POSITIVE Trial Update on Patients With Breast Cancer Attempting Pregnancy

POSITIVE trial data presented at this year’s San Antonio Breast Cancer Symposium show that among women with hormone receptor–positive (HR+) breast cancer who paused adjuvant endocrine therapy (ET) to attempt pregnancy, 94% who reported amenorrhea at enrollment resumed their periods within 6 months. In addition, embryo transfer after embryo/oocyte cryopreservation at diagnosis had higher rates of pregnancy vs ovarian tissue cryopreservation and gonadotropin hormone-releasing hormone (GnRH) agonists for ovarian stimulation.

Hatem Azim, Jr, Md, PhD

Image Credit: Tecnológico de Monterrey

Lead investigator Hatem Azim, Jr, Md, PhD, adjunct professor of oncology, School of Medicine, Tecnológico de Monterrey, Mexico, presented the updated results in this year’s session, “Fertility Preservation and Assisted Reproductive Technologies (ART) in Breast Cancer (BC) Patients (Pts) Interrupting Endocrine Therapy (ET) to Attempt Pregnancy.”

“Many breast cancer patients may opt for fertility preservation prior to starting cancer treatment and/or may use assisted reproductive technologies to increase their chances of pregnancy,” said Hazim in a press release announcing the results.¹ “Yet, there is concern within the medical community that the use of fertility preservation or ART methods, particularly those that entail the use of hormones, could have detrimental effects on patients with HR+ breast cancers.”

Data on these secondary outcomes of menstruation and use of assisted reproductive technology (ART) update POSITIVE trial (NCT02308085) primary outcome data on breast cancer–free interval presented at last year’s meeting, which showed a similar small rate of disease recurrence among the study population vs external controls from the SOFT (NCT00066690) and TEXT (NCT00066703) trials after 41 months of follow-up: 8.9% vs 9.2%.^2,3 At that time, second author Ann Partridge, MD, MPH, vice chair of medical oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, noted, “Results to date indicate that the decision to pause therapy can be made safely, in consultation between women and their physicians.”²

POSITIVE enrolled premenopausal women within 1 month of stopping ET who had stage 1-3 HR+ breast cancer, all of whom were 42 years and younger at enrollment, had 18 to 30 months of adjuvant ET, and did not have clinical evidence of recurrence. Additional secondary outcomes are pregnancy outcomes, offspring outcomes, breastfeeding, adherence to ET, and distant recurrence-free intervals. All patients were asked to keep a 2-year menstrual diary, and the use of any ART was allowed. After a 3-month washout period, there was a maximum 2-year break to allow for conception, delivery, and breastfeeding. This was followed by resuming ET for 5 or 10 years.

Data for this secondary analysis again were collected after a median 41 months of follow-up. Of the 518 overall study population, 516 were included in the menstruation analysis and 497 in the fertility preservation and ART analysis.

Statistics between the groups were comparable: 66% each were 35 years or older, 34% each were lymph node-positive, 62% each reported prior chemotherapy, and 75% each reported no prior live birth.

During the course of the study, 94% of the 273 patients who reported amenorrhea at enrollment—53% of the secondary analysis population—had restarted their periods. At the 6-month mark, breaking this down by adjuvant therapy, 90% who did not receive adjuvant ET had resumed their periods vs 85% who had received chemotherapy plus GnRH analogs and 81% who had received chemotherapy but not GnRH analogs.

Seventy-four percent reported at least 1 pregnancy, and a shorter time to pregnancy was seen among the women younger than 35 years. At 12 months since study enrollment, 64% reported at least 1 pregnancy vs 38% of those aged 40 to 42 years. This gap widened to 80% and 50% by 24 months since study enrollment. The final age group in this analysis, women aged 35 to 39, had a pregnancy rate that fell in between.

In a multivariate model that included prior birth, irregular vs persistent amenorrhea, no ET vs chemotherapy alone, and treatment with selective estrogen receptor modulator (SERM) plus ovarian function suppression vs SERM only, “only younger age was associated with a short time to pregnancy,” Azim noted. Compared with women aged 35 to 39 and 40 to 42 years, women 35 years and younger had 26% and 60% greater chances of becoming pregnant.

