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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.).

Background: Breast cancer (BC) is the most common malignancy among women of reproductive age. Given limited data describing the conception and pregnancy experience of young BC survivors, we sought to explore these outcomes to inform counseling of women interested in future childbearing. Methods: Participants with stage 0-III BC in the Young Women’s Breast Cancer Study (NCT01468246), a multi-center, prospective cohort of women diagnosed at age ≤ 40 from 2006-2016 who reported ≥ 1 live birth from a pregnancy after diagnosis were sent a survey with investigator-developed questions focused on their first post-diagnosis live birth. Women who had been diagnosed with BC during pregnancy were excluded from this analysis. The survey assessed conception, use of assisted reproductive technology (ART), pre-implantation genetic testing (PGT), endocrine therapy (ET), and peripartum complications. Summary statistics are presented. Results: 92/119 eligible women completed the survey (response rate: 77%). Median age at diagnosis was 32 (range:17-40) years and at delivery was 37 (range: 29-47) years. Median time from diagnosis to delivery was 58 months (range: 11-154). Most women had stage 2 BC (43%, 40/92); 68% received chemotherapy (63/92); about half (51%, 47/92) were nulligravida at diagnosis. Overall, 61% of pregnancies were conceived naturally (56/92) and 39% with ART (36/92): 32% by in-vitro fertilization (IVF, 29/92), 7% with fertility medications only (6/92), and 1 with intrauterine insemination. 38% of IVF pregnancies were conceived using products from fertility preservation prior to BC treatment (11/29). Among women who used ART, 74% attempted to conceive naturally (25/36) for a median of 9 (range: 2-48) months prior to pursuing ART. The most common reasons for pursuing ART include infertility following BC treatment (33%, 12/36) and expediting conception to resume treatment (17%, 6/36). 11% of those with known inherited pathologic variant mutations underwent PGT (2/19). Reasons for not pursuing PGT included belief in more effective cancer risk reduction in the future (29%, 5/17), not being offered PGT (24%, 4/17), high cost (12%, 2/17), no interest in IVF (12%, 2/17), acceptable odds for inheriting the mutation (24%, 4/17), and belief in other risk reduction strategies (18%, 3/17); 1 woman reported ethical concerns. Of 57 women who took ET pre-pregnancy (63%), nearly all (96%, 55/57) discontinued ET > 3 months prior to attempting to conceive; 1 discontinued after awareness of pregnancy. Of those who had received prior ET, 60% resumed ET (34/57) a median of 3 (range: 1-50) months after pregnancy. Among 23 women who did not resume, 13 (23%) had completed the recommended duration; the remaining 10 reported one or more of the following reasons: felt better while off (28%, 6/23), desire for another child (22%, 5/23), and desire to breastfeed (17%, 4/23). Median time to delivery was 39 (range: 28-42) weeks with 12% delivering preterm < 37 weeks (11/92). 47% had a Caesarean section (43/92), with prolonged labor the most common indication (33%, 14/43). Hypertensive disorders of pregnancy (HDP, 20%, 18/92), gestational diabetes (7%, 6/92), small for gestational age (7%, 6/92), and postpartum hemorrhage (5%, 5/92) were the most common obstetrical complications. 9% of women had newborns requiring NICU admission (8/92) and 9% had low birth weight (8/92). Conclusion: Among young BC survivors with a live birth following diagnosis, most conceived naturally, with the majority who used ART first attempting natural conception. There was limited use of PGT among mutation carriers with ¼ not having been offered testing. Patient reported peripartum complications appear consistent with population norms, though the relatively higher rate of HDP bears further research. Among those yet to complete their ET, a notable proportion did not resume following delivery. This novel data may help to inform the care of young breast cancer survivors pursuing pregnancy. Citation Format: Kimia Sorouri, Tal Sella, Shoshana Rosenberg, Margaret Loucks, Kathryn Ruddy, Shari I. Gelber, Rulla M. Tamimi, Jeffrey M. Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Ellen Warner, Ann Partridge. Conception and Pregnancy Among Young Breast Cancer Survivors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-05.

