Breast cancer patients who interrupt endocrine therapy to pursue pregnancy do not experience worse short-term recurrence rates

According to results from the POSITIVE clinical trial, young breast cancer patients who paused their endocrine therapy to try to get pregnant experienced short-term rates of breast cancer recurrence, similar to women who did not pause therapy for pregnancy. Most patients were able to conceive and more than 60% gave birth to healthy babies.

Pregnancy after breast cancer (BC) is of substantial importance for many young women at diagnosis and during follow-up. BC treatment including standard endocrine therapy (ET)  for 5-10 years may reduce ovarian reserve and the chances of subsequent successful pregnancy, given conception is contraindicated during ET. Although there is retrospective evidence that pregnancy after BC does not worsen disease outcomes, regardless of hormone receptor status, a temporary interruption of ET to attempt and carry a pregnancy in this population has never been prospectively studied.

Study design

POSITIVE is a single-arm, prospective, investigator-initiated, international trial evaluating the safety and pregnancy outcomes of interrupting ET for young women with early-stage hormone-receptor-positive (HR+) BC who desire pregnancy. The primary objective is to assess the risk of BC relapse associated with ET interruption for approximately 2 years to achieve pregnancy. Women ≤ 42 years with stage I-III HR+ BC who received adjuvant ET (SERM alone, GnRH analogue plus SERM or AI) for 18 to 30 months and wished to interrupt ET to attempt pregnancy were eligible. Up to two years of break was allowed to attempt pregnancy, conceive, deliver and breastfeed, including a 3-months washout period. If there was no pregnancy by 1 year, a fertility assessment was strongly recommended. ET resumption was strongly recommended after pregnancy to complete the planned 5-10 years of treatment.

The primary endpoint is breast cancer free interval (BCFI) defined as the time from enrolment to the first BC event (local, regional, distant recurrence or a new invasive contralateral BC). Planned sample size was 500 patients. Three interim analyses of BCFI were reviewed by the Data Safety Monitoring Committee (DSMC) to assure a 95% chance of stopping the trial early if the annual BCFI event rate exceeded 4%; with primary analysis triggered after 1600 patient years of follow-up and no more than 46 BCFI events defined as the safety threshold. The DSMC recommended continuing the study following each interim analysis. A cohort of 1499 SOFT/TEXT patients was used as external control. At SABCS, the primary analysis of breast cancer outcomes, and secondary pregnancy and offspring outcomes was presented.

Results

Between December 2014 and December 2019, the study enrolled 518 patients from 116 centres across 20 countries on 4 continents. The median time from BC diagnosis to enrolment was 29 months. At enrolment, the median age of participants was 37 years (27-43 years); 75.0% were nulliparous, 93.4% had stage I/II disease and 66.3% were node-negative. Tamoxifen alone was the most prescribed ET (41.7%), followed by tamoxifen plus ovarian function suppression (35.7%). 62.0% of participants had received (neo)adjuvant chemotherapy.

At a median follow-up of 41 months, 44 participants had experienced a recurrence of breast cancer. The three-year rate of recurrence was 8.9%, similar to the 9.2% rate in an external control cohort from the SOFT/TEXT trials, which examined adjuvant endocrine therapy in premenopausal women. Of 497 women followed for pregnancy status, 368 (74%) had at least one pregnancy (70% within two years), and 317 (63.8% of all women, 86% of those who become pregnant) had at least one live birth, with a total of 365 babies born. These rates of conception and childbirth were on par with or higher than rates in the general public. Birth defects were low (2%) and not clearly associated with treatment exposure. Trial participants were strongly recommended to resume endocrine therapy after a pregnancy attempt or success. To date, 76% have resumed their therapy (half within 26 months), 8% had cancer recurrence or death before ET resumption, and 15% had not resumed ET yet.

Finally, it should be noted that the short follow-up to date is a limitation of the study, as HR-positive breast cancer can recur many years after an initial diagnosis.

Conclusion

The POSITIVE trial demonstrated that for young women with early HR+ BC desiring pregnancy, temporary interruption of ET to attempt pregnancy does not confer a greater short-term risk of recurrence than that observed in a modern historical control group that did not interrupt ET. Most participants have had a live birth. Further follow-up is planned to confirm long-term safety. These results should be considered in counselling BC patients desiring future pregnancy.

Reference

Partridge A, et al. Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE breast cancer: Primary Results from the POSITIVE Trial (IBCSG 48-14 / BIG 8-13. Presented at SABCS 2022; Abstract GS4-09.