Melisko, Michelle

Abstract Introduction: Interstitial Lung Disease (ILD) is a known adverse event associated with Antibody Drug Conjugates (ADCs), causing fibrosis of the lung. In the DESTINY-Breast 04, TROPICS-02, and ASCENT trials the rate of ILD/Pneumonitis was 12.1%, 0.4%, and 0% respectively. In these studies, the time to first cross-sectional imaging after initiation of ADC was 6 weeks. However, prior treatment with a topoisomerase-1 inhibitor ADC was not permitted in these studies, so the influence of sequential ADC treatments remains unknown. Here, we aimed to characterize the frequency and management of ILD in sequential use of ADCs in a multi-institution retrospective analysis. Methods: We identified patients (pts) with HR+/HER2-low and HR-/HER2-low MBC who had received both Trastuzumab-deruxtecan (T-DXd) and Sacituzumab govitecan (SG) monotherapy (in either order, with or without intervening therapies) who were treated at five academic centers between 2020-2023. Patients had received treatment with the ADC in either routine clinical treatment or as a prior participant on a clinical trial with ADC monotherapy. Information regarding ILD diagnosis, imaging, timing of onset, peak and resolution along with management information was collected and analyzed. Retrospective assessment of ILD toxicity was graded using CTCAE v5.0, based on available clinical and radiographic reports. Results: 10/60 pts who received ADC therapy in this multi-institutional cohort were diagnosed with ILD (all grades). No differences in age or BMI were observed in those who developed ILD versus those who did not, and 9/10 pts were White, 1 was Asian, with a median age of 59 years (47-79 years). Pertinent history in these pts included 3/10 had a prior smoking history, 8/10 had a prior cardiac or pulmonary comorbidity (including sleep apnea, lung cancer, hypertension, hyperlipidemia, thrombosis, or stroke). Prior to receiving their first ADC, 7/10 patients had metastatic disease to the lung. All 10 patients were diagnosed with ILD during treatment with T-DXd. 4 pts initially received T-DXd, then developed ILD and then upon recovery, subsequently received SG. The remaining 6 pts initially received SG (with no reports of ILD), and then received T-DXd and subsequently developed ILD. In the entire cohort, the median time from ADC initiation to first CT scan was 8 weeks (range 1-22 weeks). Within the cohort that developed ILD, the median time from initiation of T-DXd to first CT scan was also 8 weeks (range 6-13 weeks). The median time to diagnoses of ILD was 3 months after initiation of T-DXd (range 0.4-14.5 months). Dyspnea was the most common presenting symptom in 9/10 pts and at diagnosis of ILD, dyspnea was graded as III in 6/10 pts, II in 3/10 pts, and I in 1/10 pts. Diagnostic evaluation included CT chest (9/10), pulmonary consultation (8/10), pulmonary function testing (2/10), and bronchoscopy (1/10). 4/10 patients presented at their highest-grade toxicity at diagnosis. All patients stopped T-DXd treatment, 7 were hospitalized, 7 required supplemental oxygen, and 8 were prescribed steroids for treatment. Of those receiving steroids, the most common starting dose was prednisone 1 mg/kg and doses ranged from 0.5 mg/kg to 9mg/kg prednisone equivalents. No patient received a secondary immunosuppressive agent. The steroid treatment duration ranged from 1-4 months. None of the 10 pts underwent re-challenge with T-DXd and 3/10 developed grade V ILD (death). Conclusion: We observed a 16.6% incidence of all grade ILD (5% grade V ILD) with T-DXd and 0% with SG. In this small cohort study, we did not observe a clear increased risk for ILD with sequential treatment of ADCs. Practice patterns were consistent with recommended diagnostic evaluation and steroid management. Additional strategies are needed to characterize pts most at risk for developing ILD and to identify situations where re-challenge may be safe. Citation Format: Sarah Premji, Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Hope Rugo, Karthik Giridhar. Interstitial Lung Disease (ILD) in Sequential Antibody Drug Conjugate (ADC) use in patients with Metastatic Breast Cancer (MBC): A Multi-Institutional experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-12-06.