Background: Pregnancy after breast cancer (BC) is of substantial importance for many young women at diagnosis and during follow-up. BC treatment including standard endocrine therapy (ET) (5-10 years) may reduce ovarian reserve and the chances of subsequent successful pregnancy, given conception is contraindicated during ET. A temporary interruption of ET to attempt and carry a pregnancy in this population has never been prospectively studied. Methods: POSITIVE is a single-arm, prospective, investigator-initiated, international trial evaluating the safety and pregnancy outcomes of interrupting ET for young women with early-stage hormone-receptor-positive (HR+) BC who desire pregnancy. The primary objective is to assess the risk of BC relapse associated with ET interruption for ~2 years to achieve pregnancy. Women ≤42 years with stage I-III HR+ BC who received adjuvant ET (SERM alone, GnRH analogue plus SERM or AI) for 18 to 30 months and wished to interrupt ET to attempt pregnancy were eligible. The primary endpoint is breast cancer free interval (BCFI) defined as the time from enrollment to the first BC event (local, regional, distant recurrence or a new invasive contralateral BC). Planned sample size was 500 patients. Three interim analyses of BCFI were reviewed by the Data Safety Monitoring Committee (DSMC) to assure a 95% chance of stopping the trial early if the annual BCFI event rate exceeded 4%; with primary analysis triggered after 1600 patient years of follow-up (pyfu) and no more than 46 BCFI events defined as the safety threshold. The DSMC recommended continuing the study following each interim analysis. We now report the primary results. Results: From 12/2014 to 12/2019, 518 women were enrolled. At enrollment, the median age of participants was 37 years (27-43 years); 75.0% were nulliparous, 93.4% had stage I/II disease, 66.3% node-negative. Median time from BC diagnosis to enrollment was 29 months (IQR: 25-32). Tamoxifen alone was the most prescribed ET (41.7%), followed by tamoxifen+ovarian function suppression (35.7%). 62.0% of participants had received neo/adjuvant chemotherapy. At a median follow-up of 41 months (1638 pyfu), 44 participants had experienced a BCFI event, not exceeding the pre-specified safety threshold of 46 events. The 3-year BCFI failure percent was 8.9% (95% CI: 6.3 to 11.6%), similar to the 9.2% (95% CI: 7.6 to 10.8%) calculated in the comparative external control cohort from the SOFT/TEXT trials (Sun et al, Breast 2020). Of 497 women followed for pregnancy status, 368 (74.0%) had at least one pregnancy, 317 (63.8%) had at least one live birth, with a total of 365 babies born. Based on competing risk analysis, 76.3% of patients resumed ET (half within 26 months), 8.3% had BCFI event/death before ET resumption, and 15.4% had not resumed ET yet. Conclusions: The POSITIVE trial demonstrates that for young women with early HR+ BC desiring pregnancy, temporary interruption of ET to attempt pregnancy does not confer a greater short-term risk of recurrence than that observed in a modern historical control group that did not interrupt ET. Most participants have had a live birth. Further follow-up is planned to confirm long-term safety. These results should be considered in counselling BC patients desiring future pregnancy. Citation Format: Ann Partridge, Olivia Pagani, Samuel M. Niman, Monica Ruggeri, Fedro Alessandro A. Peccatori, Hatem A. Azim, Marco Colleoni, Cristina Saura, Chikako Shimizu, Anna Saetersdal, Judith Kroep, Audrey Mailliez, Ellen Warner, Virginia F. Borges, Frédéric Amant, Andrea Gombos, Akemi Kataoka, Christine Rousset-Jablonski, Simona Borstnar, Junko Takei, Jeong Eon Lee, Janice Walshe, Manuel Ruiz Borrego, Halle Moore, Christobel Saunders, Vesna Bjelic-Radisic, Snezana Susnjar, Fatima Cardoso, Karen L. Smith, Teresa Ferreiro Vilarino, Karin Ribi, Kathryn Ruddy, Sarra El-Abed, Martine Piccart, Larissa A. Korde, Aron Goldhirsch, Richard D. Gelber. Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE breast cancer: Primary Results from the POSITIVE Trial (IBCSG 48-14/BIG 8-13) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-09.

Background: Breast cancer (BC) is the most common malignancy in women of reproductive age, and the incidence of the disease is rising in this population. Many of these women are interested in childbearing after their BC treatment and a substantial minority will go on to have a live birth. Some will also want to breastfeed. However, there is only limited information available regarding the experience of young BC survivors breastfeeding following treatment. Methods: Participants in the Young Women’s Breast Cancer Study (YWS), a multi-center, prospective cohort study of women diagnosed with BC at age ≤ 40 years between 2006-2016, who reported at least one live birth following their diagnosis with stage 0-III BC were sent an additional survey including investigator-developed questions focused on breastfeeding after breast cancer treatment. Women who had been diagnosed with BC during pregnancy were excluded from this analysis. The survey assessed whether they breastfed, reasons for attempting and stopping breastfeeding, breastfeeding with the treated breast and untreated breast, and supports. Summary statistics, including medians and proportions, are presented. Results: Of 118 eligible women sent a survey, 92 completed the survey (78% response rate). Median age at diagnosis of BC was 32 (range: 17-40) years and at delivery was 37 (range: 29-47) years. 54% of women had attempted to breastfeed (50/92). Among those who had not, 93% noted a history of bilateral mastectomies (39/42). Additional reasons for not attempting to breastfeed included no interest regardless of BC history (5%, 2/42) and 1 woman underwent a unilateral mastectomy and did not think her supply would be sufficient. Among the women who did attempt breastfeeding, 68% had undergone lumpectomy and radiotherapy (34/50) with 85% of those women reporting that the treated breast did not produce milk (29/34). The 5 women who produced milk from the treated breast noted that the supply was substantially less than the untreated breast. To assist with breastfeeding, 76% used a pump only on the untreated breast (38/50) and 14% on both breasts (7/50). Women breastfed for a median of 5.5 (range:< 1-60) months and 64% were “somewhat”/“very much” satisfied with their ability to breastfeed (32/50). The most common reasons cited for stopping breastfeeding included having completed the planned duration (36%, 18/50), to start/resume endocrine therapy (22%, 11/50), and to resume breast imaging (8%, 4/50). Among patients who had not undergone a double mastectomy, 47% recalled receiving specific information about breastfeeding after a history of breast cancer (25/53), most commonly from the oncology team (56%, 14/25), lactation consultant (48%, 12/25), or online resources (44%, 11/25). Conclusion: In the largest series to date detailing the breastfeeding experiences of young BC survivors, approximately half of young BC survivors with a successful pregnancy attempted to breastfeed. Among those who had undergone prior lumpectomy and radiotherapy, women reported no milk production or only limited supply from the treated breast. Despite these limitations, most women who attempted to breastfeed were satisfied with their ability to do so. Specific resources to support the experience of breastfeeding in BC survivors are needed. Citation Format: Tal Sella, Kimia Sorouri, Shoshana Rosenberg, Margaret Loucks, Kathryn Ruddy, Shari I. Gelber, Rulla M. Tamimi, Jeffrey M. Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Ellen Warner, Ann Partridge. Breastfeeding in Survivors of Early Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-06.

