The POSITIVE trial was designed in light of the fact that many young breast cancer patients still have not had a child or completed their family when they are diagnosed with breast cancer; they desire pregnancy both at diagnosis and in their survivorship. While retrospective evidence has demonstrated that there is no clear harm from a pregnancy after a breast cancer, the standard 5-10 years of endocrine therapy that we use to reduce risk in hormone sensitive breast cancer is associated with a lot of time that can lead to the natural decline in fertility. So we designed a practical study, the POSITIVE trial, to look at the interruption of endocrine therapy. So, temporary interruption of endocrine therapy to attempt pregnancy and then follow those patients over time after they get back on.
The study was designed to follow a cohort of women enrolled within 18-30 months of starting their endocrine therapy, so they had to have been on at least 18 months of endocrine therapy and no longer than 30 months. It was a single arm study so women were eligible if they were 42 or younger, had had early stage breast cancer treated with curative intent, no signs of recurrence, were being treated with adjuvant endocrine therapy for hormone receptor positive disease history and desired pregnancy. They were enrolled and then they had to have a three month washout of their endocrine therapy. So they stopped their endocrine therapy for at least three months before trying to get pregnant. They were encouraged to try to get pregnant for up to two years and then to get back on after either pregnancy or no pregnancy and, if they got pregnant, carrying the pregnancy obviously, hopefully, to full term, delivering a healthy baby, hopefully, and then nursing if so desired. The goal was to get them back on to endocrine therapy within two years and then following them over time for both their disease outcomes – both any breast cancer event as well as, importantly, distant events as well as psychosocial outcomes, fertility and offspring outcomes and then there was a big translational science component to the study as well.
The key findings of the POSITIVE trial are that temporary interruption of endocrine therapy, as it was done in the POSITIVE trial for at least the population enrolled, did not appear to impact short-term disease outcomes. We specifically looked at a safety threshold and there had to be no more than 46 events in the follow-up period which was about three years after enrolment and there were only 44 events in the POSITIVE cohort. We then used an external control group which was selected from the TEXT and SOFT clinical trials, similar populations, and we selected women that would have been eligible for POSITIVE, including two years into their endocrine therapy because that’s the average when people enrolled in POSITIVE. We matched them based on several prognostic and predictive factors and we did special testing to calculate the control group risks and then we compared this external control group to the POSITIVE cohort. We saw that there was no difference in all breast cancer events as well as no difference in distant events between the POSITIVE cohort and the control group. So that leads us to no clear harm in pregnancy after breast cancer with a temporary interruption among women desiring pregnancy, as we demonstrated in the POSITIVE trial. That was the key finding.
Other key findings from the POSITIVE trial included the fact that 74% of women who enrolled had at least one pregnancy, most of them had the pregnancy within two years and most of those women had live births. Birth defects were low, at about 2%, and that appeared to be similar for age populations similar in the general population.
The clinical impact of the initial results from the POSITIVE trial tell us that, at least in the short term because follow-up was only approximately three years which was on average about five years out from diagnosis, temporary interruption of endocrine therapy in patients eligible for POSITIVE is a reasonable thing to do because it does not appear to impact on at least short-term disease outcomes.
That being said, it’s not for everyone. Some people did recur during the POSITIVE trial, as one might expect in a cohort of young breast cancer patients. So women and their loved ones and their providers need to decide if a temporary interruption and to follow the POSITIVE protocol now that it’s out there and we know the results, at least early on, is the right thing for them. But certainly it’s reassuring for women who do want to try to have a pregnancy and want to take a temporary interruption of their endocrine therapy.
The other critical factor is we’re going to follow these women long term. We want to go at least ten years to follow them out for how they do with regard to their disease outcomes in particular. Because in the setting of hormone receptor positive breast cancer we know there’s a late recurrence risk.
The only other thing I would like to mention is that this study was really a labour of love, pun intended, both for the patients who could have gone and gotten pregnant on their own and not enrolled in a clinical trial to look at this. So they really did this both for themselves and for future patients to learn about the safety of having a baby after breast cancer and interrupting endocrine therapy. And also for all the investigators, the doctors who put these patients on trial, for doing this throughout the world – it really was a global effort and I’m very grateful to have been able to be a part of it.