Second Primary Breast Cancer in Young Breast Cancer Survivors.

Importance: Among women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC. Objective: To estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC. Design, Setting, and Participants: Participants were enrolled in the Young Women's Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023. Main Outcomes and Measures: The 5- and 10- year cumulative incidence of SPBC. Results: In all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70). Conclusions: Findings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.

Conception and pregnancy among women with a live birth after breast cancer treatment: A survey study of young breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common malignancy in women of reproductive age. This study sought to explore the postcancer conception and pregnancy experience of young BC survivors to inform counseling. METHODS: In the Young Women's Breast Cancer Study (NCT01468246), a multicenter, prospective cohort, participants diagnosed at age ≤40 years with stage 0-III BC who reported ≥1 postdiagnosis live birth were sent an investigator-developed survey. RESULTS: Of 119 eligible women, 94 (79%) completed the survey. Median age at diagnosis was 32 years (range, 17-40) and at first postdiagnosis delivery was 38 years (range, 29-47). Most had stage I or II (77%) and HR+ (78%) BC; 51% were nulligravida at diagnosis. After BC treatment, most (62%) conceived naturally, though 38% used assisted reproductive technology, 74% of whom first attempted natural conception for a median of 9 months (range, 2-48). Among women with a known inherited pathogenic variant (n = 20), two underwent preimplantation genetic testing. Of 59 women on endocrine therapy before pregnancy, 26% did not resume treatment. Hypertensive disorders of pregnancy (20%) was the most common obstetrical condition. Nine percent of newborns required neonatal intensive care unit admission and 9% had low birth weight. CONCLUSION: Among women with live births after BC treatment, most conceived naturally and having a history of BC did not appear to negatively impact pregnancy complications, though the high rate of hypertensive disorders of pregnancy warrants further investigation. The prolonged period of attempting natural conception for some survivors suggests the potential need for improved understanding and counseling surrounding family planning goals after BC.

Genomics of ERBB2-Positive Breast Cancer in Young Women Before and After Exposure to Chemotherapy Plus Trastuzumab.

PURPOSE: Erb-B2 receptor tyrosine kinase 2 (ERBB2)-positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. METHODS: From a large prospective cohort of women age 40 years or younger with BC, we identified patients with ERBB2-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. RESULTS: Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples. CONCLUSION: ERBB2-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

Extended adjuvant endocrine therapy in a longitudinal cohort of young breast cancer survivors.

Extended adjuvant endocrine therapy (eET) improves outcomes in breast cancer survivors. Most studies however have been limited to postmenopausal women, and optimal eET for young survivors is uncertain. We report eET use among participants in the Young Women's Breast Cancer Study (YWS), a multicenter prospective cohort of women age ≤40 newly diagnosed with breast cancer enrolled between 2006-2016. Women with stage I-III hormone receptor-positive breast cancer, ≥6 years from diagnosis without recurrence were considered eET candidates. Use of eET was elicited from annual surveys sent years 6-8 after diagnosis, censoring for recurrence/death. 663 women were identified as eET candidates with 73.9% (490/663) having surveys eligible for analysis. Among eligible participants, mean age was 35.5 (±3.9), 85.9% were non-Hispanic white, and 59.6% reported eET use. Tamoxifen monotherapy was the most reported eET (77.4%), followed by aromatase inhibitor (AI) monotherapy (21.9%), AI-ovarian function suppression (AI-OFS) (6.8%) and tamoxifen-OFS (3.1%). In multivariable analysis, increasing age (per year odds ratio [OR]: 1.10, 95% confidence interval [CI]: 1.04-1.16), stage (II v. I: OR: 2.86, 95% CI: 1.81-4.51; III v. I: OR: 3.73, 95%CI: 1.87-7.44) and receipt of chemotherapy (OR: 3.66, 95% CI: 2.16-6.21) were significantly associated with eET use. Many young breast cancer survivors receive eET despite limited data regarding utility in this population. While some factors associated with eET use reflect appropriate risk-based care, potential sociodemographic disparities in uptake warrants further investigation in more diverse populations.