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

Supplementary Table from 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

Supplementary Figure from Somatic and Germline Genomic Alterations in Very Young Women with Breast Cancer

Background: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines.Methods: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality.Results:BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P < 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P < 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening.Conclusions: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history.Impact: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40. Cancer Epidemiol Biomarkers Prev; 21(9); 1458–68. ©2012 AACR.

PDF file - 99K, Transitions in the MISCAN model. From each pre-clinical stage, a tumor may be clinically diagnosed or may grow into the next pre-clinical stage. By applying screening, the tumor may be detected by screening.

Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown.To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia.A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated.The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004).Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

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.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.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.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.

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Background: The incidence of brain metastases (BrM) has steadily increased over time as women with metastatic breast cancer (MBC) live longer and survive to experience spread of cancer to the central nervous system (CNS). Women with triple negative and HER2+ MBC, which represent 30-40% of the MBC population, are at particularly high risk of BrM. At present, MBC patients are not screened for BrM; rather, they undergo imaging of the brain only after symptoms suggestive of CNS involvement develop. Unfortunately, by the time that patients experience potentially debilitating symptoms of BrM, they often have a significant burden of disease with limited treatment options and a poor prognosis. We hypothesize that early detection of BrM via magnetic resonance imaging (MRI)-based screening may allow for early intervention and, ultimately, improved outcomes for MBC patients. Methods: A multi-centre, open-label prospective phase II study, randomizing 50 women with triple negative or HER2+ MBC to either MRI-based BrM screening or symptom-directed surveillance. Randomization is stratified for tumor subtype. Intervention arm: Contrast-enhanced MRI of the brain at baseline, 4-, 8- and 12-months with concurrent chemical exchange saturation transfer (CEST) imaging, a new metabolic MRI sequence that may detect BrM even earlier than standard MRI. Control arm: Symptom-directed surveillance (brain imaging only if patients develop symptoms suggestive of BrM). All participants complete questionnaires at baseline, 6- and 15-months to assess overall (EORTC QLQ BN20) and neurologic-specific (FACT-BR tools) quality of life (QoL) as well as cancer-related anxiety (NCI PRO-CTCAE). A blood sample is collected for ctDNA analysis at baseline in all patients at diagnosis of BrM, if applicable. Key inclusion criteria: 1) Age ≥18; 2) Triple negative MBC, with metastatic disease diagnosed ≤12 weeks prior to study entry OR HER2+ MBC with no restrictions regarding timeline of diagnosis; 3) No symptoms of BrM or known asymptomatic BrM at study entry. Key exclusion criteria: 1) ECOG>2; 2) Inability to complete an MRI (e.g., claustrophobia). Analyses: The primary goal of this study is to determine the feasibility of a randomized trial of BrM screening versus symptom-directed surveillance in the proposed patient population. The pilot study will be considered “not feasible” if 50% of patients allocated to the control arm are screened for BrM with CT or MRI. Overall survival will be assessed as a secondary endpoint. We will also investigate how screening for BrM influences the detection rate of BrM and explore how subsequent intervention affects both overall and neurologic-specific QoL. Our data will enable a power calculation to determine a sample size for a future, larger trial. 28 of 50 planned patients have enrolled in the study to-date. Citation Format: Katarzyna J Jerzak, Arjun Sahgal, Gregory Pond, Priscilla K Brastianos, Orit Freedman, Gregory Stanisz, Ellen Warner. MRI screening versus symptom-directed surveillance for brain metastases among patients with triple negative or HER2+ metastatic breast cancer: A pilot study (nct03881605) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-07-01.

