Care, compounded: Researchers delve into reasons behind pregnancy-associated breast cancer
In 2006, Pepper Schedin, PhD, researcher and professor of medical oncology at the University of Colorado School of Medicine in Denver, published an authoritative review on the little-known process of pregnancy-associated breast cancer (PABC). “What Pepper did was to pull together what she saw in the lab combined with what was going on in the overall world of breast cancer in a way that very few people could,” says her colleague, Virginia Borges, MD, an oncologist and codirector of the Young Women's Breast Cancer Translational Program at the University of Colorado Cancer Center in Denver. She and codirector Dr. Schedin founded the program in 2005 to treat and prevent breast cancer in women under the age of 45 years, with a focus on PABC.
Dr. Schedin's research indicated that most people think PABC occurs only during pregnancy, whereas only a very small percentage of cases actually do. What is far more common, and which has a much worse prognosis, is breast cancer that is diagnosed very soon after birth and possibly up to 10 years or more postpartum.
Some 27,000 cases of breast cancer occur annually in women under the age of 45 years in the United States. Of those, about half are considered to be associated with having given birth in the 6 years prior. This concept is a very different one than the typically communicated health message that pregnancy and nursing are protective against developing breast cancer. What Drs. Schedin and Borges have discovered is that pregnancy's impact on breast cancer is actually more complicated.
Although having had children, particularly before the age of 30 years, is known to provide a protective effect against developing postmenopausal breast cancer, the effect of pregnancy in young women appears to have quite the opposite effect for cancers that develop in the first 10 postpartum years. As women's breasts return to their pre-lactation state after pregnancy and nursing, milk-producing cells are killed off in a process called involution. Similar to wound healing, which is known to promote tumor cells, involution creates a microenvironment that appears to facilitate tumor cell growth and spread, says Dr. Schedin.
Both Drs. Schedin and Borges believe that PABC is underrecognized for a variety of reasons, including the fact that although many researchers collect tissue and data on breast cancer, they generally only ask women how old they were at their first pregnancy rather than when their most recent pregnancy occurred. That information is critical for developing studies comparing patients with breast cancer who are diagnosed postpartum to other patients. Such research is necessary to understand the biological differences of PABC versus other types of breast cancer.
Drs. Schedin and Borges are trying to rectify that problem by developing their own database. The team has been building a cohort of young women patients with breast cancer who they can continue to follow in an effort to seek answers to many of the unknown questions about PABC. Women from around the world younger than age 45 years can provide their tumor tissue and clinical records to this database.
Challenges of PABC
One key feature of PABC is that it is more aggressive and more likely to recur than other breast cancers in women younger than 45 years. For example, Drs. Schedin and Borges compared patients in that age range who had never been pregnant with those who had recently given birth, all the way up to 5 years postpartum. The investigators found that the women in the postpartum time frame had an almost 3-fold increased risk of the cancer recurring and of dying from the disease. In this cohort, the 5-year risk of recurrence for patients who have not had children was 14%. In contrast, the risk of cancer returning in the new-mother group was 32%.
“This is a population that is not normally screened for breast cancer, so they present at more advanced stages, and these cancers appear to be more treatment-resistant,” Dr. Borges says. “These are women in their 20s and 30s—with toddlers at home—who are dying of breast cancer.”
Researchers do not know whether risk of death is different at 2 years versus 4 years postpartum because they do not have large enough data sets to determine that level of specificity. However, several studies have shown that pregnancy can increase the risk of developing breast cancer in women for up to 10 years or more after childbirth.[3, 4] Although that risk will eventually go away for women who have babies in their 20s, it does not go away until old age for women who have children at age 30 or older.
The investigators theorize that a vast majority of patients with PABC had cancerous cells present in their breast tissue prior to their pregnancy, which may have been indolent for many years and would have been fairly treatable if they had not been stimulated to progress during the postpartum time frame.
“We have a lot of preclinical data suggesting that independent of the biological tumor subtype, when cancer finds itself in this microenvironment, it encounters signal for tumor promotion such as lymphangiogenesis and infiltration by immune cells, which have proven to be very prometastatic,” Dr. Schedin says. “That's why we think these tumor cells are getting out before their time.”
Dr. Borges emphasizes that they are not telling women that they shouldn't have children. “Our message is that pregnancy is a good thing, but that added awareness of this problem could help us to get rid of this particular aspect of breast cancer because there is such a high risk,” she says. Still, she adds, the message is not always easy to convey. “We've had to be very careful in promoting our work to get it published. People don't like to think about such a difficult issue because young motherhood is supposed to be about happiness and light.”
To overcome such challenges, their program includes a community outreach coordinator focused on educating both the medical and scientific communities as well as the general public about PABC. At the same time, both Drs. Borges and Schedin travel nationally and internationally to educate colleagues about their research.
In addition to lack of awareness, another challenge is that young mothers often are so busy raising their children, they don't notice a change in their breast or, if they do, they don't always deal with it immediately. “All too often, we hear of a primary care provider telling a patient ‘If this doesn't get better, come back,’” Dr. Borges says. “What she hears is ‘It's fine,’ and she doesn't come back. It gets lost in the translation, and they end up waiting 3 or 6 or 9 months to do anything.”
On the scientific front, Dr. Schedin is continuing to explore the unique attributes of PABC that would make it therapeutically targetable, with the ultimate goal of developing a pill that women could take to reduce their risk of developing it.
The investigators also are sponsoring a study to learn whether breastfeeding plays a role in involution. Among the questions they have is whether involution looks the same after different lengths of nursing, such as stopping at 6 months versus stopping after a year. Such information may ultimately help determine the optimal time for women to take a preventive pill.
As part of this study, they are collecting breast tissue from healthy pregnant or nursing mothers to better understand normal postpartum breast involution and to compare with that of women with breast cancer. When Denver mother Gaea Moore, 34, saw a flyer about the study shortly after she had stopped nursing her daughter, she volunteered to participate. The healthy mother of 2 young children underwent a biopsy, urine, and blood test in a procedure that lasted about an hour. “It was absolutely worth it and gave me peace of mind as a mom that I was doing something to help prevent breast cancer in the future,” she says.
And that, of course, is Drs. Schedin and Borges' main goal as they seek answers to these questions as quickly as possible.
This is a population not normally screened for breast cancer, so they present at more advanced stages. —Virginia Borges, MD