Ruddy, Kathryn J.

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

Abstract The Mayo Clinic Breast Disease Registry (MCBDR) was developed to serve as a cohort of newly diagnosed breast cancer patients to address questions of etiology, prognosis, and survivorship. Eligibility is limited to patients 18 years or older with a confirmed first stage 0-4 breast cancer diagnosis within the last year. Consent is completed via phone, patient portal, or in-person. Upon enrollment, a baseline questionnaire and blood collection are completed. Annual follow-up surveys that capture BC outcomes are sent to all living participants. The MCBDR cohort (N=9,215, enrolled between 2001 and 2023) is 99% female, with an average age at diagnosis of 58 years (SD=12.7). Currently, MCBDR has an average time since diagnosis of 9.8 years (SD=6.4). The participants are 94% white, and 55% live in Minnesota. At the time of baseline questionnaire completion, 77% were married, 84% had a bachelor’s degree or higher, and 8% reported financial hardship. Further, 35% reported a history of smoking, 11% consumed more than two drinks per day, and 9% reported fair or poor social relationships. Within MCBDR, 53% of the participants had stage 0 or 1 cancer at diagnosis, while 28% had stage 2, 9% stage 3, and 3% stage 4 BC. Tumors were triple negative in 9%, HER 2 positive in 9%, hormone receptor-positive and HER2 low or negative in 55%, and 27% had missing HER2 status. Pathological TNM staging was available on 98%, among which 33% were staged at T2 or higher and 27% were node-positive. Definitive BC surgery was completed at Mayo Clinic for 73%, with 35% undergoing mastectomies and 44% having lumpectomies. 74% were treated with radiation, 56% underwent chemotherapy, and 79% were treated with endocrine therapy. Clinical genetic testing results have been nurse-abstracted for 94% of the cohort. Of those known to be tested, 521 (6%) had a pathogenic or likely pathogenic mutation identified in a BC causing gene. In addition, whole exome sequencing was completed on 71% of MCBDR participants in 2020, in which 167 previously unknown pathogenic or likely pathogenic mutations were identified. After the initial diagnosis and active treatment phase, nurse abstraction identified 151 (2%) participants known to have been diagnosed with a contralateral BC diagnosis, and 4% known to have been diagnosed with a second primary other than breast. Recurrence in the same breast has been reported for 242 (3%), with 72% of those recurrences occurring within 5 years of initial diagnosis and another 19% occurring 5-10 years post diagnosis. Among the 1,262 (14%) who are deceased, 24% died from BC and 19% had distant metastases at diagnosis or a distant recurrence. Amongst all deceased, 6% died within 1 year of their diagnosis and 43% died within 5 years of diagnosis. For participants who died from BC, 10% died within 1 year of their diagnosis and 64% died within 5 years of diagnosis. MCBDR data has been used in numerous publications and is an essential resource for efficient observational research analyses. Citation Format: Nicole L. Larson, Janet Olson, Kathryn Ruddy, Fergus Couch, Denise Herman, Feven Abraha. Mayo Clinic breast cancer cohort: A valuable resource for breast cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7339.