Background: Chemotherapy (CTx) and hormone therapy may impair fertility in women with breast cancer (BC) by direct gonadotoxicity or delayed childbearing. Inconsistent data regarding the safety and efficacy of ovarian stimulation for fertility preservation (FP) in BC may limit clinician referral and patient uptake of FP. We previously examined the effect of FP on BC recurrence and herein present updated survival and pregnancy outcomes in relation to FP from an expanded BC cohort. Methods: Women aged ≤ 40 years diagnosed with stage I-III BC between 2007-2018 referred to one of six cancer centres and to a reproductive endocrinologist in British Columbia, Canada were identified from a central database. Clinicopathologic, treatment and outcome characteristics were compared using uni/multivariate Cox and logistic regression analyses for survival and pregnancy outcomes, respectively, for patients who did and did not undergo FP prior to systemic cancer treatment. Results: 158 patients were identified. Sixty-four (41%) had lymph node involvement, 119 (75%) had ER-positive and 39 (25%) had HER2-positive BC. The 72 (46%) patients who underwent FP were more likely to be younger (mean age 33 vs 34 y, p=0.030), ECOG 0 (p=0.013), have CTx (p0.05). After a median follow-up of 4.7 years, BC recurrence occurred in 15 (17%) non-FP patients and 9 (13%) FP patients (Table 1). FP did not affect overall survival by univariate (HR 0.9; 95% CI 0.7-1.3) or multivariate analysis controlling for age, BMI, ECOG/ER/HER2 status, tumor stage and receipt of CTx or radiation (HR 1.0, 95% CI 0.7-1.4). Post-diagnosis, 22 (31%) FP patients and 11 (13%) non-FP patients had ≥ 1 pregnancy (Table 2). The use of assisted reproductive technology (ART) was similar in both groups. Patients who had FP were 2.8 times more likely (p=0.013) to conceive at least once. The results remained significant on multivariate analysis controlling for age, BMI, ECOG status and baseline parity (p=0.030). Non-FP patients had a 31% higher miscarriage rate than those who did (p=0.26). Conclusions: FP was not associated with an increased risk of locoregional recurrence, distant recurrence or death over a follow-up period of 3-11 years, supporting its safety in young women with BC. Despite more often receiving CTx, patients who underwent FP were significantly more likely to conceive after BC than those who did not, even when accounting for differences in patient profiles. This may relate to greater use of GnRH agonists during CTx, known to protect ovarian function, and stronger desires for future childbearing in patients who pursued FP. Although there was similar use of ART in both groups, the higher pregnancy rate and more successful reproductive outcomes in FP patients support the value and promotion of pre-oncologic treatment FP in young BC patients early in their disease trajectory, to enhance survivorship family planning. Table 1.Survival outcomes of patients.CharacteristicNo FP (n=86)FP (n=72)p-valueRecurred [n (%)]0.85Locoregional6 (7)4 (6)Distant9 (10)5 (7)Deceased [n (%)]8 (9)4 (6)0.38 Table 2.Characteristics of first pregnancies in patients conceiving after diagnosis.CharacteristicNo FP (n=11)FP (n=21)p-valuePregnancy outcome [n (%)]0.26Completed3 (27)11 (52)Miscarriage7 (64)7 (33)Ongoing1 (9)3 (14)Pregnancy interval from diagnosis [n (%)]0.29≤ 2 y04 (19)2-5 y8 (73)13 (62)> 5 y3 (27)4 (19)Type of conception [n (%)]0.52Natural9 (82)15 (71)Assisted2 (18)6 (29) Citation Format: Megan E Tesch, Ying Wang, Chloe Lim, Ying Hui Xu, Shaina Lee, Kirstin Perdrizet, Dan Yokom, Ellen Warner, Jeffrey Roberts, Caroline Lohrisch. Impact of ovarian stimulation for fertility preservation in young women with breast cancer: Updated survival and pregnancy outcomes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-08.

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.

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.

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.

Background Limited knowledge exists on outcomes of children exposed prenatally to chemotherapy for breast cancer (BC). The purpose of this study was to compare long-term neurocognitive, behavioral, developmental, growth, and health outcomes of children exposed in-utero to chemotherapy for BC. Methods This is a multi-center matched cross-sectional cohort study involving seven cancer centers across the region of Southern Ontario (Canada), and the Hospital for Sick Children (Toronto, Ontario). Using standardized psychological and behavioral tests, we compared cognitive and behavioral outcomes in children exposed to chemotherapy during pregnancy for BC to age-matched pairs exposed to known non-teratogens. Results We recruited 17 parent-child pairs and their matched controls. There were more preterm deliveries in the chemotherapy-exposed group compared to controls (p, Highlights • Limited knowledge exists on outcomes of children exposed prenatally to chemotherapy for breast cancer (BC). • We compared cognitive and behavioral outcomes in children exposed to chemotherapy during pregnancy for BC to controls. • FSIQ of children in the chemotherapy group was significantly confounded by prematurity. • Chemotherapy was not found to be neurotoxic and did not affect pediatric health. • Pediatric implications of planned preterm birth for further treatment should be considered.

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. 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. 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. 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.

International audience; Purpose: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocar-ditis) may present similarly and/or overlap with other cardiac pathology including acute cor-onary syndrome presenting a challenge for prompt clinical diagnosis.Methods: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery steno-sis >70% in patients undergoing coronary angiogram.Results: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coro-nary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coro-nary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revas-cularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was margin-ally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057).Conclusion: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diag-nosis and treatment or more severe presentation of ICB-myocarditis.