Patient perspectives on testing for clonal hematopoiesis of indeterminate potential.

Clonal hematopoiesis of indeterminate potential (CHIP), an emerging biomarker for personalized risk-directed interventions, is increased in cancer survivors. However, little is known about patient preferences for CHIP testing. We surveyed participants in a prospective cohort study of young women with breast cancer (BC). The emailed survey included an introduction to CHIP and a vignette eliciting participants' preferences for CHIP testing, considering sequentially: population-based 10-year risk of BC recurrence, hematologic malignancy, and heart disease; increased CHIP-associated risks; current CHIP management; dedicated CHIP clinic; and hypothetical CHIP treatment. Preference changes were evaluated using the McNemar test. The survey response rate was 82.2% (528/642). Median age at time of survey was 46 years and median time from diagnosis was 108 months. Only 5.9% had prior knowledge of CHIP. After vignette presentation, most survivors (87.1%) recommended CHIP testing for the vignette patient. Presented next with CHIP-independent, population-based risks, 11.1% shifted their preference from testing to not testing. After receiving information about CHIP-associated risks, an additional 10.1% shifted their preference to testing. Preference for testing increased if vignette patient was offered a CHIP clinic or hypothetical CHIP treatment, with 7.2% and 14.1% switching preferences toward testing, respectively. Finally, 75.8% of participants desired CHIP testing for themselves. Among participants, 28.2% reported that learning about CHIP caused at least moderate anxiety. Most young survivors favored CHIP testing, with preferences influenced by risk presentation and potential management strategies. Our findings highlight the importance of risk communication and psychosocial support when considering biomarkers for future risk in cancer survivors. This trial has been registered at www.clinicaltrials.gov as #NCT01468246.

Clinicopathologic Features, Treatment Patterns, and Disease Outcomes in a Modern, Prospective Cohort of Young Women Diagnosed with Ductal Carcinoma In Situ.

BACKGROUND: Ductal carcinoma in situ (DCIS) is uncommon and understudied in young women. The objective of this study is to describe clinicopathologic features, treatment, and oncologic outcomes in a modern cohort of women aged ≤ 40 years with DCIS. PATIENTS AND METHODS: Patients with DCIS were identified from the Young Women's Breast Cancer Study, a multisite prospective cohort of women diagnosed with stage 0-IV breast cancer at age ≤ 40 years, enrolled from 2006 to 2016. Clinical data were collected from patient surveys and medical records. Pathologic features were examined by central review. Data were summarized with descriptive statistics and groups were compared with χ2 and Fisher's exact tests. RESULTS: Among the 98 patients included, median age of diagnosis was 38 years; 36 (37%) patients were symptomatic on presentation. DCIS nuclear grade was high in 35%, intermediate in 50%, and low in 15% of lesions; 36% of lesions had comedonecrosis. The majority of patients underwent bilateral mastectomy (57%), 16 (16%) underwent unilateral mastectomy, and 26 (27%) underwent lumpectomy, most of whom received radiation. Few (13%) patients were receiving tamoxifen therapy 1 year postdiagnosis. Over a median follow-up of 8.4 years, six patients (6%) had disease recurrence, including five locoregional and one distant event. CONCLUSIONS: A high proportion of young women with DCIS underwent mastectomy with or without contralateral prophylactic mastectomy. Although DCIS was frequently symptomatic on presentation and exhibited unfavorable pathologic factors, clinicopathologic features were overall heterogeneous and few recurrences occurred. This underscores the need for careful consideration of treatment options in young women with DCIS.

Coping strategies and anxiety in young breast cancer survivors.

