Targeting uniquely dangerous postpartum breast cancers

Breast cancers that emerge within five to ten years of pregnancy are more likely to become life-threatening. A new study finds that these postpartum breast tumors represent a unique subtype of cancer that could require different treatments than other breast cancers.

“For women diagnosed in that time window, they might have better outcomes if they had therapies targeted to the unique features of their tumors, which have been unknown until now,” said senior author Pepper Schedin, Ph.D., a professor in the Department of Cell, Developmental & Cancer Biology in the OHSU School of Medicine.

Women with postpartum breast cancers face a two- to threefold increased risk of death compared with same age patients who have not given birth. In earlier studies using mouse models, Schedin’s lab revealed how changes in the mammary gland after pregnancy create a tumor-promoting environment. At the end of lactation, 80 to 90 percent of milk-secreting cells undergo programmed cell death, in a process called mammary gland involution. The early phase of gland involution resembles an acute inflammatory response that subsides and is followed by an immune response similar to what happens during wound healing.

Image: The study found two dominant clusters of genes that are upregulated in postpartum breast cancersIn the new study using samples from breast cancer patients, Schedin and colleagues found evidence that involution leaves a lasting imprint visible in the pattern of gene activity in breast tissue, leading to more lethal cancers, including more lethal early stage, estrogen receptor positive tumors.

“We’re hoping this is really going to change the way oncologists think about this disease,” Schedin said. She and computational biologist Zheng Xia, Ph.D., an assistant professor in the OHSU School of Medicine, have published a paper describing the work in Nature Communications. Co-first authors Sonali Jindal, M.D., Nathan D. Pennock, Ph.D., and Duan Chen Sun, Ph.D., contributed equally to the research.

The team obtained preserved breast cancer tissue samples from 40 patients who consented to have their samples saved for research. The scientists profiled the pattern of gene activity in the samples by measuring and sequencing RNA, the genetic messenger molecule transcribed from active genes. Of 40 selected cases, 16 samples yielded sufficient RNA for analysis, nine postpartum cases and seven from women who had not given birth.

Pepper Schedin, Ph.D.

Postpartum cases showed a signature of gene expression clearly distinct from matching stage tumor samples from women who had not given birth. The gene activity in postpartum cases included signs of immune T-cell activation and exhaustion, altered signaling by a tumor suppressor gene, and decreased signaling via the estrogen receptor even though all of the included cases were estrogen receptor positive.

“They look like estrogen receptor negative breast cancers,” Schedin said. “The pathways the estrogen receptor should be stimulating are not functional.” That finding could have significant meaning for cancer treatment. When breast cancer is estrogen-receptor positive, it typically means that tumor growth can be stopped or slowed with drugs that lower estrogen levels or stop estrogen from acting on breast cancer cells. The gene activity signature suggests that postpartum breast cancers would be less responsive to estrogen blocking treatments.

The postpartum pattern of gene expression predicted reduced survival, the researchers found, when they analyzed gene expression and clinical outcomes data from more than 300 breast cancer cases in women age 45 and younger. They observed a significant decrease in 15-year overall survival in breast cancer patients scoring high for the postpartum genetic signature, compared with those with a low score. Decreased survival held true when the researchers restricted the cases to only those with estrogen receptor positive cancers.

All of the results combined provide evidence that postpartum breast cancer is a unique subset within young women’s breast cancer. And the findings point to avenues for tailoring treatment to make it more effective for women with postpartum breast cancer.

For example, the researchers said cancer drugs that work by inhibiting the cell cycle may have added benefit for postpartum breast cancers. The finding that these cancers have elevated T-cell level suggests there may be a select benefit for these patients from the immunotherapy drugs known as checkpoint inhibitors.

“While immunologic therapies have not been very successful in breast cancer in general; they might be in these cancers,” Schedin said.

Further reading:

Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes by Sonali Jindal, Nathan D. Pennock, Duanchen Sun, Wesley Horton, Michelle K. Ozaki, Jayasri Narasimhan, Alexandra Q. Bartlett, Sheila Weinmann, Paul E. Goss, Virginia F. Borges, Zheng Xia and Pepper Schedin. Nature Communications (Nov. 3, 2021)

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