POSITIVE Trial: Stopping Hormone Therapy for Pregnancy in Breast Cancer Patients
Stopping hormone therapy treatment to attempt pregnancy may be an option for hormone-receptor-positive breast cancer patients. Halle Moore, MD, Director of Breast Medical Oncology and Co-Director of the Comprehensive Breast Cancer Program joins the Cancer Advances podcast to discuss her research and encouraging findings of the POSITIVE trial that was presented at the San Antonio Breast Cancer Symposium (SABCS) 2022 annual meeting.
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POSITIVE Trial: Stopping Hormone Therapy for Pregnancy in Breast Cancer Patients
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Sephardi, a medical oncologist here at Cleveland Clinic overseeing our Taussig phase one and sarcoma programs. Today I'm happy to be joined by Dr. Halle Moore, Director of Breast Medical Oncology in the Department of Hematology and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute, and co-director of the Cleveland Clinic Comprehensive Breast Cancer Program. She was previously a guest on this podcast and discuss the Cleveland Clinic Breast Cancer Survivorship Program. She's here today to talk to us about research that was recently presented at the San Antonio Breast Cancer Symposium titled Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsive breast cancer primary results from the POSITIVE trial. So welcome back, Halle.
Halle Moore, MD: Thanks, Dale. Great to be back here again.
Dale Shepard, MD, PhD: So just briefly remind us, what's your role here at Cleveland Clinic? What do you do?
Halle Moore, MD: So I direct the Medical Oncology Breast Cancer program, and I'm also co-director of our Cleveland Clinic Wide Comprehensive Breast Cancer Program.
Dale Shepard, MD, PhD: And Cleveland Clinic Wide, meaning all of Cleveland Clinic.
Halle Moore, MD: All of us.
Dale Shepard, MD, PhD: There you go. So we're going to talk about this positive trial here today. And let's just start off, what was the impetus for the trial? Why was this trial sort of thought of in the first place?
Halle Moore, MD: Yeah. So breast cancer is actually one of the most common cancers in a young adult women. And so many women who are diagnosed with breast cancer may be still interested in future pregnancy. So pregnancy can be very complicated in people who have a breast cancer diagnosis for a couple of reasons. One is that most breast cancers are hormone sensitive, meaning that the normal reproductive hormones can stimulate those cancers to grow. So there's a fear that hormones associated with pregnancy may cause a breast cancer to grow or recur. The second issue that is particularly challenging in women with a prior breast cancer diagnosis is that women who have hormone sensitive disease are generally recommended to take anti-estrogen or estrogen lowering treatments long-term, so maybe five to 10 years as part of their treatment for the cancer. These medications should not be continued while pregnant. So the additional challenge that these women can face is that by the time they complete these treatments, they're older, and their fertility would be at further risk.
Dale Shepard, MD, PhD: So prior to this study, what was the usual guidance? Were women just trying to avoid being pregnant? Was there some sort of uniform guidance or was it kind of all over the map?
Halle Moore, MD: Guidance was highly variable prior to this prospective study. We do have retrospective data that do not suggest an increase in recurrence risk for women who become pregnant following a breast cancer diagnosis, including those with hormone sensitive disease and including those who became pregnant within the first five years after their diagnosis. And in fact, some of the studies suggest that these women may actually do better than similar patients who did not become pregnant. Although of course there are many challenges with retrospective data sets and the healthier patients may opt to become pregnant or may undergo additional screening prior to attempting pregnancy. So these results could certainly be biased.
Dale Shepard, MD, PhD: Got you. So this is a prospective trial. So what exactly was done here?
Halle Moore, MD: Yeah. So in this study, we sought to evaluate the safety of interrupting hormonal treatment in order to attempt pregnancy. So this included premenopausal women who were up to age 42 who had early stage hormone receptor positive breast cancer and desired pregnancy. So the participants in this study then had 18 to 30 months, so about two years of endocrine therapy under their belt, and then upon enrollment in the trial interrupted their hormonal treatment and was recommended that they within about two years, undergo a washout period of three months to allow the drugs to get out of their system prior to attempting pregnancy if pregnancy is achieved, carrying the pregnancy, then nursing if desired and able. And then the hope was that participants would resume their hormonal treatment within two years of study enrollment. And then the cohort was followed for recurrence of their breast cancer as well as for pregnancy outcomes.
