Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

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.

Second primary non-breast cancers in young breast cancer survivors.

PURPOSE: We evaluated the incidence, timing, and risk factors for second primary non-breast cancers (SPNBC) among young breast cancer (BC) survivors. METHODS: This study included participants of the Young Women's BC Study (YWS) who were diagnosed with stage 0-III BC between 2006 and 2016 and age 40 or younger at diagnosis (N = 1,230). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor and treatment data were obtained from medical record review. Five- and 10-year risks of SPNBCs were estimated via the cumulative incidence function, considering death, metastasis, or second primary BC as competing events. Fine and Gray subdistribution hazard models estimated subdistribution hazard ratios (sHRs) and 95% confidence intervals (CI) for SPNBC risk based on risk factors including demographics, germline genetics, primary BC characteristics, and treatments. RESULTS: Among 1,230 women, over a median follow-up of 10.1 years, 47 patients (4%) developed an SPNBC. Types of malignancy included melanoma (n = 10), thyroid (n = 10), ovarian (n = 4), sarcoma (n = 4), uterine (n = 3), rectal (n = 3), bladder (n = 2), cervical (n = 2), head/neck (n = 2), lung (n = 2), lymphoma (n = 2), pancreatic (n = 2), and renal (n = 1). Five and 10-year cumulative incidence were 1.4% and 3.2%, respectively. Median time between primary BC and SPNBC was 7.3 years. No patient factors, primary tumor characteristics, or treatments were statistically significantly associated with SPNBC in univariable or multivariable models. CONCLUSION: In this population, five-year cumulative incidence was higher than that reported among healthy women under 50 years of age, highlighting the importance of long-term surveillance for new non-breast cancers in young adult BC survivors.

Patterns of treatment and outcomes of patients with brain-only metastatic breast cancer.

BACKGROUND: We characterized the risk factors and survival of metastatic breast cancer (MBC) patients with brain metastases (BrM) as the first and only site of disease in a large, retrospective cohort. METHODS: MBC patients treated for BrM with radiation at a quaternary institution between 2005 and 2019 were identified. MBC patients with BrM but without concurrent extracranial metastases (ECM) or leptomeningeal disease (LMD) were classified as brain-only. Factors associated with brain-only MBC, brain-specific progression free survival (bsPFS) and overall survival (OS) were investigated. RESULTS: A total of 691 patients with MBC and BrM were analyzed. Among them, 67 patients (9.7%, n = 67/691) presented with brain-only MBC without concurrent ECM/LMD. Within this subgroup, 40 patients (5.8%, n = 40/691) remained free of any ECM or LMD, while 17 patients (2.5%) developed LMD, and 10 patients (1.4%%) developed ECM with a median follow-up of 8 months (IQR 2-35). Patients with brain-only MBC were more likely to have a single BrM [OR 3.41 (1.62-7.19), p = 0.001] and either HER2+ [OR 3.3 (1.13-9.65), p = 0.03] or TNBC [OR 4.09 (1.42-11.74), p = 0.009] subtypes. Patients who presented with brain-only MBC also had significantly longer OS [HR 0.45, (0.22-0.86), p = 0.008] and a trend toward longer bsPFS [HR 0.67 (0.44-1.03), p = 0.05] compared to those with concurrent ECM/LMD. CONCLUSION: Patients with brain-only MBC had a longer bsPFS and OS than those with ECM. Patients with HER2+ and TNBC were more likely to have brain-only disease compared to those with HR+/HER2- MBC.

American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline.

Answer questions and earn CME/CNE The purpose of the American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline is to provide recommendations to assist primary care and other clinicians in the care of female adult survivors of breast cancer. A systematic review of the literature was conducted using PubMed through April 2015. A multidisciplinary expert workgroup with expertise in primary care, gynecology, surgical oncology, medical oncology, radiation oncology, and nursing was formed and tasked with drafting the Breast Cancer Survivorship Care Guideline. A total of 1073 articles met inclusion criteria; and, after full text review, 237 were included as the evidence base. Patients should undergo regular surveillance for breast cancer recurrence, including evaluation with a cancer-related history and physical examination, and should be screened for new primary breast cancer. Data do not support performing routine laboratory tests or imaging tests in asymptomatic patients to evaluate for breast cancer recurrence. Primary care clinicians should counsel patients about the importance of maintaining a healthy lifestyle, monitor for post-treatment symptoms that can adversely affect quality of life, and monitor for adherence to endocrine therapy. Recommendations provided in this guideline are based on current evidence in the literature and expert consensus opinion. Most of the evidence is not sufficient to warrant a strong evidence-based recommendation. Recommendations on surveillance for breast cancer recurrence, screening for second primary cancers, assessment and management of physical and psychosocial long-term and late effects of breast cancer and its treatment, health promotion, and care coordination/practice implications are made.