Abstract Introduction. T-DXd is FDA-approved for patients (pts) with hormone receptor positive (HR+) or HR- HER2-low (IHC 1+ or 2+, ISH-) MBC and SG is FDA-approved for pts with HR+/HER2- and triple negative MBC. However, several outstanding questions impact the use of these drugs in clinic, including: 1) what is the efficacy and safety of these agents in real-world populations with diverse pt characteristics not well represented in the pivotal phase III trials, and 2) what is the impact of sequential treatment with ADCs on the efficacy and safety of these agents. Methods. In this multicenter retrospective cohort study, we identified pts with HR+/HER2-low and HR-/HER2-low MBC who had received both T-DXd and SG monotherapy (in either order, with or without intervening therapies) treated at 5 academic centers between 2020-2023. Pts received treatment per standard of care or on a clinical trial with ADC monotherapy. We describe pt demographic and clinical characteristics, treatment history, key safety parameters, and response and survival data by HR+ status and ADC sequence order. Results. Sixty pts with MBC treated sequentially with T-DXd and SG were included in this analysis, including 45 pts with HR+/HER2-low MBC (75.0%) and 15 pts with HR-/HER2-low MBC (25.0%). Most pts were female (n=59; 98.3%), non-Hispanic (n=49, 81.7%), and white (n=43, 71.7%). Median age at start of ADC #1 was 56.6 years (range 23-82). Prior to treatment with ADC #1, most pts had visceral disease (n=45, 75.0%) and 16 (26.7%) had central nervous system metastases. Among pts with HR+/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 49.0 months, with 4 median lines of prior therapy in the metastatic setting (2 endocrine, 2 chemo). Approximately half of the HR+ pts received T-DXd prior to SG (n=22, 48.9%; median 3.0 prior lines of therapy for MBC, range 1-9) while the other half received SG prior to T-DXd (n=23, 51.1%; median 4.5 prior lines of therapy for MBC, range 1-10). 44% (n=20) received an intervening therapy between ADCs. For HR+ pts who received T-DXd prior to SG, response and survival data is as follows for T-DXd and SG respectively: Overall response rate (ORR) [54.5% and 21.1%], time to next treatment (TTNT) [4.3 mo and 1.6 mo], and real-world overall survival (rwOS) [19.8 mo and 4.9 mo]. For HR+ pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [78.3% and 42.9%], TTNT [8.6 mo and 2.8 mo], and rwOS [22.3 mo and 7.3 mo]. Among pts with HR-/HER2-low MBC, median time from MBC diagnosis to treatment with ADC #1 was 8.2 months with 2 median lines of prior therapy in the metastatic setting (2 chemotherapy); 66.7% (n=10) received prior immunotherapy. Most HR- pts received SG prior to T-DXD (n=14, 93.3%) and 40.0% (n=6) received an intervening therapy between ADCs. For HR- pts who received SG prior to T-DXd, response and survival data is as follows for SG and T-DXd respectively: ORR [64.3% and 38.5%], TTNT [6.2 mo and 2.7 mo, and rwOS [15.7 mo and 6.5 mo]. In terms of key safety parameters during treatment with T-DXd, 13.3% of pts (8/60) required a dose reduction. 16.7% (10/60) were diagnosed with interstitial lung disease (ILD)/pneumonitis of any grade including 3 pts with grade 3-4 ILD (5.0%) and 3 pts with grade 5 ILD (5.0%). During treatment with SG, 40.0% of pts (24/60) required a dose reduction. 83.3% (50/60) received growth factor support (24 pts primary prophylaxis; 26 pts secondary prophylaxis); 9 pts (15%) required treatment delay due to neutropenia. Conclusion. This study represents the largest multicenter series to date of pts treated with sequential ADCs for HR+/HER2-low or HR-/HER2-low. ORR was higher and TTNT was longer for ADC #1 than ADC #2 in all subgroups, regardless of HR+ status and ADC sequence order. An additional ~30 pts will be reported at time of final analysis. Future prospective studies are planned to further clarify the efficacy and safety of sequential ADC use and to identify biomarkers of response and resistance. Key demographic, clinical and treatment characteristics in pts with HR+ and HR- HER2-low MBC treated sequentially with T-DXd and SG (in either order, with or without intervening therapies) Abbreviations: T-DXd (trastuzumab deruxtecan), SG (sacituzumab govitecan), MBC (metastatic breast cancer), ADC (antibody drug conjugate), HR (hormone receptor), HER2 (human epidermal growth factor receptor 2), CNS (central nervous system), ET (endocrine therapy), ORR (overall response rate), TTNT (time to next treatment), rwOS (real world overall survival), CI (confidence interval) * Several pts on ADC #2 with ongoing treatment and first scan pending, hence smaller denominator for response assessment Citation Format: Laura Huppert, Reshma Mahtani, Samantha Fisch, Naomi Dempsey, Sarah Premji, Angelina Raimonde-Taylor, Saya Jacob, Laura Quintal, Jo Chien, Michelle Melisko, Ana Sandoval-Leon, Lauren Carcas, Manmeet Ahluwalia, Natasha Harpalani, Jenna Hoppenworth, Dame Idossa, Ruta Rao, Karthik Giridhar, Hope Rugo. Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-04.

