Differential effects of oral contraceptives on lymph node metastasis in breast cancer: role of tumor size as an effect modifier

OBJECTIVE: Lymph node metastasis (LNM) is a critical determinant of breast cancer prognosis. While oral contraceptives (OC) are associated with breast cancer risk, their relationship with LNM-particularly in understudied populations like Morocco-remains unclear. This study investigates whether tumor size modifies OC-LNM associations in Moroccan patients. METHODS: We analyzed 356 breast cancer cases from Morocco's National Institute of Oncology(2009). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for OC-LNM associations were estimated using multivariable logistic regression, stratified by tumor size (≤ 2 cm vs. > 2 cm). Multiplicative and additive interactions between OC use and tumor size were assessed. RESULTS: After full adjustment for clinicopathological factors, OCs use was associated with reduced LNM risk in tumors ≤ 2 cm (OR = 0.08, 95% CI: 0.02-0.47, P = 0.005) but increased risk in tumors > 2 cm (OR = 1.97, 95%CI: 1.04-3.76, P = 0.039). Significant multiplicative interaction (P = 0.047) and evidence of additive interaction (RERI = 1.72, AP = 0.69) suggest tumor size acts as an effect modifier, though the precision of the additive interaction estimate is limited (AP 95% CI: 0.30-1.07). CONCLUSION: Tumor size critically modifies OC-LNM relationships, with protective effects in small tumors and risk-promoting effects in large tumors. This heterogeneity underscores the need for size-stratified assessments in breast cancer management.