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Breast cancer subtypes vary by gene, affecting risk prediction, screening strategies

JAMA Oncology
Reuters Health - 02/02/2022 - Variants in nine major breast cancer susceptibility genes are associated with different tumor subtypes, researchers have found.

The susceptibility genes are BRCA1, BRCA2, CHEK2, PALB2, ATM, BARD1, RAD51C, RAD51D and TP53.

"Tumors arising in women harboring pathogenic variants in (these) genes were found to differ substantially in their tumor pathology profiles, although there were some similarities that could be traced to known biological functions of the genes," Dr. Nasim Mavaddat of the University of Cambridge told Reuters Health by email.

"Risk variants in these genes were found to contribute disproportionately to more aggressive breast cancer, particularly among younger women," he said. "Together, the nine genes contributed to nearly a third of all triple-negative tumors in women aged 40 years or younger."

As reported in JAMA Oncology, Dr. Mavaddat and colleagues analyzed data from close to 43,000 patients and matched controls in 38 studies from the Breast Cancer Association Consortium. Dr. Maddavat noted, "Importantly, the studies were population- or hospital-based, and sampling was independent of family history, genotype or pathology, which would have biased the results."

The mean age at interview (controls) and diagnosis (cases) was about 55. All participants were of European or East Asian ethnicity. Among the findings:

- There was substantial heterogeneity in the distribution of intrinsic subtypes by gene.

- RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (odds ratios 6.19, 6.19 and 10.05, respectively).

- CHEK2 variants were associated with all subtypes, with ORs ranging from 2.21-3.17 except for triple-negative disease (no association).

- For ATM variants, the association was strongest for the hormone receptor (HR)+ ERBB2− high-grade subtype (OR, 4.99).

- BRCA1 was associated with increased risk of all subtypes, but the ORs varied widely, with the highest for triple-negative disease (OR, 55.32). BRCA2 and PALB2 variants were also associated with triple-negative disease.

- The protein-truncating variants in BRCA2, CHEK2, and PALB2 were associated with larger tumor size, lymph node involvement, and higher stage at diagnosis.

- TP53 variants were most strongly associated with HR+ ERBB2+ and HR- ERBB2+ subtypes.

Overall, tumors occurring in pathogenic variant carriers were of higher grade. For most genes and subtypes, a decline in ORs was observed with increasing age. Together, the 9 genes were associated with 14.4% of all tumors in women 40 years or younger but less than 4% in women older than 60.

Among younger women, the prevalence of variants combined was higher among women with TN and HR+ ERBB2− high-grade tumors than among those with other subtypes.

The authors conclude, "The results of this case-control study suggest that variants in the 9 BC risk genes differ substantially in their associated pathology but are generally associated with triple-negative and/or high-grade disease. Knowing the age and tumor subtype distributions associated with individual BC genes can potentially aid guidelines for gene panel testing, risk prediction, and variant classification and guide targeted screening strategies."

Dr. Mavaddat added, "These findings enhance our understanding of breast cancer biology and aid efforts to classify whether genetic variants of uncertain significance are also likely to be pathogenic."

Dr. Louise Morrell, medical director of Lynn Cancer Institute, part of Baptist Health South Florida, commented in an email to Reuters Health, "This study gives us the information we need to discuss with patients both the risk of cancer associated with a specific mutation, and in addition how aggressive is that tumor likely to be."

"In practical terms," she said, "women will be able to decide on a preventive mastectomy or enhanced screening with a greater understanding of their risk and what treatments they might need if they were to be diagnosed with cancer."

"This study clearly demonstrates that any family with a breast cancer diagnosis under the age 40 is at significant risk of a genetic mutation and testing of family members is the key to taking risk reducing action," she added.

SOURCE: https://bit.ly/3s94Y0p JAMA Oncology, online January 27, 2022.

By Marilynn Larkin

© 2023 The Author(s). Published by Medicom Medical Publishers.
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