AbstractBackgroundBreast cancer patients experienced heightened anxiety during the pandemic. Also, modifications to clinical trial activities allowing for virtual platforms, local assessments, and greater flexibility were introduced to facilitate participation. We sought to evaluate the association between pandemic‐related anxiety and willingness to participate in trials and how pandemic‐era modifications to trial activities affect the decision to participate.MethodsWe conducted an online survey from August to September, 2021 of patients with breast cancer assessing pandemic‐related anxiety; clinical trials knowledge and attitudes; willingness to participate during and before the pandemic; and how each modification affects the decision to participate. Fisher's exact tests evaluated differences in proportions and two‐sample t‐tests evaluated differences in means. The association of pandemic‐related anxiety with a decline in willingness to participate during compared to prior to the pandemic was modeled using logistic regression.ResultsAmong 385 respondents who completed the survey, 81% reported moderate–severe pandemic‐related anxiety. Mean willingness to participate in a trial was lower during the pandemic than prior [2.97 (SD 1.17) vs. 3.10 (SD 1.09), (p < 0.001)]. Severe anxiety was associated with higher odds of diminished willingness to participate during the pandemic compared to prior (OR 5.07). Each of the modifications, with the exception of opting out of research‐only blood tests, were endorsed by >50% of respondents as strategies that would increase their likelihood of deciding to participate.ConclusionsWhile pandemic‐related anxiety was associated with diminished willingness to participate in trials, the leading reasons for reluctance to consider trial participation were unrelated to the pandemic but included worries about not getting the best treatment, side effects, and delaying care. Patients view trial modifications favorably, supporting continuation of these modifications, as endorsed by the National Cancer Institute and others.

Abstract Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. Patients and Methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy “graduates” if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. Results: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%–99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. Conclusions: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority &gt;90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

369 Background: Patient-reported outcomes (PROs) are a valuable component to understand treatment tolerability and toxicity. We have implemented an electronic system for monitoring PROs and quality of life (QOL) for patients enrolled in the I-SPY2 trial, a phase II trial evaluating the effect of novel neoadjuvant therapies for breast cancer. We associated patient demographic factors with symptoms, decline in physical function (PF), and tolerability to treatment. Methods: Study population for this analysis includes 259 enrolled patients receiving combinations of experimental immunotherapy and chemotherapy. Patients completed PRO-CTCAE/PROMIS/FACT surveys reflecting symptom severity, symptom frequency, tolerability of drug, and physical function at baseline through follow up (12 months). CTCAE 5.0 was collected weekly at these timepoints to assess adverse events (AE). Odds ratio and regularized multi-variate regression was used to evaluate early symptoms predictive of a clinically significant decline in PF from baseline to post-treatment follow-up. Results: Of 259 patients, 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), and 25 (9.3%) were Hispanic. 25% of all patients had a clinically significant decline in PF between baseline and pre-surgery/follow-up. Symptom predictors of decline included high frequency of diarrhea and severity of joint pain. African American (AA) patients had higher severity of joint pain than White patients (OR = 14.9, P < 0.05). Within the first 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients (OR =13.22 and 12.72, P< 0.05 and P< 0.03 respectively). Overall, patients that reported lower tolerance to therapy had higher grade of AE. While patients with low-grade adverse events were less bothered by their side effects at follow-up, higher grade adverse events such as hypothyroidism impacted distress levels by more than double. Conclusions: Among I-SPY2 participants, when higher grade of symptoms is persistent through follow up, it impacts physical function and tolerability even after end of therapy. Our study can allow physicians to be more diligent in active and post treatment monitoring. Clinical trial information: NCT01042379 .

The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.

