Abstract Background: Postmastectomy lymphedema remains a significant source of morbidity in breast cancer survivors. Physical therapy (PT) and occupational therapy (OT) are commonly employed for prevention and management, but optimal referral timing remains unclear. We evaluated whether early PT and OT referral after mastectomy reduces two-year lymphedema. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, which includes de-identified electronic health records from 151 healthcare organizations worldwide. We identified adult women (≥18 years) with a diagnosis of breast cancer (ICD-10: C50) who underwent mastectomy between January 1, 2000, and December 31, 2020. Patients with pre-existing lymphedema or hereditary lymphedema were excluded. Two cohorts were defined based on the timing of PT and OT initiation relative to the mastectomy date: Early cohort: PT/OT initiated within 14 days post-mastectomy (n = 5,197) and delayed cohort: PT/OT initiated more than 14 days post-mastectomy (n = 18,817). PT/OT procedures were identified using relevant CPT codes for therapy evaluations, manual lymphatic drainage, gait training, and self-care training. The primary outcome was the incidence of lymphedema occurring between 90 and 1095 days following the index event. A Cox proportional hazards model was used to assess the association between timing of PT/OT and lymphedema risk, adjusting for age, extent of breast resection, axillary dissection, and sentinel lymph node biopsy. Results: In the multivariable Cox model, early initiation of PT/OT within 14 days post-mastectomy was significantly associated with reduced lymphedema risk (HR 0.737, 95% CI 0.608-0.893, p=0.002). Sentinel lymph node biopsy was associated with a protective effect (HR 0.721, 95% CI 0.546-0.953, p=0.021). In contrast, axillary lymph node dissection was associated with more than a twofold increased risk of lymphedema (right: HR 2.217, p=0.001; left: HR 2.101, p=0.002). Bilateral mastectomy was also protective (HR 0.597, p0.001), and increasing age was modestly protective (HR 0.981 per year, p0.001). Unilateral breast resections were not significantly associated with lymphedema risk. Conclusion: Early initiation of PT/OT and the use of sentinel lymph node biopsy were independently associated with reduced lymphedema risk following mastectomy. In contrast, axillary lymph node dissection was strongly predictive of increased lymphedema risk. These real-world findings support current American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) guidelines advocating early rehabilitation and limited axillary surgery to minimize long-term morbidity in breast cancer survivors. Citation Format: K. Doshi, S. Afridi, N. Iyer, S. A. Haddad. Impact of early vs delayed referral to physical therapy and occupational therapy after mastectomy and the risk of postmastectomy Lymphedema: A Real-World Propensity-Matched Study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-20.
Doshi et al. (Tue,) studied this question.