PURPOSE: We sought to describe coping strategies reported by young breast cancer survivors and evaluate the relationship between utilization of specific coping strategies and anxiety in survivorship. METHODS: Participants enrolled in The Young Women's Breast Cancer Study, a multi-center, cohort of women diagnosed with breast cancer at age ≤ 40 years, completed surveys that assessed demographics, coping strategies (reported at 6-month post-enrollment and 18-month post-diagnosis), and anxiety (2 years post-diagnosis). We used univariable and multivariable logistic regression to examine the relationship between coping strategies and anxiety. RESULTS: A total of 833 women with stage 0-3 breast cancer were included in the analysis; median age at diagnosis was 37 (range: 17-40) years. Social supports were the most commonly reported coping strategies, with the majority reporting moderate or greater use of emotional support from a partner (90%), parents (78%), other family (79%), and reliance on friends (88%) at both 6 and 18 months. In multivariable analyses, those with moderate or greater reliance on emotional support from other family (odds ratio (OR): 0.37, 95% confidence ratio (CI): 0.22-0.63) at 18 months were less likely to have anxiety at 2 years, while those with moderate or greater reliance on alcohol/drug use (OR: 1.83, 95%CI: 1.12-3.00) and taking care of others (OR: 1.90, 95%CI: 1.04-3.45) to cope were more likely to have anxiety. CONCLUSION: Young breast cancer survivors rely heavily on support from family and friends. Our findings underscore the importance of considering patients' social networks when developing interventions targeting coping in survivorship. CLINICAL TRIAL REGISTRATION NUMBER: NCT01468246 (first posted November 9, 2011).

Body weight changes and associated predictors in a prospective cohort of young breast cancer survivors.

BACKGROUND: Weight gain after a breast cancer diagnosis is common and is associated with inferior outcomes. Young survivors may be especially susceptible to weight changes given the impact of treatment on menopausal status. METHODS: The authors identified women who were diagnosed with stage 0 to III breast cancer at age 40 years or younger between 2006 and 2016 from a multicenter prospective cohort. Self-reported weight was collected at diagnosis and at 1 year and 3 years postdiagnosis. Tumor and treatment data were obtained from medical records and patient surveys. Multinomial logistic regression was used to identify the factors associated with weight gain (≥5%) or weight loss (≥5%) versus stable weight at 1 year and 3 years postdiagnosis. RESULTS: The cohort included 956 women with a median age of 37 years at diagnosis. Mean weight significantly increased over time from 66.54 ± 14.85 kg at baseline to 67.33 ± 15.53 and 67.77 ± 14.65 kg at 1 year and 3 years, respectively (p ≤ .001 for both comparisons). The proportion of women experiencing ≥5% weight gain increased from 24.8% at 1 year to 33.9% at 3 years. At 1 year, less self-perceived financial comfort, Black race, and stage III disease were significantly associated with weight gain; at 3 years, only less self-perceived financial comfort remained significant. Baseline overweight or obesity was significantly associated with weight loss at both time points. Chemotherapy, endocrine therapy, and treatment-related menopause were not associated with weight change. CONCLUSIONS: One third of young breast cancer survivors experienced clinically significant weight gain 3 years after diagnosis; however, treatment-related associations were not observed. Age-appropriate lifestyle interventions, including the reduction of financial barriers, are needed to prevent weight gain in this high-risk population.

Somatic and Germline Genomic Alterations in Very Young Women with Breast Cancer.

PURPOSE: Young age at breast cancer diagnosis correlates with unfavorable clinicopathologic features and worse outcomes compared with older women. Understanding biological differences between breast tumors in young versus older women may lead to better therapeutic approaches for younger patients. EXPERIMENTAL DESIGN: We identified 100 patients ≤35 years old at nonmetastatic breast cancer diagnosis who participated in the prospective Young Women's Breast Cancer Study cohort. Tumors were assigned a surrogate intrinsic subtype based on receptor status and grade. Whole-exome sequencing of tumor and germline samples was performed. Genomic alterations were compared with older women (≥45 years old) in The Cancer Genome Atlas, according to intrinsic subtype. RESULTS: Ninety-three tumors from 92 patients were successfully sequenced. Median age was 32.5 years; 52.7% of tumors were hormone receptor-positive/HER2-negative, 28.0% HER2-positive, and 16.1% triple-negative. Comparison of young to older women (median age 61 years) with luminal A tumors (N = 28 young women) revealed three significant differences: PIK3CA alterations were more common in older patients, whereas GATA3 and ARID1A alterations were more common in young patients. No significant genomic differences were found comparing age groups in other intrinsic subtypes. Twenty-two patients (23.9%) in the Young Women's Study cohort carried a pathogenic germline variant, most commonly (13 patients, 14.1%) in BRCA1/2. CONCLUSIONS: Somatic alterations in three genes (PIK3CA, GATA3, and ARID1A) occur at different frequencies in young versus older women with luminal A breast cancer. Additional investigation of these genes and associated pathways could delineate biological susceptibilities and improve treatment options for young patients with breast cancer. See related commentary by Yehia and Eng, p. 2209.