611 Background: Patient reported outcomes (PROs) capture direct feedback from patients in clinical trials. The NIH Patient-Reported Outcomes Measurement Information System (PROMIS) is an open source and validated PRO platform. Data on PROMIS score trajectories over time for breast cancer patients undergoing neoadjuvant chemotherapy (NAC) are limited. Methods: We administered paper surveys to patients enrolled on the I-SPY2 trial, a multicenter, randomized phase 2 trial comparing novel agents to standard NAC in high-risk breast cancer. PRO domains included PROMIS Physical Function, Anxiety, Depression, Applied Cognition and Fatigue. Surveys were administered at baseline (post-consent), C1D1, inter-regimen (~12 wks into NAC), pre-surgery and at 1, 6, 12, and 24 months post-surgery. Responses were scored using the HealthMeasures Scoring Service to generate a standardized T score, with a score of 50 representing the general US population mean. Higher Anxiety, Depression and Fatigue scores represent worse symptoms; higher Physical Function and Applied Cognition scores represent better symptoms. We calculated average scores by time-point and compared changes from baseline to various grouped time points using a paired t-test. Results: From 1/2012 to 7/2020, 1631 patients enrolled in I-SPY 2 with 959 completing the baseline survey. 62% had at least two “on-treatment” surveys, and 52% had at least one follow-up time-point. Average baseline PROMIS scores for Physical Function, Anxiety, Depression, Applied Cognition and Fatigue were 46.7, 55.1, 47.2, 53.3 and 46.0 respectively. Between baseline and the latest on-treatment time point we observed improvement in Anxiety (-5.2) and worsening in Physical Function, Applied Cognition and Fatigue (-5.4, -6.9 and +8.2 respectively). Between baseline and the latest post-surgery time point, we saw improved Anxiety (-5.9) and worsened Physical Function, Applied Cognition and Fatigue (-5.9, -3.6 and +4.3). Depression changed minimally. Conclusions: Using PROMIS, patients on I-SPY2 experienced worse Physical Function, Applied Cognition and Fatigue but improved Anxiety during and after treatment compared to baseline. While changes in Applied Cognition and Fatigue recovered partially after treatment, Physical Function scores did not, suggesting potential for longer term impact on quality of life. Clinical trial information: NCT01042379 . [Table: see text]

Abstract PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and &gt;94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [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 PD7-03.

Abstract Background. Patient-reported outcomes (PROs) are increasingly recognized as a valuable component to understand treatment tolerability and toxicity among patients on clinical trials. We have implemented a system for monitoring patient reported outcomes (PROs), symptoms, and quality of life (QOL) using electronic PRO (ePRO) instruments for patients enrolled in the I-SPY2 trial. I-SPY2 is a phase II multi-site clinical trial evaluating the effect of novel neoadjuvant therapies for locally advanced breast cancer. We correlated patient demographic factors with symptoms, investigated the trajectory of symptoms throughout treatment, and sought to characterize symptoms associated with decline in physical function (PF). Methods. Our study population included 259 I-SPY2 patients that completed surveys on one of 9 study arms (including novel oral taxane/immunotherapy combinations, IV paclitaxel, checkpoint inhibitor+/- LAG3 inhibitor, and control IV paclitaxel +/- trastuzumab/pertuzumab). After the 12 week period of investigational agents, most patients received standard adriamycin and cyclophosphamide (AC). Symptom severity, frequency, and interference was assessed weekly using 33 items from the PRO-CTCAE item bank. PF was assessed using the NIH PROMIS instrument and was evaluated at baseline, inter-regimen (after 12 weeks of treatment), pre-surgery, and 1 and 6 months at follow-up. An odds ratio was used to assess univariate associations between age and race, and symptoms. Regularized multi-variate regression was used to evaluate early symptoms (prior to week 6) predictive of a clinically significant (&gt;5 point T-score) decline in PF from baseline to post-treatment follow-up among all races and age groups. Results. Of 259 patients (mean age (SD) = 46.8 (13.6)), 160 (58%) were White, 13 (5%) were Asian, 26 (10%) were African American (AA), 25 (9.3%) were Hispanic, and 35 (13.5%) self-reported “Other”. At baseline, AA patients had a higher severity of joint pain than White patients (OR = 14.9, P &lt; 0.05). During study treatment with paclitaxel and/or novel agent within the first 12 weeks of treatment, AA patients and non-white (NW) patients were more likely to report severe vomiting than White patients (OR =13.22 and 12.72, P&lt; 0.05 and P&lt; 0.03 respectively). During treatment with AC, NW patients were more likely to report higher severity of neuropathy than White patients (OR = 5.43, P&lt; 0.03). Among all patients, in analysis of early symptoms predictive of a clinically significant decline in PF between baseline and 1 month post treatment, predictors included high frequency of diarrhea, severity of itching, and severity of joint pain. Further analysis of symptom trajectories revealed that frequency of diarrhea reported rose sharply between baseline and Cycle 2 with 9 patients (7%) reporting occasional or frequent diarrhea to 39 patients (28%) reporting occasional to almost constant diarrhea and remained stable at that proportion for the remainder of treatment. Frequency of diarrhea declined slightly during AC (17%) and dropped to baseline levels by follow-up. In contrast, severity of joint pain persisted post-treatment, rising consistently from baseline through follow- up with 3 patients (2%) reporting moderate to severe joint pain at baseline to 18 patients (35%) reporting moderate to severe joint pain at follow-up. Conclusion. Among I-SPY2 participants, when higher grade of diarrhea is persistent (or uncontrolled), it impacts physical function even after end of therapy. In some cases, race was also a determinant in symptom trajectory, although a higher enrollment of AA and NW patients will enable more robust estimates to be computed. While some of these early symptom predictors are transient and resolve by the time of follow-up, others persist long-term and contribute more directly towards impaired physical function at follow-up. Citation Format: Amrita Basu, Saumya Umashankar, Kaylee Blevins, Anna Northrop, Anika Christofferson, Ebunoluwa Olunuga, Jaeyoon Cha, Ananya Mittal, Julissa Molina-Vega, Laura Sit, Thelma Brown, Bev Parker, Diane Heditsian, Susie Brain, Carol Simmons, Alessandra Taboada, Tina J. Hieken, Kathryn Ruddy, Carolina Salvador, Candace Mainor, Anosheh Afghahi, Sarah Tevis, Anne Blaes, Irene M. Kang, Jane Perlmutter, Hope Rugo, Sai Kanaparthi, Garry Peterson, Lisa T. Weiss, Adam Asare, Laura J. Esserman, Michelle Melisko, Dawn Hershman. The Association Between Symptom Severity and Physical Function among Participants in I-SPY2 [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 P5-07-03.