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.

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.

Risk of recurrence and pregnancy outcomes in young women with breast cancer who do and do not undergo fertility preservation.

PURPOSE: To assess the impact of fertility preservation (FP) requiring ovarian stimulation on breast cancer outcomes and pregnancy after breast cancer. METHODS: Women aged ≤ 40 years diagnosed with stage I-III breast cancer between 2007 and 2018 and referred for FP consultation prior to systemic therapy were identified from a British Columbia fertility center database. The primary endpoint was invasive breast cancer-free survival (iBCFS) and secondary endpoints were overall survival (OS) and achievement of pregnancy. Survival and pregnancy endpoints were compared using Cox and logistic regression analyses, respectively, for patients who did and did not undergo FP. RESULTS: The study included 153 patients, with 71 (46%) in the FP group and 82 (54%) in the non-FP group. Patients who underwent FP were more likely to be ECOG 0 (99% vs. 88%, p = 0.011) and receive chemotherapy (93% vs. 67%, p < 0.001), but had similar ER positivity status to non-FP patients (70% vs. 79%, p = 0.21). Over a median follow-up of 4.1 years, there were no differences in iBCFS (HR 1.006, 95% CI 0.416-2.438, p = 0.988) or OS (HR 0.789, 95% CI 0.210-2.956, p = 0.725) between FP and non-FP groups. Patients who underwent FP had higher odds of conceiving at least once (OR 3.024, 95% CI 1.312-6.970, p = 0.008). CONCLUSION: At a median follow-up of 4.1 years, FP did not impact iBCFS or OS, supporting its safety in young women with breast cancer. In addition, patients who underwent FP were more likely to become pregnant after breast cancer, highlighting the value of pre-oncologic treatment FP in survivorship family planning.

Risk factors for psychological morbidity and the protective role of coping self-efficacy in young women with breast cancer early in diagnosis: a national multicentre cohort study.

PURPOSE: Young women with breast cancer (YWBC) are an understudied population and there are limited data on risk factors for psychological morbidity early in diagnosis. We examined psychological morbidity (anxiety, depression, stress symptoms), well-being and associated risk factors. METHODS: A total of 845 women from a pan-Canadian, multicentre inception cohort study of YWBC (age ≤ 40) who completed Patient Reported Outcome Measures (PROMs) after their initial surgical consultation and prior to surgical or other treatments were included. Multivariate regression analyses identified risk factors (i.e. parenting young children) associated with psychological morbidity and whether coping self-efficacy was protective. RESULTS: Rates of clinically significant anxiety (n = 683, 69.1%) and depression (n = 422, 42.7%) were high but lower for stress symptoms (n = 67, 6.8%). Probability of anxiety was high for women with a previous history of depression (OR 2.02, P = 0.03, CI 1.09-3.74) and working full-time (OR 1.76, P = 0.05 CI 1.02-2.77). Whereas, pre-existing depression (OR 2.91, P = 0.01, CI 1.36-6.01), younger children (age ≤ 10) (OR 1.69, P = 0.05, CI 1.01-2.93), and income > $100,000 (OR 2.06, P = 0.02, CI 1.18-3.64) were risk factors for depression. Coping self-efficacy was protective with a decreased risk of anxiety (OR 0.11, P ≤ 0.01 CI 0.04-0.28), depression (OR 0.03, P ≤ .01, CI 0.01-0.16), stress symptoms (OR 0.17, P ≤ .01, CI 0.04-0.65) and higher psychosocial well-being with a gain of 19.68 points (P < 0.01) for high levels of CSE (> mean plus 1 SD). Those with lower levels of neurosis had less negative outcomes. CONCLUSION: Young women with breast cancer are vulnerable to psychological morbidity early in diagnosis, particularly those with low coping self-efficacy and may benefit from earlier supportive care.

Surgeon and Patient Reports of Fertility Preservation Referral and Uptake in a Prospective, Pan-Canadian Study of Young Women with Breast Cancer.

