POSITIVE trial.without affecting their short-term disease outcomes, suggest results from the prospective
The study involved more than 500 premenopausal women from 20 countries who had received at least 18 months of endocrine therapy for HR+ breast cancer. After a 3-month washout, they were given 2 years to conceive, deliver, and breastfeed a baby before resuming treatment.
Crucially, taking a treatment break had no impact on recurrence rates, with the 3-year breast cancer–free interval (BCFI) failure rate of nearly 9% comparing favorably with historical controls.
Moreover, almost three-quarters of women achieved at least one pregnancy, the majority within 2 years, and the vast majority had resumed endocrine therapy by the end of the study period.
The research was presented at the San Antonio Breast Cancer Symposium.
“These data stress the need to incorporate patient-centered reproductive health care, treatments, and choices in the treatment and follow-up of our young women with breast cancer so that they can not only survive, but thrive in their survivorship,” said study presenter Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston.
She noted, however, that the results so far are from a 3-year follow-up. The team now plans on following the women for “at least a decade ... to monitor for independent therapy resumption, and disease outcomes, because of course there is great concern about the late return” of HR+ breast cancer.
This point was also raised by Marleen I. Meyers, MD, a medical oncologist New York University Langone Perlmutter Cancer Center, who was not involved in the study. While she praised the study as offering the “first real evidence” that treatment can be interrupted safely, she said she would be “cautious, as the follow-up is short and we know that hormone positive breast cancer can recur within 10 years of diagnosis and beyond.”
Meyer also emphasized that “the potential loss of fertility and ability to have biologic children ... [is] one of the most devastating results for young women with breast cancer.”
“We have come a long way with fertility preservation,” Dr. Meyers continued, but waiting to complete the recommended 5-10 years of endocrine therapy “makes the possibility of carrying a child less realistic.”
“This study offers hope for some women with hormone receptor–positive breast cancer to be able to interrupt cancer treatment and still have good outcomes,” she said.
Dr. Partridge said that “women are often discouraged” from becoming pregnant, in addition to which giving adjuvant endocrine therapy for the standard 5-10 years “compromises conception” in women with HR+ disease.
POSITIVE was a single-arm trial involving premenopausal women aged up to 42 years at study entry. They were required to have undergone at least 18 months and no more than 30 months of adjuvant endocrine therapy for stage I-III HR+ breast cancer, with no clinical evidence of recurrence. The women could also have undergone prior neoadjuvant chemotherapy with or without fertility preservation.
Women halted endocrine therapy within 1 month of trial enrollment and then underwent a 3-month washout period before having up to 2 years to attempt pregnancy, and to conceive, give birth to, and breastfeed a baby. They were then “strongly recommended” to resume endocrine therapy to complete the planned 5-10 years of treatment, with follow-up planned for up to 10 years.
In all, 518 women were enrolled at 116 centers in 20 countries on four continents, of whom 516 were available for the primary efficacy analysis. The median time from breast cancer diagnosis to enrollment was 29 months.
The median age of the participants at enrollment was 37 years, and 75% had no prior births. Stage I or II disease was diagnosed in 93%. The median duration of endocrine therapy prior to enrollment was 23.4 months.
Selective estrogen receptor modulators were given alone in 42% of patients, while 36% had a SERM plus ovarian function suppression. A further 16% of women received an aromatase inhibitor alongside ovarian function suppression. The majority (62%) of women had received prior neoadjuvant chemotherapy.
The primary endpoint of 3-year BCFI was measured after a median follow-up of 41 months. There were 44 events, with a 3-year BCFI failure rate of 8.9%. The 3-year distant recurrence–free interval (DRFI) failure rate was calculated at 4.5%, with 22 events.
To provide an external control, the researchers examined data from the SOFT and TEXT trials to assemble a cohort of 1,499 women balanced for patient, disease, and treatment characteristics.
This revealed no significant differences in BCFI between the two groups (hazard ratio, 0.81; 95% confidence interval, 0.57-1.15) and a difference in BCFI rates at 3 years of 0.2% between the SOFT, TEXT, and POSITIVE trials.
There was also no significant difference in DRFI rates (HR, 0.70; 95% CI, 0.44-1.12), with a 3-year rate difference of 1.4%.
For the secondary endpoint analysis, the team included 497 women from the POSITIVE cohort, of whom 368 (74%) had at least one pregnancy, giving a total of 507 pregnancies. At least one live birth was recorded in 64% of the women, or 86% of those who became pregnant.
Dr. Partridge noted that around 43% of women used some form of assisted reproductive technology at some point during the study period.
Pregnancy complications were observed in 11% of pregnancies, the most common of which were hypertension/preeclampsia in 3%, and diabetes in 2%.
There were a total of 350 live births in 317 women, including 335 singleton births and 15 sets of twins. Only 8% of the offspring had a low birth weight, and 2% had a birth defect. Breastfeeding was reported by 62% of women.
Conducting an 18-month landmark analysis, the team found that pregnancy did not increase BCFI rates, at an HR versus nonpregnant women of 0.53 after controlling for age, body mass index, lymph node status, prior chemotherapy, and prior aromatase inhibitor therapy.
At 48 months of follow-up, 76% of women had resumed endocrine therapy. A further 8% of women had cancer recurrence or death before they could restart therapy, while 15% had not yet resumed treatment for other reasons.
Among disease-free women who had not resumed endocrine therapy, 79% reported at their most recent follow-up continuing to pursue pregnancy, having an active or recent pregnancy, or continuing to breastfeed as the reason.
Commenting on the study, Jennifer K. Litton, MD, vice president of clinical research at University of Texas MD Anderson Cancer Center, Houston, said that this was a “challenging study to design and execute.”
“It gives us really a first look into the safety of a practice that was already happening,” she commented, and emphasized that the interruption of treatment to pursue pregnancy remains “an exceptionally individual decision.”
Dr. Litton also underlined that these results apply only to endocrine therapy and not to women on other therapies such as abemaciclib, for example, for which the course should be “fully completed” before considering any treatment interruptions.
She added more generally that “we need to continue to improve discussing fertility concerns with our breast cancer patients who want future pregnancies.”
The study was sponsored and conducted by the International Breast Cancer Study Group, a division of ETOP IBCSG Partners Foundation, and by the Alliance for Clinical Trials in Oncology in North America, in collaboration with the Breast International Group. Dr. Partridge and Dr. Litton reported no relevant relationships.
A version of this article first appeared on Medscape.com.