Perceptions of patients and medical oncologists toward biospecimen donation in the setting of abnormal breast imaging findings.

PURPOSE: We sought to understand the attitudes of individuals with abnormal breast imaging findings prompting a diagnostic breast biopsy toward donation of blood, excised tissue, or percutaneous biospecimens for research, and to understand medical oncologists' attitudes toward research biospecimen collection in this population. METHODS: We included individuals who presented to a single academic medical center for a clinically indicated, image-guided, percutaneous breast biopsy. We administered a survey prior to knowledge of biopsy results to assess willingness to consider, entirely for research purposes, donating blood or excess excised breast tissue, or having additional biospecimens (AB) obtained during a clinically indicated percutaneous biopsy. We also surveyed breast medical oncologists from National Cancer Institute-designated cancer centers to assess attitudes toward approaching patients for biospecimen research. RESULTS: Overall, 53/63 patients responded to the survey; 70% would consider donating blood, 85% would consider donating excess excised breast tissue, and 32% would consider having AB obtained during a clinically indicated biopsy. Main motivating factors for considering AB included contributing to scientific knowledge and return of study or biopsy results, whereas anxiety and the potential discomfort were the main dissuading factors. Among 191 medical oncologists, most were very comfortable (59.2%), or somewhat comfortable (32.5%) asking patients to have AB obtained during a clinically indicated breast biopsy. Medical oncologists reported hesitancy to refer a patient for AB due to potential pain/discomfort, and other procedure risks. CONCLUSIONS: Only one-third of individuals with breast imaging findings would consider consenting to AB during a diagnostic biopsy, whereas most were open to donating blood or excess excised breast tissue. Most medical oncologists would be comfortable asking patients to have AB obtained during the biopsy. Understanding patients' and oncologists' baseline attitudes may inform the design and approach to breast biospecimen-based research.

Clinicopathological features and BRCA1 and BRCA2 mutation status in a prospective cohort of young women with breast cancer.

BACKGROUND: Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status. METHODS: Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative. RESULTS: In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like). DISCUSSION: The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.

Trajectories of fear of cancer recurrence in young breast cancer survivors.

BACKGROUND: Fear of cancer recurrence (FCR) is more intense in younger women. Because FCR is a powerful determinant of quality of life, identifying those at risk for persistently elevated FCR can inform timing of interventions. METHODS: A total of 965 women with stage 0 to stage III breast cancer enrolled in the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with breast cancer at age ≤40 years, completed the 3-item Lasry Fear of Recurrence Index. Group-based trajectory modeling was used to classify distinct FCR patterns from baseline through 5 years post-diagnosis. Multinomial logistic regression was used to identify patient, disease, and treatment characteristics associated with each trajectory. RESULTS: Five FCR trajectories were identified with the majority of participants having moderate (33.1%) or high FCR (27.6%) that improved over time. A total of 6.9% participants had moderate FCR that worsened, whereas 21.7% had high FCR at baseline that remained high throughout. In the fully adjusted multinomial model, stages II and III (vs stage I) were associated with lower odds (of being in the high/stable trajectory). White (vs non-White) were associated with higher odds of being in a trajectory that improved over time. CONCLUSIONS: Although FCR improves over time for many young women with breast cancer, approximately one-third had FCR that was severe and did not improve or worsened over 5 years after diagnosis. Ongoing monitoring is warranted, with early referral to mental health professionals indicated for those at highest risk for unresolved FCR. LAY SUMMARY: Fear of recurrence is common among young women with breast cancer. The authors followed a large cohort of young women diagnosed with breast cancer when they were 40 years of age and younger, and found 5 distinct trajectories that show moderate and severe fears do not always improve over time and may require targeted mental health intervention.