Abstract Background: Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer (BC) confers poor outcomes. Trastuzumab emtansine (T-DM1) is approved for HER2+ patients with residual disease after NAC. However, many patients still develop recurrence. H2NVAC is a multi-epitope CD4 helper T cell activating vaccine that includes a pool of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Method: We conducted a safety run-in phase of H2NVAC in combination with T-DM1 in stage II-III HER2+ BC with residual disease after NAC. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 toxicity occurring within 21 days after the first vaccination. Results: 20 patients were enrolled (median age 51; 27-69 years), including 80% White and 15% Black. 90% had hormone receptor-positive disease. There was no DLT observed in the safety run-in cohort. All adverse events (AEs) during the DLT period were grades 1 and 2, with fatigue being the most common (60% G1, 5% G2), followed by peripheral sensory neuropathy (55% G1, 5% G2), and injection site reaction (50% G1). Across all treatment cycles, the 10 most common AEs that were at least possibly related to treatment in all cycles are summarized in the table below. The injection site reaction was the most common AE, with 85% G1 and 15% G2. Conclusion: H2NVAC, in combination with T-DM1, was safe, with a favorable side effect profile. There was no DLT observed. The most common AE was injection site reaction, with the majority being G1. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium (NCT04197687). Adverse Events Grades 1 2 N % N % Injection site reaction 17 85.0 3 15.0 Aspartate aminotransferase increase 13 65.0 Alanine aminotransferase increase 9 45.0 Fatigue 7 35.0 2 10.0 Peripheral sensory neuropathy 7 35.0 2 10.0 Alkaline phosphatase increase 8 40.0 Nausea 7 35.0 1 5.0 Arthralgia 7 35.0 Myalgia 5 25.0 1 5.0 Platelet count decrease 6 30.0 Citation Format: Saranya Chumsri, Sharmila Giri, Andy J. Ness, David W. Hillman, Nadine Norton, Davitte Cogen, Brian M. Necela, Aziza Nassar, Donald W. Northfelt, Pooja Advani, Rohit Rao, Kostandinos Sideras, Alvaro Moreno-Aspitia, Brenda J. Ernst, Kathryn J. Ruddy, Matthew P. Goetz, Keith L. Knutson. Safety and tolerability of multi-epitope HER2 peptide vaccines in combination with trastuzumab emtansine in HER2-positive breast cancer patients with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5005.

31 Background: Incidence of early-onset colorectal cancer (eoCRC, <50 years of age at diagnosis) is increasing globally. However, little is known regarding symptom burden in this sub-population. We compared symptoms in patients with eoCRC to those of patients with average-onset CRC (aoCRC, diagnosed at age ≥ 50). Methods: E2C2 is a stepped-wedge, cluster-randomized pragmatic trial evaluating a collaborative care model for the assessment and management of six symptoms [Sleep disturbance, Pain, Physical function impairment, Anxiety, emotional Distress, and Energy deficit (SPPADE)]. Patients were asked to complete assessments rating each of these symptoms on an 11-point numerical rating scale. Symptom severity was classified as mild (0-3), moderate (4-6), or severe (7-10). We conducted a subgroup analysis of patients with CRC, comparing SPPADE symptoms on an initial survey, regardless of timing in treatment course, between patients with eoCRC and aoCRC. Results: Patients with CRC (n=4281) completed a survey between March 2019 and December 2022. Patient demographics and SPPADE symptoms are reported in the table. Patients with eoCRC were more likely to report severe sleep disturbance ( p<0.0001), pain ( p=0.03485), anxiety ( p<0.0001), emotional distress ( p<0.0001), and fatigue ( p=0.01083). In patients with eoCRC, women were more likely to report severe pain (12.6% vs 6.9%, p=0.0069), anxiety (16.1% vs 10.0%, p=0.012), emotional distress (12.1% vs 5.4%, p=0.00066), fatigue (18.9% vs 13.4%, p=0.038), and physical function impairment (10.1% vs 5.8%, p=0.026) compared to men. Conclusions: Patients with eoCRC reported higher symptom severity than patients with aoCRC. This suggests unique needs for symptom management in patients with eoCRC. Additional research is needed to evaluate how time since diagnosis, disease characteristics, cancer-directed treatment patterns, and co-occurring symptoms are associated with specific symptoms in this population. [Table: see text]

Abstract Background Diagnosis of breast cancer in young women has been shown to affect their decision‐making with regard to fertility and family planning. Limited data are available from populations across the U.S. regarding this issue; thus, we sought to describe fertility concerns and efforts to preserve fertility in a national clinical trial population of young breast cancer patients. Methods The young and strong study was a cluster‐randomized controlled trial testing an intervention program for young women with breast cancer. Patients were surveyed within 3 months after diagnosis and at 3, 6, and 12 months after. Surveys asked about sociodemographics, psychosocial domains, fertility concerns, and fertility preservation strategies. Univariable and multivariable models were used to investigate sociodemographic, clinical, and psychosocial predictors of fertility concerns. Results Of 467 women from 54 clinical sites across the U.S. (14 academic, 40 community), 419 were evaluable regarding fertility concerns. Median age was 40 years (range 22–45), 11% were Black, 6% Hispanic, and 75% had children. Tumor stage was I (35%), II (51%), or III (14%); 82% received chemotherapy. At time of the treatment decision, 133 (32%) participants had fertility concerns, among whom 47% indicated this affected their treatment decisions. Sixty percent of participants reported having discussed fertility with their physician. Twenty percent of those with fertility concerns used fertility preservation strategies. History of difficulty becoming pregnant and younger age were associated with higher odds of fertility concerns in multivariable modeling. Conclusion Many young women with newly diagnosed breast cancer are concerned about fertility in a way that impacts their treatment decisions. Concerns were discussed, but few used fertility preservation strategies. These findings have implications for counseling young patients.

