NEW YORK (GenomeWeb) – After analyzing genetic data from thousands of breast cancer patients, researchers have concluded that women with rare germline mutations may be at increased risk for more aggressive disease and death, while those with a high polygenic risk score are more likely to have less aggressive tumors.
The information may improve understanding of breast cancer progression and be useful for making screening programs more precise, according to the researchers, led by Jingmei Li from the Genome Institute of Singapore, who published their study in Cancer Research today.
Li and colleagues analyzed data from approximately 5,000 patients diagnosed with breast cancer between 2001 and 2008 in Sweden and evaluated their tumor characteristics and survival outcomes based on whether they had rare protein-truncating variants in 31 cancer predisposition genes. They also studied how the women’s tumor characteristics and overall survival correlated with a polygenic risk score they developed using 162 single-nucleotide polymorphisms. They further sought to determine whether this information could inform screening practices.
Their evaluation showed that carriers of rare protein-truncating variants in any of the 31 cancer risk genes were more likely to develop high-grade tumors and not live as long as women who didn’t carry such variants. Additionally, carriers were more likely to be diagnosed with breast cancer between scheduled screenings compared to noncarriers.
Interval breast cancer is a term for tumors detected within a year after a mammographic screening that was determined to be normal and is among the measures used to gauge the efficacy of breast screening programs. Because most interval breast cancers are not detected during routine mammograms, they tend to be more aggressive and have worse prognosis. "More sensitive methods to predict and detect these lethal cancers are sorely needed,” Li said in a statement.
Notably, when the researchers evaluated patients using the polygenic risk score, those with a higher score — indicating a higher genetic risk for breast cancer — actually tended to have less aggressive tumors that were more likely to be detected during routine mammography screenings.
"Both rare and common variants can predict breast cancer risk," Li said. "Our study shows that different variants are associated with different kinds of breast cancer, and that women carrying rare variants have a higher risk of developing interval breast cancers and have worse overall survival compared to women with common mutations."
In the cohort of 5,099 breast cancer patients, 597 women carried a rare protein-truncating variant. These women were younger, had more aggressive tumor characteristics, and were at 1.65 times greater risk of dying from breast cancer compared to those who didn’t have these variants.
Li and colleagues also evaluated this subset of women after excluding 92 patients who carried BRCA1/2 mutations, since these are known to be associated with poor prognosis, diagnosis at a younger age, estrogen receptor negativity, and basal-like subtype. They found that women with rare protein-truncating variants in non-BRCA1/2 genes had 1.76 times the risk of death compared to non-carriers.
“Although BRCA1/2-associated cancers are often associated with worse tumor phenotypes, it has been documented that patients with breast cancer who are BRCA1/2 carriers do not necessarily exhibit worse survival patterns than BRCA1/2 non-carriers,” the authors wrote. “In agreement, a slightly stronger effect for worse survival was observed in carriers of non-BRCA1/2 protein-truncating variants after the removal of BRCA1/2 carriers.”
The researchers then analyzed genetic data from the 5,077 women who did not carry BRCA1/2 mutations with the polygenic risk score and found that a higher score was associated with less aggressive tumor phenotypes. Also, there were no significant survival differences linked to increases in polygenic risk scores.
"Polygenic risk score is a good marker for breast cancer prediction," Li said. "However, there is not enough evidence to show that this score can also predict death from breast cancer."
One reason that higher polygenic risk scores in this study were associated with less aggressive disease, which is likely to be detected during routine screening, may be due to the way the algorithm was developed. The authors noted that many of the 172 known SNPs associated with breast cancer, of which they used 162 in their study, were likely identified in large breast cancer cohorts that are enriched for estrogen receptor-positive disease, which is often associated with favorable tumor features and outcomes.
Another factor Li and colleagues considered in their study was dense breast tissue, which is a major reason why cancers are missed during routine mammography. They stratified patients into high and low risk categories based on percent breast density and found that women with low breast density who carried rare protein-truncating mutations were 1.96 times as likely to be diagnosed with interval breast cancers compared to women who did not carry such mutations.
Women with low breast density who carried protein-truncating mutations in non-BRCA1/2 genes still had a 1.89 times increased risk compared to non-carriers. However, patients with low breast density and a higher polygenic risk score were at 23 percent lower risk for developing interval breast cancer.
The study authors acknowledged that differences in local screening guidelines made the interval between mammograms inconsistent between patients in this study and noted this as a limitation of their analysis.
Still, based on their findings, Li and colleagues suggested that women who carry rare protein-truncating variants, and are therefore at greater risk for interval cancers, could benefit from screening starting at a younger age, at shorter intervals, and using more sensitive methods than mammography, such as magnetic resonance imaging and ultrasound. In contrast, although patients with higher polygenic risk scores are also at increased risk for breast cancer, their tumors are more likely to be detected during routine screening, they concluded.