Surgical Treatment After Neoadjuvant Systemic Therapy in Young Women With Breast Cancer: Results From a Prospective Cohort Study.

OBJECTIVE: We aimed to investigate eligibility for breast conserving surgery (BCS) pre- and post-neoadjuvant systemic therapy (NST), and trends in the surgical treatment of young breast cancer patients. BACKGROUND: Young women with breast cancer are more likely to present with larger tumors and aggressive phenotypes, and may benefit from NST. Little is known about how response to NST influences surgical decisions in young women. METHODS: The Young Women's Breast Cancer Study, a multicenter prospective cohort of women diagnosed with breast cancer at age ≤40, enrolled 1302 patients from 2006 to 2016. Disease characteristics, surgical recommendations, and reasons for choosing mastectomy among BCS-eligible patients were obtained through the medical record. Trends in use of NST, rate of clinical and pathologic complete response, and surgery were also assessed. RESULTS: Of 1117 women with unilateral stage I-III breast cancer, 315 (28%) received NST. Pre-NST, 26% were BCS eligible, 17% were borderline eligible, and 55% were ineligible. After NST, BCS eligibility increased from 26% to 42% (P < 0.0001). Among BCS-eligible patients after NST (n = 133), 41% chose mastectomy with reasons being patient preference (53%), BRCA or TP53 mutation (35%), and family history (5%). From 2006 to 2016, the rates of NST (P = 0.0012), clinical complete response (P < 0.0001), and bilateral mastectomy (P < 0.0001) increased, but the rate of BCS did not increase (P = 0.34). CONCLUSION: While the proportion of young women eligible for BCS increased after NST, many patients chose mastectomy, suggesting that surgical decisions are often driven by factors beyond extent of disease and treatment response.

Association of Local Therapy With Quality-of-Life Outcomes in Young Women With Breast Cancer.

Importance: Increasing rates of bilateral mastectomy have been most pronounced in young women with breast cancer, but the association of surgery with long-term quality of life (QOL) remains largely unknown. Objective: To examine the association of surgery with longer-term satisfaction and QOL in young breast cancer survivors. Design, Setting, and Participants: This multicenter cross-sectional study of a prospective cohort was conducted from October 2016 to November 2017, at academic and community hospitals in North America. Women 40 years or younger enrolled in the Young Women's Breast Cancer Study were assessed. Data analysis was performed from during a 1- to 2-year period after conclusion of the study. Exposures: Primary breast surgery, reconstruction, and radiotherapy. Main Outcomes and Measures: Mean BREAST-Q breast satisfaction and physical, psychosocial, and sexual well-being scores were compared by type of surgery; higher BREAST-Q scores (range, 0-100) indicate better QOL. Linear regression was used to identify demographic and clinical factors associated with BREAST-Q scores for each domain. Results: A total of 560 women with stage 0 to III breast cancer (median age at diagnosis, 36 years; range, 17-40 years; 484 [86%] with stage 0-II disease) completed the BREAST-Q a median of 5.8 years (range, 1.9-10.4 years) from diagnosis. A total of 290 patients (52%) of patients underwent bilateral mastectomy, 110 patients (20%) underwent unilateral mastectomy, and 160 patients (28%) received breast-conserving therapy. Among mastectomy patients, 357 (89%) had reconstruction and 181 (45%) received radiotherapy. In multivariate analyses, implant-based reconstruction (vs autologous) was associated with decreased breast satisfaction (ß = -7.4; 95% CI, -12.8 to -2.1; P = .007) and complex reconstruction (vs autologous) with worse physical well-being (ß = -14.0; 95% CI, -22.2 to -5.7; P < .001). Conclusions and Relevance: These results suggest that local therapy in young breast cancer survivors is persistently associated with poorer scores in multiple QOL domains, particularly among those treated with mastectomy and radiotherapy, irrespective of breast reconstruction. Socioeconomic stressors also appear to play a role.

Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update.

PURPOSE: This guideline updates recommendations of the ASCO guideline on chemotherapy and targeted therapy for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) that is either endocrine-pretreated or hormone receptor (HR)-negative. METHODS: An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS: The Expert Panel reviewed abstracts from the literature review and retained 14 articles. RECOMMENDATIONS: Patients with triple-negative, programmed cell death ligand-1-positive MBC may be offered the addition of immune checkpoint inhibitor to chemotherapy as first-line therapy. Patients with triple-negative, programmed cell death ligand-1-negative MBC should be offered single-agent chemotherapy rather than combination chemotherapy as first-line treatment, although combination regimens may be offered for life-threatening disease. Patients with triple-negative MBC who have received at least two prior therapies for MBC should be offered treatment with sacituzumab govitecan. Patients with triple-negative MBC with germline BRCA mutations previously treated with chemotherapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. Patients with HR-positive human epidermal growth factor receptor 2-negative MBC for whom chemotherapy is being considered should be offered single-agent chemotherapy rather than combination chemotherapy, although combination regimens may be offered for highly symptomatic or life-threatening disease. Patients with HR-positive MBC with disease progression on an endocrine agent may be offered treatment with either endocrine therapy with or without targeted therapy or single-agent chemotherapy. Patients with HR-positive MBC with germline BRCA mutations no longer benefiting from endocrine therapy may be offered a poly (ADP-ribose) polymerase inhibitor rather than chemotherapy. No recommendation regarding when a patient's care should be transitioned to hospice or best supportive care alone is possible.Additional information is available at www.asco.org/breast-cancer-guidelines.

Treatment-related amenorrhea in a modern, prospective cohort study of young women with breast cancer.

Young women with breast cancer experience unique treatment and survivorship issues centering on treatment-related amenorrhea (TRA), including fertility preservation and management of ovarian function as endocrine therapy. The Young Women's Breast Cancer Study (YWS) is a multi-center, prospective cohort study of women diagnosed at age ≤40, enrolled from 2006 to 2016. Menstrual outcomes were self-reported on serial surveys. We evaluated factors associated with TRA using logistic regression. One year post-diagnosis, 286/789 (36.2%) experienced TRA, yet most resumed menses (2-year TRA: 120/699; 17.2%). Features associated with 1-year TRA included older age (OR≤30vs36-40 = 0.29 (0.17-0.48), OR31-35vs36-40 = 0.67 (0.46-0.94), p = 0.02); normal body mass index (BMI) (OR≥25vs18.5-24. =0.59 (0.41-0.83), p < 0.01); chemotherapy (ORchemo vs no chemo = 5.55 (3.60-8.82), p < 0.01); and tamoxifen (OR = 1.55 (1.11-2.16), p = 0.01). TRA rates were similar across most standard regimens (docetaxel/carboplatin/trastuzumab +/- pertuzumab: 55.6%; docetaxel/cyclophosphamide +/- trastuzumab/pertuzumab: 41.8%; doxorubicin/cyclophosphamide/paclitaxel +/- trastuzumab/pertuzumab: 44.1%; but numerically lower with AC alone (25%) or paclitaxel/trastuzumab (11.1%). Among young women with breast cancer, lower BMI appears to be an independent predictor of TRA. This finding has important implications for interpretation of prior studies, future research, and patient care in our increasingly obese population. Additionally, these data describe TRA associated with use of docetaxel/cyclophosphamide, which is increasingly being used in lieu of anthracycline-containing regimens. Collectively, these data can be used to inform use of fertility preservation strategies for women who need to undergo treatment as well as the potential need for ovarian suppression following modern chemotherapy for young women with estrogen-receptor-positive breast cancer.Clinical trial registration: www.clinicaltrials.gov, NCT01468246.

