Why Are New Moms at Risk of Developing More Aggressive Breast Cancer?

Breast cancer in young moms isn’t rare. But when it happens, it can be quite unexpected. And while the majority of young moms diagnosed with breast cancer have a good prognosis, for a significant minority there seems to be something uniquely risky about developing breast cancer after having recently delivered a child. 

Virginia (Ginger) Borges, MD, MMSc, professor of medicine-medical oncology at the University of Colorado Anschutz Medical Campus in Aurora, Colorado, started noticing this alarming pattern 22 years ago. In her clinic, where she specializes in treating breast cancer in younger women, she saw that it was often the young mothers under the age of 45 that had more aggressive breast cancers. They were more likely to develop metastatic breast cancer (that spreads to another part of the body) and to have a worse prognosis.

“It was obvious that some of them weren’t doing as well and surviving as long as my other patients,” says Borges. “I wanted to understand why their cancers were more likely to spread and less likely to respond to treatment.” She decided to focus her research on these questions that, at the time, not many others were exploring. 

Today, researchers have a name for these breast cancer cases that emerge within five to 10 years of giving birth: postpartum breast cancer (PPBC). Several studies suggest that people who are diagnosed within five years of giving birth have a two to three times higher risk of developing metastatic breast cancer and of dying from breast cancer, compared with those who haven’t given birth. Other studies suggest that the risk window might last for 10 years after childbirth.   

“We’ve found that this group that has postpartum breast cancer stands out in terms of having worse outcomes, when compared with people of their same age who have the same subtype and stage of breast cancer but who haven’t had a child,” says Borges. “So we’re trying to find out: What’s different that’s happening in postpartum breast cancer that’s causing these worse outcomes?”  

A better understanding of postpartum breast cancer could transform treatment for the people who develop it. Currently, the guidelines that doctors use to make breast cancer treatment decisions don’t factor in whether the patient had a recent pregnancy. So for people with postpartum breast cancer, those guidelines may not be as accurate for recommending treatments or predicting the risk of the cancer coming back or spreading. 

Luckily, Borges and her colleagues have discovered intriguing clues about what fuels postpartum breast cancers, related to natural changes that happen in the breast after childbirth.

The conventional wisdom for decades has been that pregnancy and breastfeeding reduce breast cancer risk. Recent studies, however, have revealed a more complicated picture: A full-term pregnancy and breastfeeding, especially before the age of 30, does provide some degree of long-term protection from developing postmenopausal breast cancer. But during the first 10 years after a person gives birth, there’s actually a small increased risk of developing breast cancer — whether they breastfeed or not.

Not much is known about what is driving the development of the breast cancers that occur during pregnancy and in the 10 years afterward. Pregnancy-related hormonal changes probably play a role in at least some of these cancers, but how this happens isn’t clear to scientists. One theory is that rising hormone levels might stimulate the growth of a cancer cell or precancerous cell that is already in the breast. 

For more than 20 years, Borges has been collaborating with Pepper Schedin, PhD, professor of cell, developmental, and cancer biology at the Oregon Health & Science University School of Medicine in Portland, Oregon and Traci Lyons, PhD, associate professor of medicine at the University of Colorado Anschutz Medical Campus. In their research, they’re looking to understand the unique biology of postpartum breast cancer and to develop new risk-reduction and treatment strategies. 

One of the challenges that they and other scientists who study PPBC face is that the databases (called registries) that researchers use to track breast cancer statistics and trends nationwide usually don’t contain information on pregnancies.

“Doctors don’t ask women when they’re diagnosed with breast cancer, ‘When was your last full-term pregnancy?’ So we have very little real data to work with,” says Schedin. “But we know that postpartum breast cancer isn’t a rare event.”  

Schedin estimates that about half of all breast cancer diagnoses in women under the age of 45 in the U.S., or about 13,500 a year, are postpartum breast cancer cases. The number of cases worldwide is estimated to be between 150,000 and 350,000 — and those numbers are expected to increase in the future.

Fortunately, Borges, Schedin, and their collaborators have found important clues to what makes some postpartum breast cancers more dangerous: changes that happen in the breast after childbirth.   

During pregnancy, there’s an up to tenfold increase in the number of cells in the breast, as the body gears up to produce milk. When those milk-producing cells are no longer needed — either because the pregnant person did not breastfeed or is done with breastfeeding — they die. This dying-off process — called weaning-induced involution — is a natural process that happens in every person who gives birth, whether or not they actually breastfeed, as the breasts return to a pre-pregnant state. 

“When all those milk-producing cells in the breast are dying, like leaves falling off a tree, the body is reacting in a way that’s similar to healing a wound,” explains Schedin. “There’s an influx of immune cells, an increase in inflammation, and some normal tissue may be temporarily replaced by scar-like tissue.”