BACKGROUND: Prompt referral by their surgeon enables fertility preservation (FP) by young women with breast cancer (YWBC) without treatment delay. Following a FP knowledge intervention, we evaluated surgeon and patient reports of fertility discussion, FP referral offer and uptake, and FP choices and reasons for declining FP among patients enrolled in the Reducing Breast Cancer in Young Women, prospective pan-Canadian study. METHODS: Between September 2015 and December 2020, 1271 patients were enrolled at 31 sites. For each patient, surgeons were sent a questionnaire inquiring whether: (1) fertility discussion was initiated by the surgical team; (2) FP referral was offered; (3) referral was accepted; a reason was requested for any "no" response. Patients were surveyed about prediagnosis fertility plans and postdiagnosis oncofertility management. RESULTS: Surgeon questionnaires were completed for 1068 (84%) cases. Fertility was discussed with 828 (84%) and FP consultation offered to 461 (47%) of the 990 YWBC with invasive disease. Among the 906 responding YWBC, referral was offered to 220 (82%) of the 283 (33%) with invasive disease who stated that they had definitely/probably not completed childbearing prediagnosis. Of these, 133 (47%) underwent FP. The two most common reasons for not choosing FP were cost and unwillingness to delay treatment. CONCLUSIONS: Although the rates of surgeon fertility discussion and FP referral was higher than most reports, likely due to our previous intervention, further improvement is desirable. FP should be offered to all YWBC at diagnosis, regardless of perceived childbearing intent. Cost remains an important barrier to FP uptake.

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.

Trastuzumab emtansine increases the risk of stereotactic radiosurgery-induced radionecrosis in HER2 + breast cancer.

INTRODUCTION: In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS). METHODS: Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA). RESULTS: 67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2 year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2 Gy fractions (EQD2) > 90 Gy2 (HR 2.4, 95% CI 1.1-5.1, p = 0.02) as predictors of RN. Patients treated with T-DM1 and SRS had a 29.9% (95% CI 15.3-44.6%) probability of RN, with a 25.2% (95% CI 12.8-37.6%) risk at 1- and 2 years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8 months. CONCLUSION: T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

Couplelinks online intervention for young couples facing breast cancer: A randomised controlled trial.

OBJECTIVE: Young women with breast cancer and their partners are more distressed than couples who are affected later in life. While dyadic interventions in the context of cancer are promising, there are access barriers, particularly for younger couples. This study evaluated Couplelinks, a professionally facilitated, web-based program designed to help couples improve their conjoint coping. METHOD: This randomised controlled trial employed a waitlist control evaluation of the program. Outcomes included dyadic coping, relationship adjustment, depression, and anxiety. RESULTS: Seventy-five couples consented to participate and were randomised. The final analysis included 31 couples in the treatment group and 36 couples in the waitlist group. Modest improvements were found in positive dyadic coping but effects were not maintained at 3-month follow-up. No effect was seen on overall relationship adjustment. CONCLUSIONS: Our findings inform the rapidly expanding field of online programming for couples in general, and those affected by BC in particular. Intervention timing, 'dose', low overall relational distress, and the mainly enrichment rather than problem-focus of Couplelinks may help explain the lack of change on relationship adjustment.

Patients' and Oncologists' Knowledge and Expectations Regarding Tumor Multigene Next-Generation Sequencing: A Narrative Review.

BACKGROUND: Tumor multigene next-generation sequencing (NGS) is increasingly being offered to cancer patients to guide clinical management and determine eligibility for clinical trials. We undertook a review of studies examining the knowledge and attitudes of patients and oncologists regarding the primary results and potential secondary findings of such testing. MATERIALS AND METHODS: A search was conducted through the MEDLINE database using the following keywords: "neoplasms" and "molecular sequencing / genome sequencing / tumor profiling / NGS / whole exome sequencing" and "patient / oncologist" and "knowledge / attitudes / satisfaction / experience / evaluation / perspective / practice / preference." Articles meeting the inclusion criteria and additional relevant articles from their references were selected. RESULTS: From 1,142 publications identified by the search and 9 from references, 21 publications were included in the final review. Patients generally had positive attitudes toward tumor NGS despite relatively little knowledge of test-related genetics concepts, but their expectations often exceeded the reality of low clinical utility. Patients with higher education and greater genetics knowledge had more realistic expectations and a more altruistic view of the role of NGS. Attitudes toward disclosure of secondary findings were highly variable. Oncologists had poor to moderate genomic literacy; they communicated challenges with tempering patient expectations and deciding what information to disclose. CONCLUSION: Patients considering undergoing tumor NGS should be provided with easily understandable resources explaining the procedure, goals, and probable outcomes, whenever possible based on evidence-based guidelines. Continuing medical education programs on this topic for oncology health care professionals should strive to improve their genomic literacy and instruct them on how to optimally present this information to their patients. IMPLICATIONS FOR PRACTICE: Oncologists are increasingly offering tumor multigene testing to patients with advanced cancers to guide more "personalized" treatment and/or determine eligibility for clinical trials. However, patients often have inadequate understanding and unrealistic expectations. Oncologists must ensure that they themselves have sufficient knowledge of the benefits and limitations of testing and must provide their patients with appropriate educational resources. Prior to testing, patients should be told the likelihood of finding a mutation in their specific tumor type for which a targeted treatment or clinical trial is available. Patients also need clear information about the possibility and implications of secondary findings.