Introduction: Approximately 5% of breast cancers are diagnosed in women 40 years of age or younger. Known risk factors for young-onset breast cancer are few and can only account for a very small proportion of cases. In this study, we evaluated the contribution of mutations in 24 breast cancer predisposition genes in unselected Canadian women diagnosed with breast cancer at age 40 or younger. Methods: This study is a sub-study of the larger Reducing the bUrden of Breast cancer in Young women (RUBY) Study. In the RUBY study, women diagnosed with breast cancer at the age of 40 years or younger are recruited at the time of diagnosis from 33 centres across Canada. Participants in RUBY provided detailed demographic and clinical data, in addition to provision of serial biospecimens. Participants could elect to consent into the genetics substudy, and have genetic testing performed for pathogenic variants in 24 breast cancer predisposition genes, including ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, STK11, TP53 and XRCC2. Sequencing was performed and all potentially pathogenic variants were confirmed with conventional Sanger sequencing. Pathogenic and likely pathogenic mutations were reported for all 24 genes. CanRisk scores for likelihood of having a pathogenic variant in 8 cancer predisposition genes (BRCA1 BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D, and BRIP1) were generated for each participant. Results: 714 women consented and genetic testing was performed on the blood samples provided as a component of the RUBY study. The mean age of the participants was 35.8 years (range 23-40 years), and the mean CanRisk score was 13.7 (range 2.3-98.0). Overall, 150 pathogenic mutations (21.0%) were detected in 147 women (three participants had mutations in two genes). The most common pathogenic variants detected were in BRCA1 (48), BRCA2 (40), CHEK2 (24), ATM (10), and PALB2 (9), representing 87.3% of all pathogenic variants identified. The mean CanRisk score was 28.8% (range 3.2-98.0%) for those identified with a pathogenic variant compared to 9.6% (range 1.0-88.9%) for those with a negative result (p < 0.0001). The prevalence of pathogenic variants was 32.9% for women age 20-30 years, 27.5% for 31-35 years, and 16.7% for 36-40 years. Conclusions: Twenty-one percent of women with breast cancer at age 40 or younger had a pathogenic variant in a breast-cancer predisposition gene. The great majority of these pathogenic variants were found in genes (BRCA1, BRCA2, CHEK2, PALB2) for which there are validated breast cancer treatment recommendations. All women with young-onset breast cancer should be offered germline genetic testing at the time of breast cancer diagnosis to make informed surgical and medical treatment decisions. Citation Format: Kelly Metcalfe, May Lynn Quan, Steven Narod, Ellen Warner, Christine Friedenreich, Nancy Baxter, Aletta J. Poll, Mohammad Akbari. Prevalence of Pathogenic Variants in Cancer Predisposition Genes in Women with Young Onset Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-07.

Background: For patients with ABC being treated with CDK4/6is palliative (RT may still be necessary to metastatic sites that are symptomatic or at risk for complications. Although preclinical data suggests synergy between CDK4/6is and RT, clinical data regarding the safety of this combination are conflicting, with some reports of increased toxicity in the radiation field. Our aim was to review the practice regarding holding CDK4/6is during RT and subsequent clinical outcomes at the cancer centre with the largest volume of ABC patients in Canada. Methods: Chart review was completed for 313 ER positive and Her2 ABC pts treated with CDK4/6is at the Sunnybrook Health Sciences Centre from 2016 to 2020. All patients who received RT during the course of treatment with CDK4/6is were included in this analysis. Greater than expected toxicity events were defined as higher than grade 1 non-hematological toxicity as per Common Terminology Criteria for Adverse Events during RT or in the 30 days post RT. Descriptive statistics were used for demographics and treatment outcomes. Results: Fifty patients received RT to 74 different sites during treatment with CDK4/6is (46 palbociclib and 4 ribociclib). Median age was 56 (41-88) years. Most frequent RT sites were: bone (n=51), brain (n=7), lung (n=4), breast (n=4) and liver (n=3). CDK4/6is were held during RT of 55 sites (37 patients), starting a median of 7 (0-43) days prior to first fraction of RT and restarted a median of 7 (0-71) days after completing the RT. A CDK4/6i was administered concomitantly with RT to 19 sites (15 patients). No greater than expected toxicity was observed in patients for whom the CDK4/6i was held during RT. Among patients who received concomitant treatment, we observed 4 non-hematological adverse events (21%) in organs included in the field of radiation. In combination with palbociclib we observed grade 3 colitis after 30 Gy to hip/pelvis bones, grade 2 esophagitis after 30 Gy to C1-C4 vertebrae and grade 2 enteritis after 30 Gy to the upper femur. In combination with ribociclib one patient developed grade 3 hepatitis after 20Gy to T10-L2 vertebrae. Conclusions: This retrospective observational study of 50 patients with advanced ER positive Her2 negative BC treated with CDK4/6is who received palliative RT demonstrated a high rate of radiation toxicity (21%) in those patients for whom the CDK4/6i was given concurrently. Quality improvement work in this area, including practice guidelines, is warranted. Citation Format: Neda Stjepanovic, Alia Thawer, Dilshad Nathoo, Danilo Giffoni, Maria Romero, Anthony Lott, Andrea Eisen, Rossanna Pezo, Katarzyna Jerzak, Maureen Trudeau, Sonal Gandhi, Ellen Warner. Radiation therapy (RT) induced toxicity in advanced breast cancer (ABC) patients treated with CDK4/6 inhibitors (CDK4/6is) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-20.

