After early-stage breast cancer, interrupting endocrine therapy to become pregnant didn’t raise risk of recurrence

Women who’ve been treated for hormone-sensitive breast cancer often face five to 10 years of endocrine therapy to lower the chances of their tumors coming back. Because that drug regimen is toxic during pregnancy, women who haven’t begun their families yet may lose that chance before they even try. New research published Wednesday in the New England Journal of Medicine suggests there might be another option.

Women with early-stage, hormone receptor-positive breast cancer who interrupted their endocrine therapy to become pregnant had about the same risk of cancer recurrence as similar breast cancer patients who didn’t pause their treatment, the study found. After about three and half years, almost three-quarters of participants became pregnant at least once and nearly two-thirds had healthy babies while pausing hormone therapy.

“I think this data will have an immediate impact,” said Heather Neuman, a breast surgical oncologist and health services researcher at the University of Wisconsin. She was not involved in the study. “This is an extremely important question for young cancer survivors, as family planning is a critical life event.”

Motivation for the POSITIVE trial, conducted by a consortium of international study groups in 20 countries, came from the lack of rigorous, prospective data on the safety of interrupting endocrine therapy to attempt pregnancy, Ann Partridge, vice chair of medical oncology at Dana-Farber Cancer Institute and the NEJM study’s lead author, told STAT.

“It’s both an emotional and kind of a physical loss for these women if they’re told, ‘Put your lives on hold and you know, by the time you get there, both with the chemo and time, you may not be a candidate for actually getting pregnant,’” she said.

It wasn’t ethical or feasible to randomize trial participants to have a baby or not (“That wasn’t going to fly with our patients,” Partridge said), so the researchers chose the next best thing to the gold-standard randomized clinical trial: They compared women who wanted to stop taking the endocrine therapy to attempt pregnancy to a historical control group of matched participants who continued with the treatment.

All 516 patients enrolled in the trial had been treated for early-stage breast cancer and had been taking endocrine therapy for 18 to 31 months. Also called hormone therapy and often including tamoxifen, it’s intended to prevent tumor cells from spreading by choking off growth-stimulating hormones. By far, most of the women who pursued pregnancy had the earliest stage of the disease, when the chances of recurrence are lowest: 93.4% had stage 1 or 2 and 6% had stage 3. The study was designed to stop if the number of women with cancer recurrences reached 46, a safety threshold derived from previous research.

In the POSITIVE study, conducted from December 2014 to December 2019, there were 44 recurrences after a median follow-up of 41 months. That translates to a rate of 8.9% for the study group compared to 9.2% in the control group. Among 497 participants who reported pregnancies, 368 had at least one pregnancy and 317 had at least one live birth. The pregnancies did not appear to have a higher rate of complications or birth defects than in women of a similar age without breast cancer. (POSITIVE stands for Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer.)

“The good news was that the study showed that it did not appear to negatively impact their at least short-term outcomes, and we’re going to watch them for at least 10 years in the long-term outcome,” Partridge said about interrupting endocrine therapy. “The POSITIVE data are very reassuring that it doesn’t appear to increase the risk of either taking a temporary interruption to attempt a pregnancy or becoming pregnant.”

An analysis within the study comparing those who became pregnant and those who didn’t showed participants who got pregnant did just as well if not better, she said.

The pregnancy numbers are encouraging to Neuman. “If you are going to take the risk of interrupting endocrine therapy and then, say, only 40% of people were able to get pregnant, to me that is very different,” she said. “That means you’re taking all the risks and not getting the pregnancy benefit. And so the fact that the majority of women were able to get pregnant and those pregnancies were healthy, I think is an important part of the story.”

Most of the women in the study resumed their endocrine therapy, but 15.6% did not. The treatment is tolerable for most women, but can have side effects for others, including hot flashes and other symptoms of menopause, that are particularly distressing for women of childbearing age.

The researchers didn’t explore why temporarily pausing endocrine therapy worked, but it’s part of the complex relationship between breast cancer and pregnancy, Partridge said. A recent pregnancy is associated with a short-term higher risk of getting a first-time breast cancer, and yet pregnancy is also associated with a long-term protection against breast cancer. “Once someone has had a breast cancer, the major concern is, will a pregnancy increase, decrease, or stay the same for breast cancer coming back and in [estrogen receptor-]positive disease, that’s one we’ve been most concerned with,” Partridge said.

Neuman sounded a note of caution about interpreting the study, which she welcomes as both important and highly relevant to young breast cancer survivors. “This study didn’t ask the question of whether interrupting endocrine therapy for a pregnancy worsens an individual woman’s outcomes. It asked the question that for a group of women, are the risks associated with interrupting endocrine therapy acceptable,” she said. “It’s really about what’s acceptable, balancing how important it is to have families and continue your life for survivors.”

The study underscores the importance of making sure patients maintain their fertility options if they want to, including counseling before starting chemotherapy, said Hope Rugo, director of breast oncology and clinical trials education at the University of California, San Francisco. She was not involved in the research. After diagnosis, doctors now routinely discuss fertility measures young cancer patients can consider before starting chemotherapy, from harvesting eggs to storing embryos, to soften the blow of having to choose between lowering the chances of cancer recurring and trying to have a baby before it’s too late.

“This is a really important paper and study,” Rugo said. And while longer follow-up on interrupting endocrine therapy is needed, “at the moment, I think it’s safe to employ shared decision-making and talk about this option in patients who have lower-risk, hormone receptor-positive, early-stage breast cancer.”

These were reassuring results to share, Dana-Farber’s Partridge said. The data were first presented in December at the San Antonio Breast Cancer Symposium.

“It was a very joyous study to report for all of our colleagues who worked on the study and for the women. We’ve talked to lots of patients about it since,” she said. “Everybody’s very happy about these data. Obviously, they took a risk and they’re happy to see that it looks like they weren’t being crazy.”