Arm Morbidity After Local Therapy for Young Breast Cancer Patients.

BACKGROUND: The impact of patient demographics and local therapy choice on arm morbidity in young breast cancer patients is understudied despite its importance given the long survivorship period. This study assessed patient-reported arm morbidity in the Young Women's Breast Cancer Study (YWS), a prospective cohort study. METHODS: From 2006 to 2016, 1302 women with breast cancer diagnosed at the age of 40 years or younger enrolled in the YWS. The participants regularly complete surveys. The response rates are higher than 86%. Using the Breast Cancer Prevention Trial Checklist, this study examined the prevalence of patient-reported postoperative arm swelling and decreased range of motion (ROM) 1 year after diagnosis, stratified by local therapy strategy, in patients who had surgery for stages 1 to 3 disease. Logistic regression analysis was used to identify risk factors for arm morbidity. RESULTS: Among 888 eligible participants (median age, 37 years), 14% reported arm swelling and 34% reported decreased ROM at 1 year. Arm swelling was reported by 23.6% of the patients who had axillary lymph node dissection (ALND) and 24.6% of the patients who received ALND and post-mastectomy radiation therapy (PMRT). In the multivariable analysis, the patients who reported being financially uncomfortable or who had ALND were at higher risk of arm swelling at 1 year. Being overweight, receiving ALND after sentinel lymph node biopsy, and receiving PMRT were associated with decreased ROM at 1 year. CONCLUSION: High rates of self-reported arm morbidity in young breast cancer survivors were reported, particularly in patients receiving ALND and PMRT. Attention to the risks and benefits of differing local therapy strategies for ALND and PMRT patients is warranted.

Impact of fertility concerns on endocrine therapy decisions in young breast cancer survivors.

BACKGROUND: The diagnosis and treatment of breast cancer can have profound effects on a young woman's family planning and fertility, particularly among women with hormone receptor-positive breast cancer. METHODS: The Young Women's Breast Cancer Study was a multicenter cohort of women aged 40 years or younger and newly diagnosed with breast cancer from 2006 to 2016. Surveys included assessments of fertility concerns, endocrine therapy (ET) preferences, and use. Characteristics were compared between women who reported that fertility concerns affected ET decisions and those who did not. Logistic regression was used to identify factors associated with having an ET decision affected by fertility concerns. RESULTS: Of 643 eligible women with hormone receptor-positive, stage I to III breast cancer, one-third (213 of 643) indicated that fertility concerns affected ET decisions. In a multivariable analysis, only parity at diagnosis was significantly associated with fertility concerns affecting ET decisions (odds ratio for nulliparous vs ≥2 children, 6.96; 95% confidence interval, 4.09-11.83; odds ratio for 1 vs ≥2 children, 5.30; 95% confidence interval, 3.03-9.87). Noninitiation/nonpersistence was higher among women with fertility concerns versus those without fertility concerns (40% vs 20%; P < .0001). Among women with fertility-related ET concerns, 7% (15 of 213) did not initiate ET, and 33% (70 of 213) were nonpersistent over 5 years of follow-up. Of these women, 66% (56 of 85) reported 1 or more pregnancies or pregnancy attempts; 27% (15 of 56) had resumed ET at the last available follow-up through 5 years. CONCLUSIONS: Concern about fertility is a contributor to adjuvant ET decisions among a substantial proportion of young breast cancer survivors. Ensuring family planning is addressed in the setting of ET recommendations should be a priority throughout the cancer care continuum.

Tumor phenotype and concordance in synchronous bilateral breast cancer in young women.

PURPOSE: 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). METHODS: The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40 years. 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. RESULTS: Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38 years (range 18-40 years). 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 8.2 years, 14 patients are alive with no recurrent disease. CONCLUSIONS: 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.