Abstract Background: Chemotherapy (CTX) for breast cancer (BC) can have a detrimental effect on cardiorespiratory fitness (CRF), as measured by VO2max. This decline may be attenuated by physical activity, which can also reduce mortality risk and improve quality of life (QoL) for patients (pts) with BC. During the COVID-19 pandemic, many have pivoted to home-based exercise routines, which have been shown to be safe and feasible for pts with BC receiving CTX. We conducted the STRENGTH Trial to evaluate the effect of a 12-week virtual supervised exercise program in BC pts receiving CTX on CRF. Methods: This is a single-center, prospective, single-arm study designed to evaluate the effect of a 12-week virtual supervised exercise training program on CRF in BC pts receiving CTX. Participants aged ≥18 years with stage I-IV BC who were planned to receive at least 12 weeks of CTX of investigator’s choice were eligible for inclusion. Participants were asked to complete a total of 150 minutes (min) of moderate intensity physical activity/week, as a combination of a 45 min weekly virtual personal training session and workout classes streamed from the Peloton® Digital platform (i.e. walking, running, cardio, yoga, strength training, and cycling). The primary endpoint was the distance walked on a Six-Minute Walk Test (6MWT), an accepted surrogate marker for VO2max, at the start and completion of the program. Secondary endpoints included assessment of QoL using the Functional Assessment of Cancer Therapy - General (FACT-G) and symptom assessment using the MD Anderson Symptom Inventory (MDASI) questionnaires at the beginning, middle and end of the study. Exploratory endpoints included treatment adherence, toxicities, completion and response. Results: 33 participants signed consent for the clinical trial and 2 withdrew voluntarily prior to beginning the program. 5 participants discontinued prematurely due to a diagnosis of COVID-19 (N=3) and pulmonary embolism (N=2) and were not included in the primary endpoint. One participant remains on study at this time. Median age 49 yrs; range 33-68. Mean BMI 29.55; range 18.1-46.5. 13 HR+/HER2-, 7 HR-/HER2-, 11 HER2+. 14 (45%) pts had Stage I, 11 (35%) pts had Stage 2, 5 (16%) pts had Stage 3, 1 (3%) pt had Stage 4. 23 pts (70%) received either an anthracycline or HER2-based therapy. 19 pts (61%) received neoadjuvant CTX on study, 11 pts (35%) received adjuvant CTX and 1 pt (3%) received treatment in metastatic setting. The average number of exercise min per week per participant was 123.2 min (95% CI, 104.1-142.2), with a relative dose intensity of 82%. In the pts that completed the study thus far (N=25), there was no statistically significant difference between the distance walked during the 6MWT at the start and end of the study (median difference= -10m, range: -129-150m, p= 0.67). There was no statistically significant difference in the FACT-G score at the start and end of the study (median difference= -1.0, range -17.83- 30.0, p=0.54). Pts scored higher on the MDASI (median difference= 0.33, range -1.55-4.62, p=0.04) at the end of the exercise program compared to the beginning. There were no new or unexpected treatment toxicities observed. Conclusion: Pts who participated in a 12-week virtual supervised exercise program during CTX for BC did not experience a statistically significant difference in the distance walked during the 6MWT between the beginning and end of the exercise program. Exercise may attenuate the decline in cardiorespiratory function that has historically been observed with CTX for BC. Some pts were not able to adhere to the recommended 150 min of exercise/week suggesting a potential need for modified exercise targets for pts with BC undergoing CTX. This study is limited by a small sample size and larger, randomized clinical trials are needed to further evaluate optimal exercise recommendations for patients with BC undergoing CTX in order to maintain and potentially, even improve, cardiorespiratory function. Citation Format: Eleonora Teplinsky, Amanda Podolski, Kasey Bessada, John Rutledge, Benita Burke, Moira Christoudias, Laura Klein, Kariann Abbate. Effect of a 12 Week Virtual Supervised Exercise Program on Cardiorespiratory Fitness in Breast Cancer Patients Undergoing Chemotherapy: Results from the STRENGTH Trial 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 P5-07-13.