Pregnancy history, recency of childbirth, and outcomes in young women with early-stage breast cancer.

<div>Abstract<p>Background: Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping. Materials and Methods: We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women’s Breast Cancer Study. Results: We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in non-cancer cohorts. At nine years median follow up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non-breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over four years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM. Conclusions: Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow up and may not require additional monitoring if discovered incidentally.</p></div>

<div>AbstractPurpose:<p>Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping.</p>Experimental Design:<p>We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study.</p>Results:<p>We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were <i>DNMT3A</i> and <i>TET2</i>, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non–breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as <i>TP53</i> and <i>ATM</i>.</p>Conclusions:<p>Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.</p></div>

<div>AbstractBackground:<p>Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping.</p>Materials and Methods:<p>We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study.</p>Results:<p>We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were <i>DNMT3A</i> and <i>TET2</i>, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non–breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as <i>TP53</i> and <i>ATM</i>.</p>Conclusions:<p>Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.</p></div>

Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping. We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study. We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non-breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM. Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally.

Background: Young women's breast cancer[YWBC] affects 27,000 US women age ≤45 annually. Half of these cancers occur within 5-10 years of a prior childbirth, a postpartum breast cancer[PPBC], incurring a 3 fold increased risk for metastasis and death. Recently, extracellular vesicles[EV] have been identified in human circulation, released from cancer cells, that have paracrine and autocrine effects, alter the tumor microenvironment and establish metastatic niches. EVs isolated from breast cancer lines increase proliferation and invasion of other breast cancer cells in vitro. However, the impact of EVs isolated from primary breast cancer patients on tumor invasion, metastasis and their role in tumor immune suppression is largely unknown. We hypothesized that EVs from YWBC/PPBC patients may contain unique pro-metastatic cargo, influence aggressive breast cancer cell behavior and may demonstrate the ability to alter immune cell function. Method: We isolated EVs using size-exclusion chromatography [SEC] from the plasma of 10 unaffected young women and 20 YWBC patients balanced for parity, age, subtype and stage. We compared the breast cancer-specific EV proteins within various clinical groups of YWBC and PPBC to identify significant proteomic differences by parity, sub-type, stage, and disease recurrence. We determined the functional impact of these EVs on tumor cell motility and proliferation, and analyzed the effect of breast cancer derived EVs on immune cell phenotype, function, and T cell proliferation assays. Results: Of the 582 proteins, 22 proteins are significantly increased in the EVs of YWBC compared to unaffected donors. The protein set includes breast cancer antigens [MUC 1, 2, 5b], transcriptional regulators [Myc target protein], enzymes [catalase, MMP inhibitor 1], and signaling molecules [Annexin 1, latent TGFb binding protein 1], among others. Several identified proteins specifically track with those YWBC cases with subsequent metastases. Furthermore, 8 unique proteins track with PPBC, including cartilage oligomeric matrix protein, a novel breast cancer biomarker that correlates with increased invasiveness, and decreased recurrence-free survival. EVs isolated from the plasma of newly diagnosed YWBC increase breast cancer invasion and EVs derived from breast cancer are engulfed by the majority of monocytic immune cells, including dendritic cells, classical and activated monocytes, but not by lymphocytes. Specifically, CD14+ monocytic myeloid derived suppressor cells engulfed the EVs while the CD15+ granulocytic subset did not. Once engulfed, phenotypic changes occurr in the EV containing monocytes and a significantly reduction in T cell stimulation in standard mixed-lymphocyte reactions is observed. Conclusion: EVs isolated from YWBC & PPBC cases have unique protein content and increase breast cancer invasiveness, which suggests potential mechanistic roles for EVs as increasing metastatic risk and provides novel candidate biomarkers. We identified an immunomodulatory effect of breast cancer EVs on human monocytes that may contribute to immunosuppression in breast cancer and a role for EVs as directly modulating the host and tumor microenvironment. Citation Format: Borges VF, Jordan KR, Hall JK, Schedin T, Hansen K, Schedin P. Extracellular vesicles from young women's and postpartum breast cancer display unique proteomic content, alter breast cancer aggressive behavior, and influence immune cell function [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-05.

