https://orcid.org/0000-0003-2833-6051
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Abstract
Background
Genetic testing for at-risk patients with breast cancer should be routinely offered. Knowledge generated may influence both treatment decisions and cancer prevention strategies among the patients themselves and their relatives. In this study, we report on the prevalence and patterns of germline mutations, using commercially available next-generation sequencing (NGS)-based multi-gene panels (MGP).
Patients and Methods
Consecutive at-risk breast cancer patients, as determined by international guidelines, were offered germline genetic testing using a 20-gene NGS-based panel at a reference lab. Samples of peripheral blood were obtained for DNA extraction and genetic variants were classified as benign/likely benign (negative), pathogenic/likely pathogenic (positive) or variants of uncertain significance (VUS).
Results
A total of 1310 patients, median age (range) 43 (19–82) years, were enrolled. Age ≤45 years (n = 800, 61.1%) was the most common indication for testing. Positive family history of breast, ovarian, pancreatic or prostate cancers, and triple-negative disease were among the common indications. Among the whole group, 184 (14.0%) patients had pathogenic/likely pathogenic variants; only 90 (48.9%) were in BRCA1 or BRCA2, while 94 (51.9%) others had pathogenic variants in other genes; mostly in APC, TP53, CHEK2 and PALB2. Mutation rates were significantly higher among patients with positive family history (p = 0.009); especially if they were 50 years or younger at the time of breast cancer diagnosis (p < 0.001). Patients with triple-negative disease had relatively higher rate (17.5%), and mostly in BRCA1/2 genes (71.4%). Variants of uncertain significance (VUS) were reported in 559 (42.7%) patients; majority (90.7%) were in genes other than BRCA1 or BRCA2.
Conclusion
Pathogenic mutations in genes other than BRCA1/2 are relatively common and could have been missed if genetic testing was restricted to BRCA1/2. The significantly high rate of VUS associated with multi-gene panel testing can be disturbing.
Abbreviations
CI, Confidence Intervals; ER, Estrogen Receptors; FISH, Fluorescent in Situ Hybridization; HER2, Human Epidermal Growth Factor Receptor; IHC, Immunohistochemistry; IRB, Institutional Review Board; MDT, Multidisciplinary Team; MGP, Multi-gene Panel; NCCN, National Comprehensive Cancer Network; NGS, Next-Generation Sequencing; PFS, Progression-Free Survival; PR, Progesterone Receptors; VUS, Variant of Uncertain Significance.
Data Sharing Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Ethics Approval and Consent to Participate
The study was approved by Institutional Review Board (IRB) at King Hussein Cancer Center (approval number, 20-KHCC-198), and all patients signed informed consent for genetic testing.
Consent for Publication
Data submitted are entirely unidentifiable, and there are no details on individuals reported within the manuscript.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
First author HA received an institutional grant from Pfizer International to study genetic mapping of breast cancer. All other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript, this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. The abstract of this paper was presented at the 44th annual Breast Cancer Symposium (7–10 Dec 2021) as a poster presentation with interim findings. The poster’s abstract was published in “Poster Abstracts”, Cancer Res 2022; 82(4 Suppl): Abstract number P3-07-06.