Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy

Abstract

Purpose: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy.

Patients and methods: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months.

Results: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5).

Conclusion: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Figure 1

Cumulative incidence of menstruation recovery, in the presence of competing risks (competing events that occur prior to menstruation recovery), among 273 women in the POSITIVE trial who had persistent amenorrhea at enrollment. A: Recovery in all patients (also showing curves for competing events occurring prior to menstruation recovery) B: Recovery according to no prior chemotherapy use and the prior use of chemotherapy with or without GnRH analogues for fertility preservation (curves for competing events occurring prior to menstruation recovery are not shown)

Figure 1

Cumulative incidence of menstruation recovery, in the presence of competing risks (competing events that occur prior to menstruation recovery), among 273 women in the POSITIVE trial who had persistent amenorrhea at enrollment. A: Recovery in all patients (also showing curves for competing events occurring prior to menstruation recovery) B: Recovery according to no prior chemotherapy use and the prior use of chemotherapy with or without GnRH analogues for fertility preservation (curves for competing events occurring prior to menstruation recovery are not shown)

Figure 2

A: Cumulative incidence of menstruation recovery over time by age amongst the 273 patients who had amenorrhea at enrollment, in the presence of competing risks. At 6 and 12 months from enrollment, patients younger than 35 years of age had a cumulative incidence of menstruation recovery of 85.4% (95% CI: 76.4 – 91.2%) and 93.8% (95% CI: 86.1– 97.3%), respectively, compared to 89.3% (95% CI: 81.3 – 94.0%) and 95.1% (95% CI: 88.2% - 98.1%) in patients aged 35 – 39, and 75.4% (95% CI: 62.2 – 84.5%) and 93.4% (95% CI: 81.6 – 97.8%), in patients 40 – 42 years of age. B: Cumulative incidence of pregnancy over time since enrollment, in the presence of competing risks, among 497 women in the POSITIVE trial according to age at enrollment. At 1 and 2 years from enrollment, patients younger than 35 years of age had a cumulative incidence of pregnancy of 63.5% (95% CI: 55.6 – 70.4%) and 80.3% (95% CI: 73.1 – 85.7%), respectively, compared to 54.3% (95% CI: 47.4 – 60.7%) and 73.7% (95% CI: 67.1% - 79.1%) in patients aged 35 – 39, and 37.7% (95% CI: 28.7 – 46.6%) and 50% (95% CI: 40.2 – 59.0%), in patients 40 – 42 years of age.

Figure 2

A: Cumulative incidence of menstruation recovery over time by age amongst the 273 patients who had amenorrhea at enrollment, in the presence of competing risks. At 6 and 12 months from enrollment, patients younger than 35 years of age had a cumulative incidence of menstruation recovery of 85.4% (95% CI: 76.4 – 91.2%) and 93.8% (95% CI: 86.1– 97.3%), respectively, compared to 89.3% (95% CI: 81.3 – 94.0%) and 95.1% (95% CI: 88.2% - 98.1%) in patients aged 35 – 39, and 75.4% (95% CI: 62.2 – 84.5%) and 93.4% (95% CI: 81.6 – 97.8%), in patients 40 – 42 years of age. B: Cumulative incidence of pregnancy over time since enrollment, in the presence of competing risks, among 497 women in the POSITIVE trial according to age at enrollment. At 1 and 2 years from enrollment, patients younger than 35 years of age had a cumulative incidence of pregnancy of 63.5% (95% CI: 55.6 – 70.4%) and 80.3% (95% CI: 73.1 – 85.7%), respectively, compared to 54.3% (95% CI: 47.4 – 60.7%) and 73.7% (95% CI: 67.1% - 79.1%) in patients aged 35 – 39, and 37.7% (95% CI: 28.7 – 46.6%) and 50% (95% CI: 40.2 – 59.0%), in patients 40 – 42 years of age.

Figure 3

Cumulative incidence of breast cancer among women in the POSITIVE trial A: Among 497 women, by use of embryo/oocyte cryopreservation status at diagnosis (prior to enrollment to POSITIVE) B: Among 397 women breast-cancer free with known ovarian stimulation status, and in follow-up at 24 months after enrollment (landmark analysis), by ovarian stimulation during the POSITIVE study. 10 women who had an unknown ovarian stimulation status (0 events) are not included in this figure.

Figure 3

Cumulative incidence of breast cancer among women in the POSITIVE trial A: Among 497 women, by use of embryo/oocyte cryopreservation status at diagnosis (prior to enrollment to POSITIVE) B: Among 397 women breast-cancer free with known ovarian stimulation status, and in follow-up at 24 months after enrollment (landmark analysis), by ovarian stimulation during the POSITIVE study. 10 women who had an unknown ovarian stimulation status (0 events) are not included in this figure.