Background: For Hormonal Receptor positive/HER2 negative (HR+/HER2-) metastatic Breast Cancer (mBC) the optimal treatment post-progression on a CDK4/6 inhibitor is still not defined. We aim to identify real-world patterns of systemic treatment choice following palbociclib use at a large tertiary cancer centre and to determine the outcomes for this patient population. Methods: We identified HR+/HER2- mBC patients treated with palbociclib between January 2016 and June 2020 using the institutional computerized prescriber order entry (CPOE) system. Patients with a 2nd primary other than breast, male, or with HER 2 overexpression were excluded. Electronic medical records were retrospectively reviewed to determine clinical, pathological characteristics, and treatment patterns. Our primary outcome was Time to Treatment Failure (TTF) for the subsequent treatment, using the Kaplan Meier survival method. Results: A total of 136 patients were included. At first diagnosis the median age was 52 years; 52% were premenopausal, the most prevalent primary tumor features were ductal histology (79%), and lymph node positive disease (54%). Regarding initial treatment 77% underwent surgery, 52% had adjuvant radiation therapy, 61% had chemotherapy (CT) and 67% had endocrine therapy (ET). The most frequent metastatic sites were bone 70%, liver 36%, and lung 33%. 63 tumors were rebiopsied, in 21 (33.3%) biomarkers had changed. Palbociclib was indicated as 1 Line in 45% of patients, 2 Line 26%, and ≥ 3 Line 27%. The most tolerated dose was 75 mg (44% v 33% tolerating 125 mg). The most prescribed endocrine backbones were AI (66%) and fulvestrant (30%). mTTF was 29.9 mo. (95%CI 12.68-47.11) for 1L, 33.2 mo. (95%CI 22.45-44.08) for 2L, 7.03 mo. (95%CI 2.29-11.76) for ≥ 3L. After a median follow-up of 18.7 mo, 74 patients (54%) had discontinued palbociclib due to progression (46%), toxicity (5%), or death (4%). Sites of progression were liver 37%, bone 29%, pleura 11%, lung 10% and peritoneum 6.5%. 63 patients had subsequent systemic therapy, with mTTF of 5.6 mo. 46 patients (34%) received chemotherapy, 29 patients had capecitabine, mTTF was 4.8 mo. 13 patients (9%) received endocrine therapy, 9 patients had fulvestrant +/- others, mTTF was 8.9 mo. For 5 patients (4%) the subsequent treatment was CDKi-based, 4 patients continued with palbociclib plus another endocrine backbone, mTTF was 16.5 mo. Only 1 patient (.7%) received everolimus-based subsequent treatment, with a TTF 5.6 mo. Conclusion: In this real-world analysis, we found that palbociclib was most tolerated at 75 mg and most prescribed with an AI. After progression on CDKi, the tendency was to prescribe a chemotherapy-based subsequent line, mainly capecitabine. Citation Format: Maria Luisa Romero Lagunes, Faisal Sickandar, Alia Thawer, Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni M. M. Mata, Abdullah MA Al-Humiqani, Anthony Lott, Rossanna C Pezo. Single-centre retrospective study of treatment choices and outcomes of metastatic breast cancer post-progression on the CDK4/6 inhibitor palbobiclib [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-54.

Background: Pregnancy is a major concern for young breast cancer (BC) survivors. Conception after BC in women with hormone receptor positive (HR+) disease is affected by the standard 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may be waning. The POSITIVE Trial (IBCSG 48-14/BIG 8-13/Alliance A221405/NCT02308085) investigates the impact of temporary ET interruption to allow pregnancy. Methods: POSITIVE enrolled premenopausal women with stage I-III HR+ early BC, ≤42 years of age, who had received adjuvant ET (SERM alone, ovarian function suppression (OFS) plus SERM or AI) for 18 to 30 months, and wished to interrupt ET to attempt pregnancy. An interruption of ET for up to 2 years was foreseen to allow pregnancy (after a 3-month ET washout period), delivery, and breastfeeding if desired/feasible. Resumption of ET to complete 5-10 years of treatment was planned as soon as pregnancy/breastfeeding was completed or after it was ensured conception was not possible. We report baseline characteristics of participants enrolled in POSITIVE by region of enrollment. Results: From 12/2014 to 12/2019, 518 participants were enrolled at 116 centers in 20 countries across 4 continents. The table shows the baseline characteristics of the enrolled women. Several differences were seen across regions: A higher proportion of participants Conclusion: Regional variation of baseline characteristics of women enrolled in the POSITIVE trial may provide important insights into different medical and sociocultural attributes and attitudes of the study participants and investigators from those regions. Affiliation: POSITIVE Investigators, International Breast Cancer Study Group, Alliance for Clinical Trials in Oncology, Breast International Group, North American Breast Cancer Group CharacteristicRegion: Europe / North America / Asia-Pacific61% / 23% / 16%Median age at enrollment, yrs (IQR)37 (33-39)Caucasian race77%No children prior to enrollment74%Prior fertility preservation measures taken51%Stage I / II46% / 45%0 / 1 positive nodes65% / 21%Grade 2 / 348% / 33%HER2-negative74%Mastectomy46%Chemotherapy61%ET: SERM alone / SERM+OFS / AI+OFS41% / 35% / 16%Median duration of prior ET, mos (IQR)23 (20-27) Citation Format: Ann H Partridge, Samuel M Niman, Monica Ruggeri, Fedro A Peccatori, Hatem A Azim, Jr, Marco Colleoni, Cristina Saura, Chikako Shimizu, Anna Barbro Sætersdal, Judith Kroep, Ellen Warner, Virginia F Borges, Andrea Gombos, Akemi Kataoka, Christine Rousset-Jablonski, Simona Borstnar, Hideko Yamauchi, Jeong Eon Lee, Janice M Walshe, Manuel Ruíz Borrego, Halle CF Moore, Christobel Saunders, Fatima Cardoso, Snezana Susnjar, Vesna Bjelic-Radisic, Karen L Smith, Martine Piccart, Larissa A Korde, Aron Goldhirsch, Richard D Gelber, Olivia Pagani. Baseline characteristics of women enrolled in the POSITIVE trial (pregnancy outcome and safety of interrupting therapy for women with endocrine responsIVE breast cancer) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-17.

