Pregnancy Outcome & Safety of Interrupting Therapy for Women with Endocrine ResponsIVE Breast Cancer.

Research remains an essential part of cancer care. In this blog, we will provide information about recent updates or new approvals as it applies to breast cancer written by Dr. Sharon Wilks. 

POSITIVE TRIAL Pregnancy Outcome & Safety of Interrupting Therapy for Women with Endocrine ResponsIVE Breast Cancer.

(Initial Results from the POSITIVE Trial presented by Ann Partridge Harvard Medical School at the 2022 San Antonio Breast Cancer Symposium).

The background for this study is that after young women complete treatment for breast cancer, there may be a desire to proceed with trying to get pregnant particularly if the person has not been pregnant before and is growing older and becomes nervous that she may not be able to become pregnant. Most patients are directed to check with her oncologist before attempting pregnancy. However, there has been limited prospective data to guide clinicians and patients on the safety of pregnancy post diagnosis. There have been retrospective analysis that have suggestive safety as far as breast cancer survival, avoidance of birth defects and the ability of survivors to become pregnant but there still has been some uncertainty of timing and how to manage the treatment with endocrine blockade for women with hormone receptor (Estrogen and/or Progesterone Receptor positive Breast cancers) if there is interest to become pregnant. If someone is on hormone therapy, many treatments last a minimum of 5-10 years which is beyond the time that it may be possible for a survivor to become pregnant. There has been uncertainty of when it might be safe to interrupt endocrine blockade (usually in the form of Tamoxifen/Nolvadex® or use of Ovarian Function Suppression/OFS) and if pregnancy has been successful, there is limited time to know how long it may be safe to wait to resume endocrine blockade particularly if a survivor is interested in breast feeding.

This international study sponsored by IBCSG was a prospective single arm trial designed to address if it is safe (from a breast cancer recurrence risk) to interrupt use of endocrine treatment to allow for a person to become pregnant after a diagnosis of breast cancer. This study enrolled only patients with Hormone Receptor positive breast cancer who had been on adjuvant endocrine therapy. The investigators looked at the duration or prior endocrine blockade prior to stoppage of this therapy and the timing of pregnancy and the time of resumption of endocrine blockade therapy after completion of pregnancy to complete the previously recommended treatment.

Individuals that were eligible for this study were women ages </= 42 years of age who remained premenopausal who had already taken a minimum of 18 – 30 months of adjuvant endocrine blockade therapy. Patients were eligible if they had a history of early stage breast cancer that had hormone receptor positive breast cancer and who had no evidence of metastasis. Individuals who participated could have received prior chemotherapy in the preoperative or postoperative setting and could have also received fertility preservation therapy.

The Trial procedure was as follows: use of prior endocrine therapy from a minimum to 18-30 months prior to enrollment in study and then one month after enrollment, this endocrine blockade therapy was then stopped for  three months to allow for a washout before pregnancy was attempted.  A  two-year period was allowed to have the person attempt to get pregnant (if no pregnancy occurred within one year, the patient was strongly recommended to consider undergoing fertility assessments). Once the pregnancy did occur and breastfeeding, if desired was completed, then adjuvant endocrine blockade was strongly advised to resume to complete the original proposed 5-10 years.

The primary endpoint was Breast Cancer Free Interval (BCFI) defined as the time of enrollment on study to the first ipsilateral or contralateral invasive disease or distant recurrence.

Secondary outcomes looked at pregnancy outcomes, breastfeeding, use of assisted reproductive measures, adherence to endocrine blockade and distant recurrence free interval (defined from the time of study enrollment to an event with cancer diagnosed in a distant site).

To allow for a perspective on these findings, the investigators compared outcomes with a cohort of early stage breast cancer survivors (1499 patients were included) who had participated in a separate study: SOFT/TEXT study as an external control.

There were 518 patients enrolled in this international study from 116 centers from 20 countries from December 2014 to December 2019. Median time from enrollment from the diagnosis of breast cancer was 29 months. Median follow-up at the time of this report was 41 months. Median age at time of enrollment was 37 years of age. 75% of the participants were nulliparous (never had a pregnancy before enrollment on study). 47% of the participants had a stage 1 diagnosis and another 47% had been diagnosed with a stage 2 breast cancer. Thus, the majority of this data is more applicable to patients with stages 1 & 2 breast cancer with hormone receptor positive disease. Median time of endocrine blockade use (most used a SERM/Tamoxifen with or without use of OFS) at study entry was  about 23 months.

8.9% BCFI at three years with 4.5% DRFI was reported. These findings were compared to the SOFT/TEXT trial cohort and similar outcomes were seen with a slightly lower rate of DRFI in the experimental group from the POSITIVE trial. BCFI was influenced by a personal history of node positive and HER 2 Neu positive (high expression):  Individuals with low or no nodal involvement and who did not have HER 2 NEU overexpressing tumors had less risk of distant recurrences. Importantly, when the subgroup of patients who successfully became pregnant versus those who did not become pregnant, there was no difference in the BCFI reported. Another important finding indicated that 64% of participants were able to become pregnant and had at least one live birth from this study (84% of the cohort who became pregnant were able to have a successful delivery of at least one infant). 11% of the patients who became pregnant had complications related primarily to preeclampsia/hypertension or Diabetes. 19% of participants who became pregnant did experience a miscarriage. 96% of patients who became pregnant did not have any birth defects.

Endocrine adherence for resumption of therapy at 48 months, 76% of the participants had resumed therapy; 8% had suffered a recurrence prior to the resumption of Endocrine blockade therapy.

Study investigators demonstrated that short term interruption of Endocrine blockade does not adversely affect short term outcomes for women who desire pregnancy after a diagnosis of an early-stage hormone receptor positive breast cancer. 74% of women were able to become pregnant with a 2% birth defect rate.

This study, amongst many at the recent SABCS, shows us how important research is and without it, we have limited information on how to guide individuals who are survivors on next steps of interest in their lives. We at NEXT Oncology focus primarily on novel ways via research to improve outcomes for patients with cancer and encourage all who are eligible for a clinical trial to consider participation.