by R. Graffeo, H.Q. Rana, F. Conforti, B. Bonanni, M.J.
Cardoso, S. Paluch-Shimon, O. Pagani, A. Goldhirsch, A.H. Partridge, M.
Lambertini, J.E. Garber
The Breast: Published: June 18, 2022
Breast cancer risk associated with germline likely
pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high
>50% or moderate 20–50%), and specific locus.
Germline PVs in BRCA1 and BRCA2 play
important roles in the development of breast and ovarian cancer in particular,
as well as in other cancers such as pancreatic and prostate cancers and
melanoma. Recent studies suggest that other cancer susceptibility genes,
including ATM, CHEK2, PALB2, RAD51C and RAD51D confer
differential risks of breast and other specific cancers.
In the era of multigene panel testing, advances in
next-generation sequencing technologies have notably reduced costs in the
United States (US) and enabled sequencing of BRCA1/2 concomitantly
with additional genes. The use of multigene-panel testing is beginning to
expand in Europe as well.
Further research into the clinical implications of variants
in moderate penetrance genes, particularly in unaffected carriers, is needed
for appropriate counselling and risk management with data-driven plans for
surveillance and/or risk reduction. For individuals at high risk without any
pathogenic or likely pathogenic variant in cancer susceptibility genes or some
carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2,
polygenic risk scores offer promise to help stratify breast cancer risk and
guide appropriate risk management options.
Cancer patients whose tumours are driven by the loss of
function of both copies of a predisposition gene may benefit from therapies
targeting the biological alterations induced by the dysfunctional gene e.g.
poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in
cancers with DNA repair deficiencies. A better understanding of mechanisms by
which germline variants drive various malignancies may lead to improvements in
both therapeutic and preventive management options.
