SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Majority of these patients are diagnosed with early stage disease and are often cured with a combination of surgery, radiotherapy, adjuvant chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment.
The median age at the time of breast cancer diagnosis in the US is 62 years. However approximately 5% of new diagnoses each year occur in those who are under 40 years. These young patients with Hormone Receptor (HR)-positive breast cancer receiving modern adjuvant endocrine therapy have excellent long-term outcomes. Nonetheless, 40-60% of patients who are diagnosed with breast cancer at age 40 or younger are concerned about their future fertility and pregnancy, as many have not completed their family planning at diagnosis due to delay in childbearing.
The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer) trial is a multicenter, global, single-arm prospective study, designed to evaluate whether temporary interruption of adjuvant endocrine therapy to attempt pregnancy is associated with a higher risk of breast cancer recurrence. This study included 517 women with Stage I-III Hormone Receptor (HR)-positive early breast cancer, 42 years or less, who had received 18-30 months of adjuvant endocrine therapy and wished to interrupt endocrine therapy for pregnancy. The study permitted treatment interruption for up to 2 years (after a 3 month endocrine therapy washout period) to allow pregnancy, delivery and breastfeeding, followed by endocrine therapy resumption to complete the planned duration of 5-10 of adjuvant endocrine therapy. The median age was 37 years, 75% were nulliparous, fertility preservation was used by 51% of women, 93% had Stage I/II disease, 66% were node negative and 62% had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed endocrine therapy (42%), followed by Tamoxifen plus Ovarian Function Suppression (OFS) (35%).
The Primary endpoint of the study was Breast Cancer-Free Interval (BCFI), defined as the time from study enrollment to the first invasive breast cancer event (local/regional/distant recurrence or contralateral breast cancer). Three interim safety analyses were conducted by a Data Safety Monitoring Committee, and determined that the trial would be suspended if there were more than 46 breast cancer recurrences within approximately 3 years of average follow-up. This threshold however was not reached.
At a median follow up of 41 months, of the 497 patients evaluated for pregnancy status, 74% (N=368) had at least one pregnancy, with 70% of the pregnancies occurring within 2 years. Additionally, 63.8% (N=317) had at least one live birth, with a total of 365 babies born. Birth defects were low at 2% and the rates of conception and childbirth were similar to rates in the general public. The 3-year breast cancer recurrence rate among patients who halted therapy 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 patients. Long term follow up is ongoing to assess recurrence risk over time, and trial participants were strongly recommended to resume endocrine therapy following their pregnancy attempts or success.
The authors concluded that these data provide guidance to younger patients diagnosed with early breast cancer on endocrine therapy, who may be hoping to have children. They added that such decisions should be made in close consultation with health professionals.
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). Partridge A, Niman SM, Ruggeri M, et al. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.