Premenopausal patients with node-positive, hormone receptor-positive, early breast cancer derive benefit from extended endocrine therapy (EET) following 5 years of luteinizing hormone-releasing hormone (LHRH) agonist-based treatment. The benefit of EET may differ according to surrogate breast cancer subtypes in postmenopausal patients. To evaluate the risk of invasive and distant recurrence across all surrogate breast cancer subtypes among patients with node-positive, hormone receptor-positive early breast cancer who remained premenopausal after completing 5 years of adjuvant therapy with an LHRH agonist who received and did not receive EET. This multicenter cohort study conducted in the United States and Italy used data from 2 prospectively maintained datasets: the Young Women's Breast Cancer Study and the European Institute of Oncology Breast Cancer cohort. Eligible patients were diagnosed with early breast cancer at 40 years of age or younger between January 2005 and December 2016, had node-positive hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRH agonist therapy with no evidence of recurrence. Median (IQR) follow-up was 7.3 (4.9-10.3) years. Data were analyzed June 2025. EET (with tamoxifen monotherapy, LHRH agonist plus tamoxifen, or LHRH agonist plus aromatase inhibitor), irrespective of the duration of EET, measured at study baseline (defined as the first day of the sixth year after the initiation of adjuvant ET). Invasive breast cancer-free survival and distant recurrence-free survival (DRFS) distributions were estimated using the adjusted Kaplan-Meier method among patients with or without the exposure, weighted through propensity score (PS) weighting analysis, with the scientific approach. In total, 487 patients were included (median [IQR] age at diagnosis, 37 [35-39] years in the EET group and 37 [33-39] years in the no EET group), and 276 received EET for a median (IQR) duration of 3.7 (2.2-5.0) years. Overall, 89 patients (18%) had luminal A-like disease, 298 (61%) had luminal B-like disease, and 100 (21%) had ERBB2 (formerly HER2)-positive disease. The PS-weighted hazard ratio (HR) for invasive breast cancer-free survival comparing the EET with the no EET group was 0.68 (95% CI, 0.32-1.45) in luminal A-like, 0.63 (95% CI, 0.40-1.00) in luminal B-like/ERBB2-negative, and 0.62 (95% CI, 0.21-1.87) in ERBB2-positive subgroups. The cause-specific PS-weighted HR for DRFS was 0.25 (95% CI, 0.08-0.75) in luminal A-like, 0.54 (95% CI, 0.32-0.94) in luminal B-like/ERBB2-negative, and 0.54 (95% CI, 0.12-2.53) in ERBB2-positive subgroups. In this cohort study, a lower estimated risk with EET use was observed across all surrogate breast cancer subtypes. However, the lower estimated risk was greatest among patients with luminal A-like disease, a finding that warrants confirmation in larger, prospective cohorts.

PURPOSEThe 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor–positive (ER+) and human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles.METHODSThe Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2− breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node–negative (N0) and limited node–positive (N1) breast cancer.RESULTSAmong eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively.CONCLUSIONThe RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.

Little is known about how a breast cancer diagnosis and treatment affects job-related outcomes in young women with breast cancer, who are an integral part of the workforce. We sought to describe employment trends among young breast cancer survivors. 911 women with non-metastatic breast cancer were surveyed about employment-related outcomes 1 year post-diagnosis. Participants were enrolled in the Young Women's Breast Cancer Study an ongoing, multi-center cohort of women diagnosed with breast cancer at age ≤ 40. Among 911 women, median age at diagnosis was 36years (range 17-40). Most women (80%, n = 729) were employed 1 year post-diagnosis. Among the 7% (n = 62) employed before diagnosis but who reported unemployment at 1 year, approximately half reported they were unemployed for health reasons. Among employed women, 7% said treatment affected their ability to perform their job. Women with stage-three disease (vs. stage 1 disease, odds ratio (OR): 3.73, 95% CI 1.39-9.97) and those who reported having money to pay bills after cutting back or difficulty paying bills at baseline (vs. having enough money for special things, OR 2.70, 95% CI 1.32-5.52) at baseline were more likely to have transitioned out of the workforce. Our results suggest an impact of disease burden and socioeconomic status on employment in young breast cancer survivors. There is a need to ensure young survivors who leave the workforce following diagnosis are sufficiently supported given the potential adverse psychosocial and financial impacts of unemployment on survivors, their families, communities, and society.