Treatment Patterns and Outcomes of Women with Symptomatic and Asymptomatic Breast Cancer Brain Metastases: A Single-Center Retrospective Study.

BACKGROUND: Breast cancer is the most common cancer among women worldwide and the second leading cause of brain metastases (BrM). We assessed the treatment patterns and outcomes of women treated for breast cancer BrM at our institution in the modern era of stereotactic radiosurgery (SRS). MATERIALS AND METHODS: We conducted a retrospective analysis of women (≥18 years of age) with metastatic breast cancer who were treated with surgery, whole brain radiotherapy (WBRT), or SRS to the brain at the Sunnybrook Odette Cancer Centre, Toronto, Canada, between 2008 and 2018. Patients with a history of other malignancies and those with an uncertain date of diagnosis of BrM were excluded. Descriptive statistics were generated and survival analyses were performed with subgroup analyses by breast cancer subtype. RESULTS: Among 683 eligible patients, 153 (22.4%) had triple-negative breast cancer, 188 (27.5%) had HER2+, 246 (36.0%) had hormone receptor (HR)+/HER2-, and 61 (13.3%) had breast cancer of an unknown subtype. The majority of patients received first-line WBRT (n = 459, 67.2%) or SRS (n = 126, 18.4%). The median brain-specific progression-free survival and median overall survival (OS) were 4.1 months (interquartile range [IQR] 1.0-9.6 months) and 5.1 months (IQR 2.0-11.7 months) in the overall patent population, respectively. Age >60 years, presence of neurological symptoms at BrM diagnosis, first-line WBRT, and HER2- subtype were independently prognostic for shorter OS. CONCLUSION: Despite the use of SRS, outcomes among patients with breast cancer BrM remain poor. Strategies for early detection of BrM and central nervous system-active systemic therapies warrant further investigation. IMPLICATIONS FOR PRACTICE: Although triple-negative breast cancer and HER2+ breast cancer have a predilection for metastasis to the central nervous system (CNS), patients with hormone receptor-positive/HER2- breast cancer represent a high proportion of patients with breast cancer brain metastases (BrM). Hence, clinical trials should include patients with BrM and evaluate CNS-specific activity of novel systemic therapies when feasible, irrespective of breast cancer subtype. In addition, given that symptomatic BrM are associated with shorter survival, this study suggests that screening programs for the early detection and treatment of breast cancer BrM warrant further investigation in an era of minimally toxic stereotactic radiosurgery.

Clinical outcomes and prognostic biomarkers among pregnant, post-partum and nulliparous women with breast cancer: a prospective cohort study.

PURPOSE: To compare clinical-pathologic characteristics and outcomes of pregnancy-associated, post-partum (PP) and nulliparous (NP) breast cancer (BC) patients and explore mediators of the poor prognosis associated with post-partum BC. METHODS: A prospective database of 233 women ≤ 40 years of age diagnosed with BC between February 2008 and January 2015 was analysed. Clinical-pathologic characteristics and outcomes among pregnant, PP and NP patients were compared using chi-square or Kruskal-Wallis tests. The Kaplan-Meier method was used to estimate disease-free survival (DFS), distant DFS and overall survival (OS). Survival curves were compared using the log-rank test. Univariable Cox proportional hazards regression models were used to evaluate factors that were potentially prognostic for the clinical outcomes of interest; a multivariable Cox model was constructed using a forward stepwise selection process. Androgen receptor (AR), GATA3, PDL1 status and the presence/absence of tumour-infiltrating lymphocytes (TILs) were assessed when possible. Pre-treatment neutrophil and lymphocyte counts were abstracted retrospectively. Statistical significance was defined as a p value ≤ 0.05. RESULTS: Women ≤ 2 years PP had a numerically higher incidence of lymph node-positive and high-grade disease and were significantly more likely to have estrogen receptor-negative BC compared to NP controls. With a median follow-up of 7.2 years, increasingly poor outcomes were observed among NP (longest OS), > 2 years PP, ≤ 2 years PP and pregnant (shortest OS) patients, but these differences were not statistically significant. The ≤ 2 years PP group had significantly lower AR expression, a strong trend toward higher PDL1 expression and a higher expression of stromal TILs compared to NP women. CONCLUSIONS: PPBC patients had numerically lower DFS and OS compared to NP controls. Higher PDL1 and stromal TILs in PPBC suggest that adjuvant immunotherapy may be effective in the post-partum BC subgroup.

Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population.

PURPOSE: CompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC. METHODS: Patients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL). RESULTS: Overall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment. CONCLUSION: Safety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2- ABC. TRIAL REGISTRATION: linicalTrials.gov NCT02941926.

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.

Response to neoadjuvant chemotherapy and the 21-gene Breast Recurrence Score test in young women with estrogen receptor-positive early breast cancer.

PURPOSE: The 21-gene Breast Recurrence Score test predicts benefit from adjuvant chemotherapy in estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer (BC). We examined whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NCT). METHODS: We identified patients with stage I-III ER+/HER2- BC treated with NCT from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤40 years. The 21-gene assay was performed on tumor specimens removed prior to NCT either as part of clinical care or retrospectively for research. Pathological complete response (pCR) was defined as ypT0/is ypN0. The relationship between Recurrence Score result and pCR was evaluated using logistic regression modeling. RESULTS: 76 women received NCT for ER+/HER2- BC and were eligible for this analysis. Median age at diagnosis was 37 years (range 24-40). Scores ranged between 5 and 77 with 50% >25 and 5% <11. Median Recurrence Score result was significantly higher among tumors achieving pCR vs. non-pCR response (61.5 vs. 23, pwilcoxon = 0.0005). pCR rate in patients with scores >25 was 21% (8/38) vs. 5% in patients with scores <25 (2/38) (p = 0.09), with both pCRs in the <25 group in patients with scores between 21 and 25. In multivariable analysis, only Recurrence Score result was significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01). CONCLUSIONS: In young women with ER+/HER2- BC who received NCT, higher pretreatment Recurrence Score result was associated with an increased likelihood of pCR. Gene expression profile assays may have a role in decision making in young women in need of neoadjuvant therapy.

Reproductive concerns and fear of cancer recurrence: a qualitative study of women's experiences of the perinatal period after cancer.

BACKGROUND: Young female cancer survivors are at a disproportionate risk of suffering significant psychological distress following treatment, particularly fears of cancer recurrence (FCR). While previous research has established the robust relationship between FCR and family matters (e.g., family planning and motherhood), there is a paucity of information about how a history of cancer affects women's psychological functioning throughout the perinatal period. The present investigation sought to better understand women's experiences of pregnancy and the postpartum period following cancer treatment through a qualitative analysis. METHODS: Ten women participated in a semi-structured, one-on-one interview either over telephone or video conferencing (Zoom). Women were recruited from Sunnybrook Health Sciences Centre in Toronto, as well as through online cancer support platforms, and social media sites. Participants all had a past cancer diagnosis; no active disease; were 45-years of age or younger; currently in the perinatal period; and spoke English fluently. The study employed a grounded theory analysis by which verbatim interview data were analysed using a constant comparison method until data saturation was reached. RESULTS: The qualitative analysis yielded I'm So Happy, But Also Terrified, as the core category, indicative of the duality of emotional experience that characterized the perinatal period for these women. Additionally, four higher-order categories emerged revealing how women go through a process of grief related to potential fertility loss; conditional joy during and after pregnancy due to the lingering weight of cancer; frustration with a lack of resources regarding perinatal health after cancer; and hope as they enter into motherhood. CONCLUSION: These results suggest that women in the perinatal period with a history of cancer may be at an increased risk for psychological distress and require additional fertility and reproductive resources both during and after cancer treatment. This research is an important step in further understanding women's experiences of pregnancy after cancer and may help to inform future research and healthcare practices, in addition to improving perinatal care after cancer.