Background: Pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) is associated with improved survival outcomes among women with HER2 positive (HER2+) breast cancer. We aimed to analyze the clinical, pathological and molecular factors associated with pCR in our series of HER2+ breast cancer patients. Methods: Between 2009 and 2019, breast cancer patients receiving NAC at our centre were enrolled in a prospective database. For this study we selected women with HER2+ unilateral breast cancer stages II or III who received anthracycline-taxane NAC regimens (with trastuzumab given concurrently with the taxane) and subsequently underwent breast and axillary surgery with curative intent. Medical charts of these 161 women were retrospectively reviewed to determine what clinical, pathological and molecular characteristics were associated with pCR using bivariate and multivariate analysis. Results: Of the 161 HER2+ women median age at diagnosis was 49 years (range 25-78) with 90 (56%) women under age 50. Total of 104 (65%) tumors were stage II, 108 (67%) expressed estrogen and/or progesterone receptors, 139 (86%) had HER2 3+ expression by immunohistochemistry (IHC) and 22 (14%) had HER2 IHC 2+ expression with amplified HER2 on fluorescence in situ hybridization (FISH) test. The NAC regimens were: Doxorubicin-Cyclophosphamide-Paclitaxel for 83 (52%) and Fluorouracil-Epirubicin-Cyclophosphamide-Docetaxel for 78 (48%) women. A total of 73 patients [45%; 44/108 HR+ (41%) and 29/53 HR- (55%)] achieved pCR (p=0.94). pCR rate among HER2 IHC 3+ tumors was 69/139 (50%), while for HER2 IHC 2+ tumors was 4/22 (18%). On bivariate analysis HER2 IHC 3+, absence of estrogen receptors and absence of progesterone receptors were predictive of pCR, while age, menopausal status, histologic subtype, tumor grade and NAC regimen were not. In the multivariate model only HER2 IHC 3+ expression remained a significant predictor of pCR (OR =4.443, 95% CI 1.376 - 14.344). Conclusion: Our analysis suggests that for HER2+ breast cancers treated with NAC with anthracycline-taxane and trastuzumab, HER2 IHC 3+ expression is associated with a higher rate of pCR compared to HER2 IHC 2+ expression with FISH amplification. Further analysis in a larger cohort is warranted. Citation Format: Neda Stjepanovic, Katarzyna Jerzak, Maureen Trudeau, Andrea Eisen, Sonal Gandhi, Ellen Warner, Danilo Giffoni MM Mata, Anthony Lott, Maria Romero, Sharon Lemon-Wong, Althea VanMassop, Xingshan Cao, William Tran, Rossanna Pezo. Analysis of factors associated with pathological complete response (pCR) in patients with HER2+ breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-33.

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 NAC influences surgical decisions in young women. METHODS The Young Women's Breast Cancer Study (YWS), 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 (cCR and pCR), 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), cCR (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 choose mastectomy, suggesting that surgical decisions are often driven by factors beyond extent of disease and treatment response.

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).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).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 GyT-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

To assess the impact of fertility preservation (FP) requiring ovarian stimulation on breast cancer outcomes and pregnancy after breast cancer.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.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).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.

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 ≤ 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. 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. 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.

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). 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. 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% 25 was 21% (8/38) vs. 5% in patients with scores

KEY POINTS Breast cancer is the most common cancer in Canadian women, including those of reproductive age.[1][1] About 50% of women aged 40 years or younger in developed countries currently diagnosed with breast cancer have not yet completed their families, possibly because of delayed childbearing.[

Background: The steady decline in breast cancer (bca) mortality has come at the cost of increasingly toxic and expensive adjuvant therapies. Trials evaluating the addition of 2 or 3 years of cyclin-dependent kinase 4/6 (cdk4/6) inhibitors to adjuvant endocrine therapy (et) are ongoing, but the willingness of patients to take such additional therapy is unknown. Methods: We surveyed 100 consecutive postmenopausal women with nonmetastatic estrogen receptor–positive bca who had initiated adjuvant et within the preceding 2 years. Participants were asked about perceived recurrence risk, bca worry, and overall health. They were then asked about their willingness to accept 2 years of treatment with an additional oral drug that would reduce recurrence by 40% for a range of baseline recurrence risks in 2 hypothetical scenarios. Results: Mean age of the 99 evaluable participants was 61.7 years. In the scenario with no drug toxicity, 85% of respondents were likely to accept the new drug for a reduction in recurrence to 30% from 50%, but only 49% would take the drug if risk was reduced to 3% from 5%. In a scenario with drug-induced fatigue, the corresponding drug acceptance rates were 55% and 39% respectively. For the second scenario, bca worry was correlated with increased willingness to take the drug, even for only a 2% absolute reduction in recurrence risk. Conclusions: The willingness of patients with estrogen receptor–positive bca to take an adjuvant cdk4/6 inhibitor will greatly depend on the expected benefit and toxicities described to them as well as on worry about bca recurrence.