Background: Prior studies have suggested a higher prevalence of high grade, ER-negative and HER2-positive tumors as well as basal-like carcinomas in young women with breast cancer; features that are associated with a more aggressive phenotype and decreased survival. However, studies are limited by small numbers among the very young (&amp;lt;35 years). Thus the distribution of poor prognostic features of breast cancers arising in young women remains unclear. We examined the clinical and pathologic features and biomarker expression patterns in relation to patient age in a large group of young women with invasive breast cancer.Design: The Young Women's Breast Cancer Study is an ongoing multi-center prospective cohort enrolling women with newly diagnosed breast cancer at age ≤ 40 years old. Medical records are reviewed for clinical characteristics, tumor stage and receptor status. HER2 positivity is defined as IHC 3+ or FISH amplified. Pathologic features are examined by central review, with detailed evaluation of phenotypic features associated with basal-like carcinomas. Univariate logistic regression models were used to evaluate the relationship to age, as a continuous variable and each clinico-pathologic feature.Results:The first 248 women for whom pathology has been reviewed (71% of participants enrolled to date) are included in this analysis. The table below presents the distribution of pathologic features by age group. There are no statistically significant differences in ER expression, PR expression or HER2 overexpression by age at diagnosis. Nor are the youngest women more likely to have higher stage or higher grade tumors. However, the youngest women are more likely to have pushing tumor margins and zones of tumor necrosis (p=0.03 and p=0.01 respectively).Clinico-pathologic Feature&amp;lt;30 years (n=27) (%)31-35 years (n=70) (%)36-40 years (n=151) (%)ER positive17 (63)47 (67)96 (64)PR positive15 (56)44 (63)90 (60)HER2 positive7 (26)26 (37)40 (27)Grade 316 (59)44 (63)80 (53)Poor stage5 (19)14 (20)27 (18)Ductal type22 (81)58 (83)132 (87)Fibrotic focus present12 (44)18 (26)51 (34)Tumor necrosis present14 (52)13 (19)38 (25)Prominent lymphocytic infiltrate8 (30)13 (19)36 (24)Pushing tumor margins11 (41)21 (30)36 (24) Conclusion:We find no differences in the distribution of poor prognostic features such as higher tumor stage, high tumor grade, ER/PR negativity or HER2 positivity among the very young. However, our study does indicate that the youngest women are significantly more likely to have tumors with pushing margins and zones of tumor necrosis, which are some of the morphologic features associated with the basal-like phenotype. Further research is warranted to evaluate the implication of these findings with regard to the etiology, treatment and prognosis of breast cancer in young women. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6007.