Schedin and Borges believe this temporary, wound-like environment in the breast can give a single cancerous cell a window of opportunity to grow and maybe even metastasize. In studies in rodents, they found that putting a tumor cell in this environment causes it to spread.  

“We don’t think involution is creating cancer cells. What we think it can do is allow mutant cells that were already in the breast to escape detection by the immune system and to potentially transform into a more aggressive cancer than they otherwise would have,” Schedin says. Those cells may be permanently changed by that wound-healing environment in ways that make them behave more aggressively, she adds. 

“Who wants to hear that something as natural as having a baby and breastfeeding could be detrimental? It goes against hundreds of years of evidence that pregnancy is protective. That was a hurdle we were up against.”

—Pepper Schedin, PhD

Weaning-induced involution takes place over a period of months. It starts right after childbirth in people who don’t breastfeed, or whenever weaning takes place in people who do. Some of the involution-related changes can be happening in people who are still breastfeeding but are slowly weaning. Schedin notes that a cancer that develops during involution may end up being detected soon after or much later. Some can hide out in the body for years. 

“We don’t know if involution is playing a role in the development of every case of postpartum breast cancer,” says Jasmine A. McDonald, PhD, an associate professor of epidemiology at the Mailman School of Public Health at Columbia University in New York City. She studies the windows of time in women’s lives when they may be particularly susceptible to breast cancer, including the postpartum years. “But Pepper’s work suggests that involution is a window of time when a rogue cell has an enriched environment in which to progress and spread.” 

Surprisingly, there might be a relatively simple way to reduce inflammation in the breast and lower the risk of postpartum breast cancers. Schedin and Borges have found, in a series of studies in rodents, that treatment with a common non-steroidal anti-inflammatory drug (NSAID) like ibuprofen could reduce the severity of postpartum breast cancers. 

“Our idea for this prevention strategy is: Let’s see if we can block some of involution’s effects in the breast and prevent breast cancer from arising or, if it does develop, from ever becoming metastatic,” says Borges.  

Now they’re ready to start testing the strategy in people. They’re fundraising for a clinical trial that would give NSAIDs to healthy women during and right after weaning. The study would test if the treatment is safe and could reduce inflammatory changes in the breast. If it proves safe, the next step will be to do a trial enrolling a larger number of women and tracking how taking an NSAID during weaning affects breast cancer incidence and outcomes over time.         

“Postpartum breast cancer is a global problem. In some other countries, the rates of young women getting diagnosed in the early years of motherhood are even higher than in the U.S.,” says Borges. “So we knew we wanted to test using a drug that is globally available, inexpensive, and won’t cross into breast milk.”  

“We’ve found that this group that has postpartum breast cancer stands out in terms of having worse outcomes, when compared with people of their same age who have the same subtype and stage of breast cancer but who haven’t been pregnant. So we wanted to know: What’s…causing these worse outcomes?” —Virginia Borges, MD, MMSc

Currently there aren’t any guidelines for doctors to follow on tailoring treatment differently for people with postpartum breast cancer. As scientists learn more, that’s likely to change, says Megan Tesch, MD, MPH, a medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, who specializes in the care of young adults with breast cancer.

“In the future, when we understand the unique disease biology better, I think we may be treating these breast cancers in a more individualized way,” says Tesch. 

Researchers are developing new targeted therapies to block specific molecules in postpartum breast cancer cells that make them more aggressive. They’re also exploring how to target these molecules with new treatment regimens that include breast cancer drugs already in use. And they’re making progress in figuring out who is most at risk for developing postpartum breast cancer. For instance, McDonald did a study that found that individuals who are at higher-than-average risk for breast cancer because they have a genetic mutation such as BRCA1 or BRCA2 also have an elevated risk of PPBC. Other factors thought to raise PPBC risk include having more full-term pregnancies and having a first birth at the age of 26 or older.    

“What makes me optimistic is that there are many more research groups trying to answer these questions now compared with 10 or 15 years ago,” says Borges. “The pace of learning is going faster and I hope that soon postpartum breast cancer will be far more understood.”  

Schedin recalls that when she and Borges first started their work together, it was sometimes hard to convince people that there could be a connection between pregnancy and the development of aggressive breast cancers.

“Who wants to hear that something as natural as having a baby and breastfeeding could be detrimental?” says Schedin. “It goes against hundreds of years of evidence that pregnancy is protective. That was a hurdle we were up against.” 

But that has since changed.

“It’s hugely gratifying to see people recognizing that postpartum breast cancer is a unique subtype that needs targeted intervention and understanding,” Schedin says. “It’s going to be game-changing for young women with breast cancer.”