Unraveling the long history of breast cancer formation

From the early stages of cell mutations starting in puberty to their manifestations as breast cancer in later years, the entire process has remained shrouded in mystery.

Now, a team of researchers at Kyoto University has revealed the mechanism by which breast cancer is formed in the cells of the mammalian epithelium, whose main function is to secrete milk.

According to the team's first analysis, approximately 20 mutations accumulate annually in each epithelial cell until menopause. After menopause, however, the mutation rate significantlydecreases.

"Additionally, our results suggest that estrogen influences mutation accumulation in mammary epithelium, which correlates with our discovery of decreased accumulation after childbirth," says corresponding author Seishi Ogawa of KyotoU's Graduate School of Medicine.

As 70% of breast cancers are understood to be estrogen-sensitive, Ogawa's team may shed light on estrogen's role in the initiation of breast cancer.

Further investigation of the genetic relationship between breast cancer, its surrounding lesions, and normal epithelial cells led to mapping breast cancer's translocation-positive expansion. During this expansion process, cells of multiple origins that would subsequently develop breast cancer manifested themselves at the average age of 30. Previous studies have focused on driver mutations -- the genetic changes in cells that are already cancerous -- leading to abnormal growth. But these findings only paint a partial picture of the process and do not reveal the timing and order of driver mutations or cancer formation.

"Normal-looking tissues may already contain numerous populations of non-cancer cells -- or clones -- that have acquired mutations in cancer-related genes," says co-author author Tomomi Nishimuraof KyotoU's Graduate School of Medicine.

After examining the similarities and differences in the mutations of both cancer and non-cancer lesions originating from the clones, the team reconstructed an evolutionary tree to visualize the unique pattern of cancer evolution.

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Earlier mammograms for women with family history of breast cancer may not be needed

A new study released in the American Cancer Society journal Cancer reconsiders guidelines for when to start screening with mammograms if a woman has a mother, sister, or daughter who was diagnosed with breast cancer.

Women with a first-degree family relative diagnosed with breast cancer, who are otherwise at average risk, are often advised to get screened 10 years earlier than the relative's diagnosis age. However, there is little evidence to support the long-standing recommendation.

UC Davis Comprehensive Cancer Center researcher Diana Miglioretti joined Danielle Durham, with the Department of Radiology at University of North Carolina at Chapel Hill, and five other researchers on the study. They analyzed data from the Breast Cancer Surveillance Consortium on screening mammograms conducted from 1996-2016 to evaluate when screenings should begin for women with a family history of breast cancer.

More than 300,000 women were included in the national study. Researchers compared cumulative 5-year breast cancer incidence among women with and without a first-degree family history of breast cancer by relative's age at diagnosis and screening age.

"The study concluded that a woman with a relative diagnosed at or before age 45 may wish to consider, in consultation with her doctor, initiating screening 5-8 years earlier than their relative's diagnosis age, rather than a decade earlier. That puts them at a risk that is equal to that of an average-risk woman who is age 50, which is the most recommended age for starting mammograms," said Durham.

BRCA gene mutation carriers may benefit from starting screenings earlier. Women ages 30-39 with more than one first-degree relative diagnosed with breast cancer may wish to consider genetic counseling.

Increasing the age for initiating screening could reduce the potential harms of starting breast cancer screenings too early. These include increased radiation exposure and false positive results that require women to return to the clinic for diagnostic imaging and possibly invasive procedures, but do not result in a breast cancer diagnosis. The earlier a woman starts receiving mammograms, the more screenings they will undergo over their lifetime -- and that increases the chances of experiencing these harms.

"Mammography also may not perform as well in younger women because they are more likely to have dense breasts which increase the difficulty of finding cancer on the images and results in more false-positives," Miglioretti said.

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