Breast cancer in young women is genetically different from that in older women, according to database analysis led by researchers at Sanford Burnham Prebys. Breast cancer in men, their work suggests, may also be genetically distinctive.
Cell-cycle dysregulation, a prerequisite for cancer formation, may underpin these disparities, the researchers report. They describe it as “distinct event that determines subtype, metastatic potential, and treatment responsiveness.”
“This is a radical shift in how we look at cancer, which could have implications well beyond breast cancer,” said senior author Svasti Haricharan, Ph.D.
The findings, published in the journal Science Advances, could help improve precision medicine and suggest a brand-new way of classifying breast cancer, they said.
The rate of breast cancer has been increasing among younger women. About a decade ago, the rate of the disease was between 4% and 6% in this subgroup. Now, about 9% of all new cases are found in women younger than 45 years old. It is the most common cancer among women aged 15 to 39 and it is estimated that more than 12,000 young women a year are diagnosed with the disease. Younger women are 39% more likely to die from breast cancer than older women.
Most of this increase is due to an increase in the prevalence of regional or distant, stage II to IV breast cancer. A significant number of these patients carry germline cancer predisposition mutations, but that doesn’t explain the total disparity.
“The prevalence of breast cancer by stage is quite different between AYA [adolescent and young women] women younger than age 40 and older women,” said Rebecca H. Johnson, M.D., in a recent ASCO Post. “In young AYA women, two-thirds are diagnosed with regional or distant disease, including stage II, III, or IV, whereas in older women, about one-third are diagnosed with stage II, III, or IV disease.”
The study analyzed a meta-dataset composed of six independent studies of breast cancer patients. It revealed that in ER+/HER2- breast cancer patients, certain gene mutations had a strong correlation with response to treatment—and the effects were dependent on age. Some gene mutations were only linked with treatment-resistant breast cancer in younger women.
“This was a strange finding, so much so that we almost didn’t believe it at first,” said Haricharan. “But the same patterns emerged over and over again in database after database.”
The mutations the researchers identified were in genes involved in cell replication. These genes are responsible for repairing mistakes when they happen—a process that goes awry in virtually all cancers.
They found that ATM mutation is linked to primary estrogen receptor (ER)+/human epidermal growth factor (HER)2- cancer in older women. Conversely, CHK2 dysregulation induces formation of metastatic, treatment resistant, premenopausal ER+/HER2- breast cancer.
The researchers also analyzed the effect of cell cycle mutations on patient outcomes in other types of cancer. They found that in many cancer types, the mode of cell cycle dysregulation is significant for cancer in women, but less so for cancer in men. This suggests that the influence of cell-cycle dysregulation could depend on sex as well as age.
“These findings emphasize why it is important to study cancer in the context of the life history of the patient,” said Haricharan. “Too often, cancer research is focused narrowly on cells in a petri dish, forgetting the whole, complex host system in which these cells transform and grow.”
“It’s well established that as you get older, you’re more likely to develop cancer,”. But she added that, “There may be completely different mechanisms driving cancer in younger and older people, which requires adjusting our view of aging and cancer.”
