Breast Cancer: Targets and Therapy (Jan 2023)

Guideline-Based, Multi-Gene Panel Germline Genetic Testing for at-Risk Patients with Breast Cancer

  • Abdel-Razeq H,
  • Abujamous L,
  • Al-Azzam K,
  • Abu-Fares H,
  • Bani Hani H,
  • Alkyam M,
  • Sharaf B,
  • Elemian S,
  • Tamimi F,
  • Abuhijla F,
  • Edaily S,
  • Salama O,
  • Abdulelah H,
  • Daoud R,
  • Abubaker M,
  • Al-Atary A

Journal volume & issue
Vol. Volume 15
pp. 1 – 10

Abstract

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Hikmat Abdel-Razeq,1,2 Lama Abujamous,3 Khansa Al-Azzam,1 Hala Abu-Fares,1 Hira Bani Hani,1 Mais Alkyam,1 Baha’ Sharaf,1 Shatha Elemian,1 Faris Tamimi,1 Fawzi Abuhijla,4 Sarah Edaily,1 Osama Salama,1 Hazem Abdulelah,1 Rand Daoud,1 Mohammad Abubaker,1 Areej Al-Atary5 1Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan; 2School of Medicine, The University of Jordan, Amman, Jordan; 3Department of Cell Therapy & Applied Genomic, King Hussein Cancer Center, Amman, Jordan; 4Department of Radiation Oncology, King Hussein Cancer Center, Amman, Jordan; 5Department of Nursing, King Hussein Cancer Center, Amman, JordanCorrespondence: Hikmat Abdel-Razeq, Department of Internal Medicine, King Hussein Cancer Center, School of Medicine, University of Jordan, Queen Rania Al Abdullah Street, P.O. Box 1269, Amman, 11941, Jordan, Tel +962-6 5300460, Ext 1000, Email [email protected]: 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.Keywords: breast cancer, BRCA1, BRCA2, multigene panel, hereditary breast cancer, next generation sequencing

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