Background: Genetic counseling and fertility resources are often underutilized in young women with early stage breast cancer (ESBC) due, in part, to concerns about treatment delays. At our institution, women newly diagnosed with ESBC typically see a breast surgeon, medical oncologist and radiation oncologist in a multidisciplinary clinic with additional cancer related subspecialist referrals occurring at those providers' discretion. We hypothesized that time to treatment (TTT) and utilization of fertility, genetics and social work consultations would improve after implementing a Young Women's Breast Cancer Clinic. As of January 1, 2015, all patients under age 50 seen at Cleveland Clinic for new diagnosis of ESBC were automatically offered scheduling of appointments with medical genetics, reproductive endocrinology and social work in addition to the usual multidisciplinary team. Methods: Women under age 50 diagnosed with ESBC seen at Cleveland Clinic from 1/2014-12/2015 were identified using our tumor registry. Demographics, tumor pathology, clinical and treatment histories were obtained through medical chart review as per IRB approved protocol. Time from initial visit in our system to date of treatment initiation was calculated for all patients and compared between the 2014 (pre-intervention) and 2015 (post-intervention) cohorts as was time from diagnosis (biopsy date) to treatment initiation. Completed reproductive endocrinology, genetic counseling and social work consultations were documented. Welch two sample t-test was used to compare time to treatment between groups. Chi squared test was used to compare frequency of subspecialty consultations between groups. Results: 207 young women with ESBC were identified over the 2 year period, 99 in 2014 and 108 in 2015. Median age was 45 in 2014 and 44 in 2015. Most were diagnosed outside of our hospital system, 58% in 2014 and 76% in 2015. The most common initial treatment was surgery with reconstruction (S+R) (54% and 50% for 2014 and 2015 respectively) followed by chemotherapy (23% and 27%) then surgery without reconstruction (S) (20% and 24%). Median TTT from first encounter was 30 days in 2014 and 28 days in 2015 (p=0.33) and was 36 days versus 33.5 days (p=0.23) when calculated from biopsy date. TTT in the S and S+R groups was 37 vs 28 days (p=0.84) and 36.5 vs 32 days, (p=0.21), respectively. Genetics, reproductive endocrinology and social work consults in 2014 vs 2015 were documented as 89% vs 94%, 4% vs 9% and 58 vs% 55% (p=0.22, 0.32, 0.77). For patients under age 40, 27% in 2014 and 30% in 2015 completed reproductive endocrinology consultations. Conclusions: Offering upfront scheduling of breast cancer related subspecialty appointments for young women with newly diagnosed ESBC did not significantly improve overall TTT. There was a trend towards improved TTT in those receiving surgery with or without reconstruction as first treatment and no suggestion of delay in TTT. A modest numeric increase in completed genetic counseling and reproductive endocrinology consultations was not statistically significant, but may have been clinically meaningful for affected individuals. Citation Format: Kruse ML, Raska P, Abraham J, Budd GT, Montero A, Grobmyer S, Moore H. Impact of institution of young women's breast cancer clinic on time to treatment and utilization of fertility, genetics and social work consultations in women under age 50 with new diagnosis of early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-12-04.

Background: Women age 20-40 have a higher ten year risk for developing breast cancer than the five other leading cancers in this gender and age group combined. Women currently in their 30s have a 1/203 risk for breast cancer in the ensuing ten years. Cancers diagnosed in this age population of breast cancer have a higher risk for death for reasons that are not fully identified. Regulatory T cell (Tregs) and myeloid derived suppressor cells (MDSC) have a role in suppressing anti-tumor immunity. MDSC function through Jak/Stat pathway activation by generation of reactive oxygen species and/or arginase-1, and have been correlated pre-clinically with cancer progression and poorer prognostic features and outcomes. Our Young Women's Breast Cancer Translational Program seeks to identify immunologic differences potentially contributing to the poorer prognosis and potential targets for development of immunomodulatory treatment. Hypothesis: We hypothesized that newly diagnosed, treatment-naive young breast cancer cases would have higher percentage of circulating Tregs and MDSC with T cell suppressive function that similar age women without breast cancer. Methods: We conducted an IRB-approved, prospective translational study of women age 40 and under both affected and unaffected by breast cancer. Exclusion criteria included pregnancy, known autoimmunity or immunosuppressive medications, or other cancers. Tregs and MDSC were isolated from peripheral blood and phenotyped through standard protocols. The ability of MDSC to suppress T cell function were tested in co-culture assays for expression of activation marker CD25, production of gamma-interferon and production of arginase-1 and generation of reactive oxygen species. Results: As expected, Tregs were in higher number in young women with breast cancer than unaffecteds. Contrary to prior publications no difference was detected in number of MDSC identified in breast cancer (n=61) versus unaffected subjects (n=18). However, statistically significant increase in the MDSC ability to suppress T cell activation was identified in the breast cancer cohort with decreased CD25 expression and gamma-interferon production. MDSC from young women with breast cancer also secreted higher arginase-1 but not ROS from their MDSC. Level of MDSC suppression was independent of stage or biologic subtype of the breast cancer and did not correlate with the level of Tregs in the patient. Conclusions: The presence of equal rather than higher numbers of MDSC circulating in young onset breast cancer versus unaffected subjects was unexpected in comparison to prior publications. Our results may differ due to our larger sample size or the alignment by gender and age between the cohorts. Also, these are the first data on Tregs and MDSC to specifically focus on a young female population. Despite the equal numbers, MDSC from the breast cancer cohort demonstrated increased ability to suppress T cell function which was independent of cancer stage, biologic subtype or number of Tregs in the subject. These data suggest a functional difference to MDSC in the young breast cancer-bearing woman that could be exploited in even early stage breast cancer and that is not directly dependent on Tregs numbers. Moreover, the data indicate that unaffected young women have a higher than expected number of MDSC available for cancer to usurp and induce immune suppression. Identification of secretion of arginase-1 as a potential mechanism of immune suppression in young women's breast cancer warrants further investigation. Citation Format: Virginia F. Borges, Oscar Ramirez, Michelle Borakove, Elizabeth Manthey, Christina Finlayson, Anthony Elias, Martin McCarter, Kimberley Jordan, Jennifer Diamond, Nicole Kounalakis. Young women's breast cancer demonstrates increased immune suppression through ciculating regulatory T cells and myeloid-derived supressor cells independent of stage or subtype. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A98.

