While research has shown that younger women with breast cancer face an increased risk of dying from their disease if they have recently given birth, the characteristics of their tumors have not, until now, been thoroughly studied.
For the first time, Public Health Sciences Division researchers have offered comprehensive, biological evidence that younger women diagnosed with breast cancer within two years of childbirth are at twice the risk of dying from the disease as compared to women with less recent or no history of childbirth.
Drs. Janet R. Daling and Kathi Malone and colleagues reported their findings in the March edition of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research.
Armed with medical records and breast-tumor samples from the largest population-based group of young women with breast cancer ever studied, Daling and colleagues at the Hutch and the University of Washington produced the first comprehensive assessment of tumor characteristics associated with recent childbirth and breast-cancer death.
"We looked at a broad panel of tumor markers associated with poor prognosis and found that the histologic grade, or evidence of aggressiveness, was almost six times higher in the tumors of these women," Daling said.
These findings narrow the search for tumor markers linked to poor survival in younger women who have recently given birth, and they provide new clues about the mechanisms involved in their cancer development and progression.
Aggressiveness of treatment
Such markers may be used to determine the aggressiveness of treatment for such women. Understanding these mechanisms also could lead to the development of new drugs to prevent and treat breast cancer.
The study was based on 1,174 Western Washington women 45 and younger who were diagnosed with invasive ductal breast cancer (the most common form) between 1983 and 1992. The women were followed for an average of nearly nine years. At the end of follow-up, 48 percent of those whose last birth occurred within two years of diagnosis had died, compared to 23 percent of the women who had never given birth and 24 percent of the women whose last birth was at least five years before diagnosis.
Why were women who had recently given birth prior to breast-cancer diagnosis at more than twice the risk of dying from their disease? The researchers suspect it has to do with hormones, although no one knows for sure.
"The hormones of pregnancy are most likely causing pre-existing abnormal breast cells or tumors to grow very quickly and become very aggressive in these women," said Daling, also a professor of epidemiology at the UW School of Public Health and Community Medicine.
So that the biology behind this aggressiveness could be understood, breast-tumor samples were obtained from 70 percent of these women and analyzed by the study's pathologist, Dr. Peggy Porter, head of Hutch's Breast Cancer Research Program. If tumor samples were unavailable, original pathology reports were used.
"Many studies rely on data from lab tests that were done as part of the patient's clinical work-up," said Porter, an investigator in the Human Biology and PHS divisions.
"This study is unique in that the pathology review was comprehensive and centralized, performed by a single pathologist. This kind of careful evaluation of tumor characteristics and quality control certainly adds to the value of this study."
The researchers also evaluated tumor size, lymph-node involvement and cancer stage (how far the cancer had metastasized, or spread).
All of these markers are being used clinically, particularly at academic medical centers. Potentially they could be used in breast-cancer patients with a recent childbirth history to help determine the aggressiveness of treatment, said Porter, also an associate professor of pathology at the UW School of Medicine.
"One wouldn't want to treat these women aggressively based on the sole fact that they had a recent pregnancy," she said. "But one would want to test their tumors with this panel of screening tools and treat them based on the aggressiveness of the tumor."
Women in the study were identified by the Hutch's Cancer Surveillance System, a population-based registry of cancer incidence in Western Washington that is part of a system run by the National Cancer Institute. The NCI, a branch of the National Institutes of Health, funded the study.
THE IMPLICATED MARKERS
The tumors of the women who had most recently given birth exhibited a distinct array of characteristics associated with active cell division. Such markers of rapid cancer growth implicated in the aggressiveness of their cancers included:
- Estrogen- and progesterone-receptor status (positive or negative): a marker that has been tested and used to assess the likelihood of outcome regarding mortality or cancer recurrence. Loss of estrogen and progesterone receptors on tumor cells (such as ER-negative or PR-negative status) is associated with poor clinical outcome and lack of response to anti-hormonal therapies such as tamoxifen.
- Mitosis: active cell division as determined by looking at the cancer cells under a microscope. Tumors with a high mitotic count are more aggressive.
- S-phase: the "synthesis phase" of the cell cycle in which the DNA duplicates, a characteristic of active cell division.
- P53: a protein product made by the p53 tumor-suppressor gene. When detected in large amounts, it often is associated with abnormal function of p53 and loss of cell-cycle control, which can lead to cancer. Women with a recent history of childbirth were two and-a-half times more likely to have "p53-positive" tumors.
- Ki-67: another marker of active cell division. A high percentage of tumor cells positive for the Ki-67 protein is an indicator of rapid tumor growth.
- c-erB-2: an oncogene (also known as HER-2/neu) which, when amplified, is associated with poor prognosis. This gene, an attractive cancer-vaccine target, is abnormally expressed in 20 to 30 percent of breast cancers.