In well-matched comparisons to an external control cohort, the POSITIVE study showed no clear worsening of breast cancer outcomes in the short term after temporary interruption of endocrine treatment to allow for pregnancy in select women with a history of hormone receptor (HR)-positive early breast cancer. Longer-term follow-up is needed to further inform the safety of this strategy.
The results suggest that although endocrine treatment for a period of 5 to 10 years substantially improves disease outcomes in patients with HR-positive early breast cancer, its temporary interruption to attempt pregnancy does not appear to have an appreciable negative short-term effect. The study findings are published by Dr. Ann H. Partridge of the Department of Medical Oncology, Dana–Farber Cancer Institute in Boston, MA, US, and colleagues on 4 May 2023 in The New England Journal of Medicine.
Breast cancer is the most common type of cancer among women 40 years of age or younger. The incidence continues to rise, being even higher in developing countries. Fertility preservation and subsequent childbearing are of paramount importance to many of these patients. Among women with HR-positive early breast cancer, concerns that subsequent pregnancy might increase the risk of breast cancer recurrence can affect decisions regarding pregnancy. However, retrospective data have shown that subsequent pregnancy is not associated with worse disease outcomes. Decision making is further complicated by the recognition that the adjuvant endocrine treatment for 5 to 10 years substantially reduces the risk of recurrence, but that during this time, pregnancy is contraindicated and ovarian reserve is naturally declining.
Prospective data regarding pregnancy after breast cancer and interruption of endocrine treatment to attempt pregnancy are lacking. The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) study was designed to address the safety, with respect to a breast cancer event, of temporary interruption of endocrine treatment to attempt pregnancy in premenopausal women with endocrine-responsive early breast cancer. In the latest article published in the NEJM, the study team reports results of the prespecified primary analysis of breast cancer outcomes, as well as pregnancy and birth outcomes.
Eligible women for this single-group study were 42 years of age or younger who had had stage I, II, or III HR-positive breast cancer, had received adjuvant endocrine treatment for 18 to 30 months and desired pregnancy. The primary endpoint was the number of breast cancer events, defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer, during follow-up.
The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current study.
Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrolment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born.
At 1638 patient-years of follow-up with median follow-up of 41 months, 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI] 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI 7.6 to 10.8) in the control cohort.
The authors commented that these results provide an improved understanding of the effect of subsequent pregnancy on breast cancer outcomes in women.
In the current study, nearly three quarters of the women had at least one pregnancy, most of which (70.5%) occurred within 2 years after enrolment. More than 40% of the women used assisted reproductive technology during the study which is a relatively high percentage that was probably attributable, at least in part, to the practice of using oocytes or embryos that are banked before gonadotoxic treatment in order to achieve pregnancy and resume endocrine treatment rapidly. In addition, the percentage of women who became pregnant (53.6% at 12 months) appears to be higher than the percentages reported among women of similar age irrespective of a breast cancer diagnosis.
Recent research involving the assessment of pregnancy and birth outcomes after breast cancer has shown increased risks of cesarean section, preterm birth, and low birth weight. However, the timing of pregnancy appears to be critical; women who conceive within 1 year after initiation of chemotherapy for any cancer have a higher risk of preterm birth than women who conceive at least 1 year after starting chemotherapy. In this study, women were enroled at least 18 months after initiation of chemotherapy, and the percentages of women with pregnancy complications are consistent with those of populations of women of a similar age who did not have breast cancer.
Endocrine treatment, in particular tamoxifen can be teratogenic and thus should be avoided during pregnancy. The protocol-specified washout period of 3 months between pausing endocrine treatment and attempting pregnancy took into account the median half-lives of selective oestrogen-receptor modulators and aromatase inhibitors. The incidence of birth defects was low, 2.2% of the 365 offspring, and consistent with general population estimates.
Investigations focusing on assisted reproductive technology, birth outcomes, and breast-feeding are under way.
In an accompanied editorial article, Dr. Sharon H. Giordano of the Departments of Health Services Research and Breast Medical Oncology, the University of Texas M.D. Anderson Cancer Center in Houston, TX, US wrote that the POSITIVE study results provide the strongest evidence to date on the short-term safety of this approach. However, the enroled patients were a selected cohort of women who were highly motivated to become pregnant. In addition, recurrences of breast cancer are reported to occur at a steady rate for up to 20 years after diagnosis among patients with HR-positive disease and the protocol-specified 10-year follow-up data will be essential to establish longer-term safety.
Meanwhile, the POSITIVE study provides prospective data showing that the temporary interruption of endocrine treatment to attempt pregnancy after HR-positive early breast cancer does not appear to increase the risk of recurrence or of contralateral breast cancer in the subsequent 3 years. Physicians should now incorporate these data into their shared decision-making process with patients.
The study was supported by ETOP IBCSG Partners Foundation globally and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group (BIG), the BIG cooperative groups, and the National Clinical Trials Network of the US National Cancer Institute.
References
- Partridge AH, Niman SM, Ruggeri M, et al. for the International Breast Cancer Study Group, and the POSITIVE Trial Collaborators. Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer. N Engl J Med 2023;388:1645-1656.
- Giordano SH. POSITIVE Results for Breast Cancer Survivors Who Desire Pregnancy. N Engl J Med 2023;388:1709-1710.