. Citation Format: Poorvu PD, Gelber SI, Rosenberg SM, Ruddy KJ, Tamimi RM, Collins LC, Peppercorn J, Schapira L, Borges VF, Come SE, Warner E, Jakubowski DM, Russell C, Winer EP, Partridge AH. Prognostic impact of the 21-gene recurrence score assay among young women with node-negative and node-positive ER+/HER2- breast cancer [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 P2-08-07.

Abstract Background: Young women with breast cancer (BC) are increasingly choosing contralateral prophylactic mastectomy (CPM), yet little is known about the impact of surgical choices on quality of life (QOL) and psychological health. Using a large, prospective cohort of young women with BC, we sought to evaluate psychosocial outcomes following surgery. Methods: Among participants of the Young Women's BC Study, a multi-center cohort of women dx'd with BC at age ≤40, we identified women with Stage 0-3 unilateral BC who had surgery and completed surveys that included measures of QOL (CARES) and psychological health (HADS). Linear mixed-effects models were fit to assess changes from 1 to 3 years (yrs) post-dx in anxiety, depression, psychosocial, body image, and sexual scores. Adjusted (stage, hormone receptor status, chemotherapy, age) means were estimated and differences compared (Bonferroni adjusted p-values) between CPM vs breast conserving surgery (BCS) and unilateral mastectomy (UM) at 1, 2, and 3 yrs. Results: Of 863 women, 30% had BCS, 24% UM, 46% CPM. Median age at dx was 37 (range: 22-40). Of women who had UM/CPM, 84% had reconstruction. Among women who had CPM, mean body image (p=.02), psychosocial (p<.0001), sexual (p<.0001), and depression p=.0007) scores decreased, indicating improvement, from yr 1 to 2 but remained stable from yr 2 to 3 (Table). Anxiety decreased from yr 1 to 2 for women who had BCS (p=.0007) and M (p=.03), and from yr 2 to 3 for women who had CPM (p=.003). Body image scores did not change significantly between any time points among women who had M or BCS. Overall change trajectories for sexual (p=.03) and anxiety scores (p=.008) differed by surgery. Compared to BCS and UM, psychosocial scores were higher in women who had CPM at 1 yr (p<.05) and remained higher compared to BCS at 2 yrs (p=.04). Anxiety was higher among women who had CPM vs UM at 1 and 2 yrs (p<.01), vs BCS at 2 yrs (p=.004). Depression was higher among women who had CPM vs UM in yr 1 (p=.05). By yr 3, there were no significant differences in anxiety, depression, and overall psychosocial scores between groups. Compared to BCS, women who had CPM had higher sexual and body image scores (p<.01), indicating worse QOL, at all timepoints. Compared to UM, women who had CPM had higher sexual scores at 1 and 3 yrs (p<.05) and body image scores at 3 yrs (p=.02). Conclusions: While psychosocial health improves over time, differences by surgery persist, with women who have CPM experiencing more sexual and body image issues compared to women who undergo BCS or M in the years following surgery. Given that surgical choices may be affected by distress experienced before or at dx, ensuring young women receive adequate support when making surgical decisions as well as after surgery is warranted. Mean CARES and HADS scores Year 123Psychosocial*CPM.89.78.76 UM.75.69.66 BCS.72.65.66 Sexual*CPM1.641.371.40 UM1.411.291.08 BCS1.181.071.04 Body image*CPM1.331.221.30 UM1.161.131.04 BCS.64.57.56 Anxiety**CPM7.657.406.79 UM6.505.916.39 BCS7.036.226.50 Depression**CPM3.723.213.25 UM3.022.802.70 BCS3.332.823.13**CARES range: 0-4;higher scores=worse QOL **HADS range 0-21;higher scores=more anxiety/depression Citation Format: Rosenberg SM, Hu J, Dominici LS, Poorvu PD, Ruddy KJ, Tamimi RM, Schapira L, Come S, Peppercorn JM, Borges VF, Partridge AH. Longitudinal changes in psychosocial health in young women following breast cancer surgery: Results from a multi-center cohort study [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 P2-14-03.

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<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 <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 <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<0.01; OR=0.37 for EGFR+ vs. OR=1.11 for EGFR- tumors, p-heterogeneity<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.

10065 Background: Prospective data regarding fertility and pregnancy after breast cancer are limited. Many young survivors are interested future fertility, but pregnancy rates among women attempting and not attempting pregnancy have not been studied prospectively. Methods: As part of a multicenter cohort study, women diagnosed age ≤40 with stage 0-3 breast cancer are surveyed at baseline then annually regarding fertility interest, attempts, and pregnancies. Chi-square tests were used to compare proportions attempting and achieving pregnancy. Results: At least once in the 5 years (yrs) after Dx, 334/959 (35%) women reported interest in future biologic children. The percent interested was stable in the first 3 yrs then declined: 256 (27%, baseline), 244 (27%, 1 year), 209 (25%, 2 yrs), 176 (25%, 3 yrs), 106 (18%, 4 yrs), and 72 (16%, 5 yrs). Pregnancy was attempted by 104/334 (31%) of women who reported interest and 4/625 (1%) who did not. Pregnancy occurred in 118 women (12%), including 76/108 (70%) who attempted and 42/851 (5%) who did not. Attempts and achieving pregnancy were associated with younger age, partnered status, and not having children prior to Dx (table). Lower stage was associated with attempting pregnancy and ER negative disease with achieving pregnancy. Conclusions: A substantial number of young women become pregnant in the 5 years after a breast cancer diagnosis. Given that over 1/3 of pregnancies were among women who did not report attempting, additional attention to contraception counseling should be considered. Further evaluation of assisted reproductive technology use, pregnancy and disease outcomes in this cohort, and the POSITIVE Trial (NCT02308085) will shed light on the feasibility and safety of pregnancy after breast cancer. [Table: see text]