Dale Shepard, MD, PhD: And so patients had been on therapy for about two years. They had that washout period. How long on average were people off their hormone therapies before they got pregnant? So what kind of time period are we thinking that they were off treatment?
Halle Moore, MD: So I don't have the data for how long they were typically off before they were successful in achieving the pregnancy. About three quarters of the patients in the study did achieve a pregnancy, and by the end of the study at the current follow up of about three and a half years, about three quarters of the patient were back on their hormonal therapy.
Dale Shepard, MD, PhD: And certainly the hormonal manipulations can affect the likelihood of becoming pregnant. Was there an increased risk of not becoming pregnant because of those hormonal manipulations?
Halle Moore, MD: So it's hard to know what the fertility rates would've been in this population. The average age was late 30s. So I think the fact that three quarters of the patients did become pregnant, many of these had prior chemotherapy, about two thirds of these patients had prior chemotherapy. So I think it was actually a pretty good pregnancy rate. But there are many things that may have affected the fertility, but since they were off of the hormonal treatments, that probably was not the major factor.
Dale Shepard, MD, PhD: Right. Right. So what did the study show?
Halle Moore, MD: So as part of the study design, it was felt that a greater than 4 percent per year breast cancer free interval event. So basically, a recurrence of breast cancer, either locally distant or a new primary, and event rate of about 4 percent per year would be a red flag for safety. So at 41 months, which is about three and a half years of follow up, the annual event rate was about two and a half percent for this cohort. So at first glance, it appears to be relatively safe to further analyze the safety though, a very interesting analysis was done. And that was taking another modern cohort of patients receiving endocrine therapy, specifically participants in these soft and text trials, which were adjuvant hormonal trials looking at different endocrine treatments. So tamoxifen alone, tamoxifen with ovarian ablation or ovarian ablation and an aromatase inhibitor.
And these were the types of treatments that the patients in the positive cohort received. So what they did was matched patients from the soft and text trial for age, types of treatments, stage, variables that should affect recurrence risk, and looked at the anticipated outcomes in the soft and text trial. And over that follow-up period, so there were a total of about 8.9 percent of patients had a breast cancer-free interval event on the positive trial. When they looked at a similar cohort in the soft and text trials, that event rate was about 9.1 percent. So very similar results and no suggestion of an increase. And similarly, when they looked specifically at distant relapse free events, they found slightly less actually in the positive trial than in the softened text trials. So again, recurrence rates very similar to what we would expect in a modern cohort treated with similar treatments.
Dale Shepard, MD, PhD: That's great. The nature of the trauma might not be possible to tease out, are there any particular patients that are maybe more or less at risk to have this sort of hold on their endocrine therapy?
Halle Moore, MD: So we found that if you looked at the risk factors for recurrence, they were basically primarily related to what you would expect to be risk factors for recurrence. So moral lymph nodes involved, larger tumors, typical risk factors. Another analysis that was very interesting that was done was looking at amongst the participants in the positive trial outcome by whether or not they achieved a pregnancy. So remember about a quarter of the patients did not become pregnant in spite of attempting. And it showed that the recurrence rate in those patients who became pregnant was about half of what it was in the patients who didn't become pregnant. Now, we're talking secondary analyses. This must be taken with a grain of salt, but certainly no evidence that the pregnancy itself increased the risk. But it does raise a question of whether interrupting hormonal treatment and not becoming pregnant may be a risk factor for recurrence.
Dale Shepard, MD, PhD: And I guess that being said, just thinking practically ahead and how this sort of data you can use for guiding patients, is there a sense of how long you might be comfortable having a patient try to become pregnant before going back on their therapy?
Halle Moore, MD: Yeah. So in this trial, the attempt, the hope was to get them back on treatment within two years. So really not trying for more than a year or so to get pregnant. But I think this suggests to me that it's going to be very important for patients that do interrupt treatment and to attempt pregnant to have an assessment upfront of what their likelihood is of achieving pregnancy and working with reproductive endocrinologist perhaps to improve the prospects of getting pregnant and shorten the time before they become pregnant. So I think this really supports this multidisciplinary care to help patients to try to achieve pregnancy if they're going to interrupt treatment.
