Researchers find that inherited genetic mutations can predict breast cancer at intervals

An investigation by researchers at Karolinska Institutet has led to a discovery in the field of breast cancer diagnosis and treatments that could reshape screening programs and clinical approaches. The study, published in JAMA Oncologyunveils the impact of rare genetic variants on interval breast cancers, providing new insights into tailored screening strategies.

Interval cancers, a type of breast cancer diagnosed between routine screenings, have long posed problems due to their aggressive nature and less favorable patient outcomes than cancers detected by screening. However, until now, the role of genetic variants in these types of breast cancer has been largely unexplored.

The study, involving 4,121 breast cancer patients and 5,631 controls, carefully examined 34 breast cancer susceptibility genes. The primary objective was to discern the influence of carrying deleterious variants on the differentiation between interval cancers and screen-detected cancers, taking into account mammographic density.

The survey provided two take-home clinical messages. First, researchers found that protein-truncating variants (genetic mutations that shorten the protein-coding sequence) of the five major breast cancer genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) increased the likelihood of being diagnosed with interval cancer. Notably, this elevated risk was mainly attributed to BRCA1/2 and PALB2 variants.

“Women with a family history of breast cancer, in combination with genetic variants in any of these five genes, were four times more likely to develop interval cancer compared to screen-detected breast cancer, which which suggests that additional large-scale sequencing efforts are needed to uncover the full genetic contribution of the observed interaction,” explains first author Juan Rodriguez, a postdoctoral researcher in the Department of Medical Epidemiology and Biostatistics.

Second, if a patient was diagnosed with interval cancer, carriers of deleterious variants in any of these five genes had significantly worse survival than women carrying none.

According to the researchers, this is the first report examining genetic differences between screen-detected and interval cancers using the top five breast cancer genes. The results suggest that screen-detected and interval cancers are indeed distinct in both underlying genetic and biological terms, providing valuable information for identifying women who are at very high risk of developing aggressive breast cancer.

“These results show new and important information about the genomic differences between interval breast cancer and screen-detected breast cancer,” said Juan Rodriguez. “Our work clarifies the picture of the type of breast cancer that is likely to escape detection in population-based screening programs, with potential applicability to clinical care and future optimizations of screening programs aimed at reducing mortality.”

“Enhancing the ability to detect breast cancer at an earlier stage will ultimately lead to better treatment outcomes, improved quality of life for affected women, and a reduction in the financial burden on the health system,” says the last author. of the study, Professor Kamila Czene at the same department.