Breast cancers that develop within five years after giving birth are more likely to spread and become fatal. In addition, a new study shows that recent childbirth alone is an independent risk factor for breast cancer progression.
The findings suggest that current clinical guidelines that do not take postpartum status into account are less able to accurately predict the risk of cancer recurrence and guide optimal treatment strategies in young patients.
“This has profound implications for prognosis,” said the lead author Pepper Schedin, Ph.D., professor of cell, developmental and cancer biology at the OHSU School of Medicine and the OHSU Knight Cancer Institute. “Postpartum diagnosis can push women who appear to have a good prognosis into a high-risk category.”
An article describing the research, published today in JAMA Open Network. OHSU Knight Cancer Institute researchers Zhenzhen Zhang, Ph.D., MPH, and Solange Bassale, MS, are co-first authors.
Using a large population-based database in Utah, the researchers were able to confirm the association between pregnancy and breast cancer outcomes in collaboration with Ken Smith, Ph.D., co-author of the paper and Distinguished Professor of Family Studies and Population Sciences at the Huntsman Cancer Institute at the University of Utah. The database combines statewide birth and death records, data from the Utah Cancer Registry, and patient records from statewide inpatient and outpatient records.
The final study included 2,970 subjects with breast cancer diagnosed at age 45 or younger, including 860 who had never given birth. Those who gave birth were categorized based on time since last birth: diagnosed within less than five years, five to less than 10 years, or 10 years or more since birth.
The risk of metastasis – the spread of cancer to other organs – was 50% higher in those diagnosed within five years of giving birth, as was the risk of breast cancer-specific death compared to those who had not given birth. And these increased risks of metastasis and death were independent of tumor stage or estrogen receptor status—factors that are now used to judge how aggressive a cancer is likely to be and to decide which treatment is appropriate.
Breast cancers that lack estrogen receptors, known as ER-negative tumors, are generally considered more dangerous than ER-positive tumors. But in the study population, the proportion of women who progressed was the same for ER-negative and ER-positive tumors. The primary risk factor for progression to metastases was not ER status, but rather diagnosis of breast cancer within five years postpartum.
“This doesn’t match everything we thought we knew about ER-negative disease,” Schedin said.
In earlier research, Schedin and colleagues discovered how changes in the breast after childbirth can alter the development of breast cancer. At the end of lactation, most milk-secreting cells undergo programmed cell death in a process called involution. It is an inflammatory process that resembles wound healing, and in studies using mouse models, Schedin’s lab has revealed how involution creates a tumor-promoting environment. Using samples from breast cancer patients, the researchers found evidence that involution leaves a permanent imprint on the pattern of gene activity in breast tissue that could help tumors metastasize.
Schedin’s team also showed in mouse studies that as the liver recovers from the demands of pregnancy and lactation, it becomes an inviting landing spot for escaping cancer cells to take root and grow. Similar processes appear to take place in the liver of women after childbirth. A new study found a high rate of liver metastases in those diagnosed within five years of giving birth.
“It’s a two-hit issue,” Schedin said. “Involution causes early tumor cells to move out of the breast. And these cancer cells see the liver as an excellent host for the formation of metastatic tumors.”
Factoring in the postpartum state should help doctors make more accurate predictions about breast cancer aggressiveness and guide treatment decisions, such as the need for chemotherapy after surgery to remove tumors. The knowledge may even enable new and more effective treatment strategies, Schedin said.
Knowing that postpartum cases show a distinct gene expression signature, it may be possible to develop treatments that specifically target signaling pathways active in postpartum cancers.
This research was supported by pilot funding from the OHSU Knight Cancer Institute and funding from the National Institutes of Health (grant K12HD043488). The Utah Population Database receives support from the National Cancer Institute (grant P30 CA2014), part of the NIH.
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