Among the women reporting fertility preservation at breast cancer diagnosis or who underwent ART after POSITIVE enrollment, ovarian stimulation for embryo/oocyte cryopreservation (36%), ovarian stimulation for IVF (16%), and cryopreserved embryo transfer (14%) were the top 3 methods used. Overall, 51% of the secondary analysis population underwent fertility preservation at diagnosis and 43% underwent ART.

When looking at patient characteristics by choice of ART, women who underwent embryo or oocyte cryopreservation reported the highest rates of prior adjuvant chemotherapy (71%). The women who underwent transfer of cryopreserved embryos were more likely to be 35 years or older (76%), be lymph node-positive (44%), and report prior adjuvant chemotherapy (71%). Those who underwent ovarian stimulation for IVF were more likely to be older (71%). Just over 85% overall were nulliparous.

In addition, cryopreserved embryo transfer was the only modality significantly associated with a higher chance of pregnancy, with women who underwent the procedure having a 2.41 greater odds of pregnancy vs those who underwent a different ART procedure (1.8 higher odds) or no ART (1.41 higher odds), with no effect on their breast cancer prognosis. Independent of the use of ART, younger age (younger than 35 vs 35-39 and 40-42 years) was associated with 50% and 84% greater chances of pregnancy, respectively.

Lastly, when looking at ovarian stimulation and breast cancer outcomes, “We did not find any meaningful difference between patients who underwent ovarian stimulation and those who did not,” Azim said. There were equivalent rates in BCFI cumulative incidence after 3 years. After diagnosis in those who did this as part of their embryo/oocyte cryopreservation vs those who did not, the BCFI rates were 9.7% and 8.7%, respectively. For those who did ovarian stimulation for IVF as part of ART vs those who did not, at 2 years, there were 2 and 8 BC events, respectively.

“Obviously, this is the largest prospective study to investigate fertility preservation and assisted reproductive technology in patients with early HR+ breast cancer who desire future pregnancy, underscoring the importance of oncofertility counseling in young patients with breast cancer," Azim said in a press conference announcing these results.

Previous research showed safety for pregnancy after breast cancer, regardless of HR status and that adjuvant ET can have an adverse impact on future fertility, but that uncertainty remains for pregnancy outcomes among those with HR+ disease undergoing ovarian stimulation.^4-6

The estimated primary completion date for POSITIVE is December 2025, and the estimated study completion date is December 2028.⁷

References

1. Patients with HR-positive breast cancer may use fertility preservation and assisted reproductive technologies without increased risk of recurrence. News release. American Association for Cancer Research. December 7, 2023. Accessed December 8, 2023. https://aacr.ent.box.com/s/iim2ep4gyeux1k985golspb3qotpk691
2. Pausing breast cancer treatment to get pregnant, and other news from SABCS 2022. American Association for Cancer Research. January 12, 2023. Accessed December 8, 2023. https://www.aacr.org/blog/2023/01/12/pausing-breast-cancer-treatment-to-get-pregnant-and-other-news-from-sabcs-2022/
3. Highlights from SABCS 2022 clinical trial data. Pharmacy Times®. January 16, 2023. Accessed December 8, 2023. https://www.pharmacytimes.com/view/highlights-from-sabcs-2022-clinical-trial-data
4. Azim HA, Kroman N, Paesmans M, et al. Prognostic impact of pregnancy after breast cancer according to estrogen receptor status: a multicenter retrospective study. J Clin Oncol. 2013;31(1):73-79. doi:10.1200/JCO.2012.44.228
5. Turan V, Lambertini M, Lee D-Y, et al. Association of germline BRCA pathogenic variants with diminished ovarian reserve: a meta-analysis of individual patient-level data. J Clin Oncol. 2021;39(18):2016-2024. doi:10.1200/JCO.20.02880
6. Partridge AH, Niman SM, Ruggeri M, et al. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388(18):1645-1656. doi:10.1056/NEJMoa2212856
7. Pregnancy outcome and safety of interrupting therapy for women with endocrine responsive breast cancer (POSITIVE). Clinicaltrials.gov. Updated March 16, 2023. Accessed December 8, 2023. https://clinicaltrials.gov/study/NCT02308085