Dale Shepard, MD, PhD: And so now that we have the primary results here, is this going to lead to further study of a subsets or durations, or where does this go next?
Halle Moore, MD: Yeah. So there are a number of correlative studies that are being done. Blood was collected for looking at circulating tumor DNA. So there are a number of different analyses that are planned, but what I think is the number one most important thing is the 10-year follow-up that's planned. So this cohort will be followed long term. And remember, we're only looking at three year recurrence risk, and it's quite possible that the results will change over time. So I think it's really going to be important to continue to follow this cohort and assure the long-term safety of this approach.
Dale Shepard, MD, PhD: And again, because there's a number of people who might be listening in and may not necessarily treat breast cancer often, when would be the anticipated peak of recurrence? So we're looking at three years, we're going out to 10 years. What's most likely in terms of recurrence from a time standpoint?
Halle Moore, MD: Yeah. So with hormone receptor positive breast cancer, recurrence risk is fairly steady over time. So different from triple negative or more aggressive histologies where most of the recurrence occur early on, such as within the first five years with estrogen sensitive breast cancer, late recurrences are not at all uncommon. And so it's really important that we continue to monitor beyond 10 years.
Dale Shepard, MD, PhD: So there may well be some changes over time.
Halle Moore, MD: Correct.
Dale Shepard, MD, PhD: Interesting. So let's shift gears briefly here. In terms of the trial itself. We talked about the patients and the results, big undertaking, how did these things happen? And specifically, this was a related to cooperative group. And so give us a little bit of an idea, just big picture, how do these things work?
Halle Moore, MD: So this was an international effort. So this was run primarily through the IBCSG, the International Breast Cancer Study Group. So this study enrolled patients from 20 different countries on four continents and accrued patients over about five years. And there were more than 500 patients involved in this study.
Dale Shepard, MD, PhD: So it's just important when people think about these studies, these aren't quick and easy. These are massive efforts.
Halle Moore, MD: Yeah. And I think the fact that in a relatively short amount of time this trial was able to complete its accrual just highlights what an important survivorship issue this is for so many of our patients.
Dale Shepard, MD, PhD: So I guess speaking of the survivorship, and of course with your interest in it, what's the biggest gap you think right now, and this is related to pregnancies after treatment and how that might work, do you think are some of the biggest gaps that remain?
Halle Moore, MD: Oh my goodness. There are so many areas in survivorship. So fertility has been an important interest of mine. There are a number of late effects that can affect quality of life. I think neuropathy is a large one that we're really looking for more helpful interventions to prevent and treat. There's a lot of interest in cognitive effects of chemotherapy, fatigue, other sort of mood issues, other sort of chronic changes that can occur following a cancer diagnosis. Cardiac toxicity is an important area that we're interested in. And then financial toxicities and probably one of the biggest gaps in our system here in the United States.
Dale Shepard, MD, PhD: So chipping away, but lots of questions remain.
Halle Moore, MD: Yes, indeed.
Dale Shepard, MD, PhD: So I guess doubling back to this particular trial, what would you recommend, what's the best guidance you could provide to people to tell their patients about trying to get pregnant while on hormonal therapy?
Halle Moore, MD: Yeah. So pregnancy after a breast cancer diagnosis is very complicated. And I think these discussions with patients really need to be individualized. There need to be frank discussions about what their risk of recurrence is because even if recurrence risk is not necessarily increased by stopping treatment temporarily to attempt pregnancy, patients do recur. And if that risk is higher that they need to really think about what would that look like in the setting of pregnancy or having a young child. So these really need to be carefully thought out conversations. And then also, what is the likelihood of becoming pregnant if a 45-year-old is thinking about interrupting therapy to attempt pregnancy, that might not be the same as a 35-year-old looking at interruption of treatment. And so they may spend more time off therapy, they may be less successful. And from the very early look that we've had, there's a hint that might not be as safe if they actually don't achieve the pregnancy.
Dale Shepard, MD, PhD: Very good. Well, you've provided some great insight for us today. Appreciate you being with us.
Halle Moore, MD: Well, thanks for the opportunity.
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