PURPOSE There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2–enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Abstract Aims The objective of this study was to assess the effect of HER2-directed therapy (HER2-Tx) on peripheral vasoreactivity and its correlation with cardiac function changes and the additive effects of anthracycline/cyclophosphamide (AC) therapy and baseline cardiovascular risk. Methods and results Single-centre, prospective cohort study of women with newly diagnosed stage 1–3 HER2-positive breast cancer undergoing HER2-Tx +/− AC. All participants underwent baseline and 3-monthly evaluations with Endo-Peripheral Arterial Tonometry (Endo-PAT), vascular biomarkers [C-type natriuretic peptide (CNP) and neuregulin-1 beta (NRG-1β)], and echocardiography. Cardiotoxicity was defined as a decrease in the left ventricular ejection fraction (LVEF) of &gt;10% to a value &lt;53%. Of the 47 patients enrolled, 20 (43%) received AC in addition to HER2-Tx. Deterioration of reactive hyperaemia index (RHI) on Endo-PAT by ≥20% was more common in patients receiving HER-Tx plus AC than HER2-Tx alone (65% vs. 22%; P = 0.003). A decrease in CNP and log NRG-1β levels by 1 standard deviation did not differ significantly between the AC and non-AC groups (CNP: 20.0% vs. 7.4%; P = 0.20 and NRG-1β: 15% vs. 11%; P = 0.69) nor did GLS (35% vs. 37%; P = 0.89). Patients treated with AC had a significantly lower 3D LVEF than non-AC recipients as early as 3 months after exposure (mean 59.3% (SD 3) vs. 63.8% (SD 4); P = 0.02). Reactive hyperaemia index and GLS were the only parameters correlating with LVEF change. Conclusion Combination therapy with AC, but not HER2-Tx alone, leads to a decline in peripheral vascular and cardiac function. Larger studies will need to define more precisely the causal correlation between vascular and cardiac function changes in cancer patients.

ImportanceYoung women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers.ObjectiveTo investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers.Design, Setting, and ParticipantsInternational, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023.ExposurePregnancy after breast cancer.Main Outcomes and MeasuresPrimary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer–specific survival, overall survival, pregnancy, and fetal and obstetric outcomes.ResultsOf 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer–specific survival and overall survival.Conclusions and RelevanceIn this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival.Trial RegistrationClinicalTrials.gov Identifier: NCT03673306

Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential associations between peripheral immunity and breast tumor progression, here, we assessed the peripheral blood TCR clonotype of 485 breast cancer patients diagnosed with either DCIS or de novo stage IV disease at younger (<45) or older (≥45) age. TCR clonotype diversity was significantly lower in older compared to younger breast cancer patients regardless of tumor stage at diagnosis. In the younger age group, TCR-α clonotype diversity was lower in patients diagnosed with de novo stage IV breast cancer compared to those diagnosed with DCIS. In the older age group, DCIS patients with higher TCR-α clonotype diversity were more likely to have a recurrence compared to those with lower diversity. Whole blood transcriptome profiles were distinct depending on the TCR-α Chao1 diversity score. There were more CD8 + T cells and a more active immune environment in DCIS tumors of young patients with higher peripheral blood TCR-α Chao1 diversity than in those with lower diversity. These results provide insights into the role that host immunity plays in breast cancer development across different age groups.