Abstract Background: Historically, less than 10% of adult patients with cancer enroll in clinical trials, however, enrollment dropped further at the onset of the COVID-19 pandemic. Barriers to trial participation during the pandemic have not been reported. As part of the TBCRC 057 survey on the impact of the pandemic on willingness to participate in breast cancer trials, we assessed reasons for reluctance to participate in trials during the pandemic. Methods: US residents who self-reported a breast cancer diagnosis were eligible to complete the online survey 8/6/21-9/30/21. Respondents indicated whether they were current trial participants and, if not, their willingness to consider participating in a trial during the pandemic using a 5-point scale (0-not at all willing to 4-definitely willing). Respondents who were not current trial participants and who were not “definitely willing” to consider participation during the pandemic were characterized as “reluctant” and asked to select reasons for their reluctance from a checklist. Pandemic-related anxiety was assessed on an 11-point scale (0-no anxiety to 10-worst anxiety possible). Respondents indicated how the option to conduct trial activities online would affect their decision to participate in a trial (much less likely, somewhat less likely, would not affect my decision, somewhat more likely, or much more likely). In exploratory analyses, we evaluated whether pandemic-related anxiety and favorable reactions towards opportunities to conduct trial activities online were associated with reluctance to consider trial participation during the pandemic due to fear of SARS-CoV-2 exposure. Means were compared with two sample t-tests and proportions with Fisher’s exact tests. Results: Of 385 survey respondents, 185 (48%) were characterized as reluctant to consider trial participation during the pandemic. Among these 185, median age was 55 (range 25-80), 85.7% were non-Hispanic White, 48.1% had metastatic disease and 44.2% received care at academic centers. Reasons for reluctance to consider trial participation during the pandemic cited by ≥15% of the 185 reluctant respondents are shown in the Table. Respondents who selected fear of exposure to SARS-CoV-2 as a reason for their reluctance to consider participating in a trial during the pandemic had higher mean pandemic-related anxiety (7.0 vs 5.2, p&lt; 0.001). These respondents were more likely to indicate telemedicine doctor visits (p=0.01), virtual consents (p=0.001) and online study questionnaires (p=0.001) would make them somewhat or much more likely to participate in trials than respondents who did not select fear of exposure to SARS-CoV-2 as a reason for their reluctance. Conclusions: Reasons for reluctance of patients with breast cancer to consider participation in clinical trials during the pandemic are multifactorial. Although concerns about safety and efficacy remain prominent, fear of exposure to SARS-CoV-2 drives unwillingness to participate in &gt;25% of reluctant patients. Trial accrual may benefit from incorporation of electronic activities when possible. Table Citation Format: Karen L. Smith, Carolyn Mead-Harvey, Gina L. Mazza, Albert E. Holler, Eileen Shinn, Elizabeth Frank, Michelle Melisko, Cyd Eaton, Jeannine M. Salamone, Teri Pollastro, Patricia Spears, Antonio C. Wolff, Gabrielle B. Rocque. Reasons for Reduced Willingness to Participate in Clinical Trials During the COVID-19 Pandemic: The Translational Breast Cancer Research Consortium (TBCRC) 057 Survey [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 P6-08-07.