Optimal timing of endocrine therapy interruption for pregnancy in young women with hormone receptor–positive early breast cancer.

627 Background: The POSITIVE trial showed that temporary interruption of adjuvant endocrine therapy (ET) after 18–30 months to attempt pregnancy did not increase short-term recurrence risk in young women with hormone receptor–positive (HR+) breast cancer (BC). However, whether this effect varies by baseline recurrence risk and the timing of interruption remains uncertain. Methods: Using the French National Health Data System (SNDS), we emulated two target trials among women aged ≤42 years with early-stage HR+ BC diagnosed between 2011 and 2020. Trial 1 emulated the POSITIVE design, comparing ET interruption at 18–30 months with uninterrupted ET for ≥24 months. Trial 2 compared nine ET-interruption windows (6-month intervals) with uninterrupted ET for ≥24 or ≥60 months. The primary endpoint was the 5-year risk of BC events. Analyses used a clone–censor–weight approach with marginal structural models. Results: In Trial 1 (n = 10,835), ET interruption at 18–30 months was associated with a 5-year BC event risk of 17.2%, compared with 16.0% for uninterrupted ET ≥24 months (risk difference, 1.2 percentage points; 95% CI, −0.7 to 3.1). Risk varied by baseline recurrence risk: interruption had minimal impact in low- or intermediate-risk women (risk difference, −0.6 percentage points; 95% CI, −2.7 to 1.6) but increased risk in high-risk women (risk difference, 5.8 percentage points; 95% CI, 1.8 to 10.0). In Trial 2 (n = 22,916), earlier ET interruption was associated with higher 5-year BC risk, which decreased with longer prior ET duration. Compared with uninterrupted ET ≥24 months, interruption at 6–12 months increased risk by 8.3 percentage points, whereas interruption at 24–30 months increased risk by 2.7 percentage points. Low- or intermediate-risk women showed comparable risk when interruption occurred at 24–30 months, whereas high-risk women required ≥36–42 months of ET to achieve similar safety. Among pregnancy-seeking women, 64% conceived, and 47% resumed ET. Conclusions: The oncologic impact of temporary ET interruption depends on baseline recurrence risk and prior ET duration. Interruption after 24 months appears safe for low- or intermediate-risk women, whereas high-risk patients may benefit from delaying interruption to at least 36 months. These findings support a risk-adapted approach to fertility counseling.