Background: Young patients with breast cancer (BC) are often diagnosed before completing their families. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcomes overall and in patients with endocrine responsive disease, and is safe for the offspring. However, given also the possibility of extended adjuvant endocrine therapy (ET) (5-10 years), it is not feasible for many of these women to delay pregnancy until completion of therapy. Prospectively evaluating the safety of temporary interruption of ET to allow conception is an unmet, patient-oriented, medical need. Trial Design: Young patients with endocrine responsive early BC who desire pregnancy will interrupt ET for up to 2 yrs to attempt child-bearing. As resumption of menses and conception depends on many factors (e.g. patient’s age and adjuvant treatment received), the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos), conception (~3-6 mos), delivery (~9 mos), and breast feeding (~6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts/deliveries are concluded, and to complete the planned 5-10 yrs of ET. Major Eligibility Criteria - Histologically-proven stage I-III endocrine-responsive BC. - Patient’s wish to become pregnant. - Age ≥ 18 and ≤ 42 years at enrollment. - Adjuvant ET (selective estrogen receptor modulator [SERM] alone, GnRH analogue plus SERM or aromatase inhibitor) for ≥18 months but ≤30 months, stopped within 1 month prior to enrollment. - Premenopausal status at BC diagnosis. Specific Aims 1. To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy. 2. To evaluate pregnancy success rate and offspring outcome. Statistical Methods: With 500 pts enrolled and followed for a median of 3 years, the statistical design is based on the 95% CI for the 3-year BC recurrence rate. Interim monitoring assumes a 2% BC recurrence risk/yr with continuous ET and a recommendation to stop the study early if the BC risk exceeds 4%/yr with ET interruption. Translational Research will evaluate fertility, pregnancy and BC biology determinants (e.g. ovarian function, uterine evaluation and circulating tumor DNA). Fresh frozen paraffin embedded tissue of the primary tumour will be collected to evaluate parameters related to the biology of BC in young women. All material will be banked centrally. Psycho-oncological Companion Study (POCS) will evaluate fertility concerns, psychological well-being and decisional conflict. It is mandatory in North America and open to interested centers elsewhere. Accrual: Target: 500; Actual: 421 (30 June 2019) Psycho-oncological Companion Study Accrual: Target: ~200; Actual: 196 (30 June 2019) Contact Information: POSITIVE is conducted and sponsored by the International Breast Cancer Study Group. The Alliance for Clinical Trials in Oncology is the US sponsor for NCTN. Contact Monica Ruggeri, IBCSG Coordinating Center, monica.ruggeri@ibcsg.org, or Trial Coordinators at ibcsg48_positive@fstrf.org. Citation Format: Olivia Pagani, Ann H Partridge, Fedro A Peccatori, Hatem A Azim, Chikako Shimizu, Cristina Saura, Ellen Warner, Anna B Sætersdal, Judith R Kroep, Monica Ruggeri, Richard D Gelber. POSITIVE: A study evaluating pregnancy, disease outcome and safety of interrupting endocrine therapy for premenopausal women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/big 8-13) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-02.

Background: Women with locally advanced triple negative breast cancer (LA-TNBC) have a high risk of disease recurrence and are monitored clinically and with annual mammograms. High risk women, such as BRCA1/2 carriers, are additionally monitored for second primary breast cancers (BC) with annual MRIs and may opt for risk reducing mastectomy (RRM) as a prophylactic measure. Our aim was to explore the clinical outcomes of patients (pts) with average BC risk and high BC risk (known BRCA1/2 carriers) who undergo RRM at the time of LA-TNBC diagnosis. Methods: We included 78 consecutive LA-TNBC pts, stages IIB and III, with resectable unilateral disease, treated at the Sunnybrook Health Sciences Centre from 2009 to 2018. Pts who did not undergo systemic chemotherapy and surgical treatment were excluded, as well as pts with a history of prior BC. Medical records were reviewed for clinical outcomes, pathology and germline BRCA1/2 testing results. Log rank test was used to determine the time to recurrence (TTR) and overall survival (OS) differences among women who underwent RRM and those who did not. Results: Median age at diagnosis of LA-TNBC was 49 years (range 27-82) and 14 (18%) pts were BRCA1/2 carriers. All pts underwent neoadjuvant chemotherapy with 27 (35%) presenting complete pathological response. Fifteen pts underwent RRM, out of which seven were BRCA1/2 carriers. Mean follow up time was 34 (2-86) months, during which 25 pts (32%) were diagnosed with distant disease recurrence and none with second primary BC. Median TTR was 10 months (range 1-48) and median OS was 18 months (range 2-86). RRM was not associated with TTR (p=0.45) and OS (p=0.98). Presence of germline BRCA1/2 also did not correlate with TTR (p=0.16) and OS (p=0.21). Conclusions: In our cohort of pts with LA-TNBC, the prognosis was driven by the risk of recurrence rather than the risk of second primary BCs. RRM was not associated with improved clinical outcomes, regardless the BRCA1/2 status and larger studies are required to support this procedure at the time of diagnosis of LA-TNBC. Citation Format: Neda Stjepanovic, Danilo Giffoni, Sonal Gandhi, Katarzyna Jerzak, Sharon Lemon, Karen Ott, Rossanna Pezo, Kathleen Pritchard, Samuel Tabbarah, Maureen Trudeau, Ellen Warner, William Tran, Andrea Eisen. Risk reducing mastectomy in average and high risk patients with locally advanced triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-08.