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age &lt; 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts &gt;5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p &lt; 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p &lt; 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous &lt;5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS). The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance. Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38years (range 18-40years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2years, 14 patients are alive with no recurrent disease. Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.

Breast cancer in young women: challenges, progress, and barriers.

Breast cancer in women aged younger than 35 years old comprises approximately 3 % of Japanese breast cancer patients [1]. Interestingly, the estimated breast cancer incidence in young women under 40 years of age is approximately 25 per 100,000 women be it in Japan or the USA or the European Union, whereas breast cancer incidence in all ages is higher in Western than in Asian countries [2]. Younger women with breast cancer are known to have worse prognoses than their older counterparts [3, 4]. The worse prognosis may be because greater numbers of younger women have tumors with poor clinicopathological features, i.e., more advanced TNM stage at presentation and more hormone receptor negative tumors as demonstrated in previous studies [1, 5]. The underlying biology of breast cancer in the young woman has yet to be fully elucidated. Association with age-related biological processes, such as pregnancy, parity, and breast-feeding, has been suggested to have prognostic impact in clinical and preclinical studies [6, 7, 8]. Adjuvant chemotherapy is used more frequently in young women than in older women [1], probably because of longer life-expectancy and better tolerability to aggressive treatments and documented survival advantages compared to women not treated with adjuvant therapy. Recently, the ATLAS and aTTom trials have demonstrated statistically significant superiority of adjuvant tamoxifen of 10 years duration compared to that of 5 years [9, 10]. Biases that ‘‘young women have worse prognosis’’ and the fear of the disease with its accompanying threat to life that it instils in patients as well as healthcare providers might lead to overuse of ‘‘one-size-fits-all’’ chemotherapy and endocrine therapy demonstrated to be of clinical benefit in randomized clinical trials. However, we have to be aware that this approach may well affect patient quality of life once a patient becomes a survivor. For example, treatmentrelated infertility is one of the major concerns of cancer patients of reproductive age [11]. In this issue of Breast Cancer, topics specific to breast cancer in young women were selected in the hope that readers might gain some insights into optimization of the care of the young breast cancer patient and future research needs for this group. Kataoka et al. [1] provide a crosssectional data analysis of breast cancer in young Japanese women by utilizing the database of the Japanese Breast Cancer Society. They confirm that younger women in Japan present with larger tumors, more advanced disease stage, and a greater proportion of triple negative and HER2? tumors. Suggestions for research to be developed and the results of formal prognostic analyses to help guide these efforts are awaited. Shien et al. [12] summarized the current status of fertility preservation in breast cancer patients in Japan. They provide a review of available options and a framework for clinical discussion with the patient. Regardless of family history, in Western countries, manifestation of breast cancer in younger women is utilized as a criterion for recommendation of genetic counseling [13]. Bando reviews the problems to be addressed and resolved in Japan, where clinical genetic services are still immature [14]. The issues of lack of data, social concerns, and availability of clinicians with good knowledge regarding genetics are noted. Finally and importantly, Takahashi warns that psychosocial distresses of young women with breast cancer extends beyond genuine physical medical issues [15]. C. Shimizu (&) Breast and Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Japan e-mail: cshimizu@ncc.go.jp