Abstract 1838P
Background
Germline mutations of HRR genes have been proven to be associated with familial cancers. Recently, FDA has approved olaparib for adult patients (pts) with deleterious germline or somatic HRR gene-mutated metastatic castration-resistant prostate cancer. Here, we reported an analysis of germline mutations of HRR genes in a multi-cancer cohort for pts who might benefit from PARP inhibitors in clinical development.
Methods
We retrospectively reviewed next-generation sequencing data of 49,895 pts with solid cancers in a Chinese cohort. The deleterious germline mutations in HRR genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C and RAD51D) were analyzed.
Results
A total of 110 (0.22%) pts with germline mutations in HRR pathway were detected in 12 types of cancer. The germline HRR mutation-positive rates were 6.52% (18/276) in ovarian cancer pts, 2.50% (1/40) in tongue cancer pts, 2.08% (3/144) in prostate cancer pts, 2.01% (12/596) in breast cancer pts and less than 1% in pts with other types of cancer. The most common mutated HRR gene was BRCA1 (gBRCA1m, 50.00%), followed with BRCA2 (gBRCA2m, 29.09%) and BRIP1 (8.18%). For cancers (breast, ovary, pancreas and prostate) that the FDA has approved for treatment with PARP inhibitors, 35 of the 38 pts harbored gBRCA1/2m. Besides, there are another 52 pts with other cancers carrying gBRCA1/2m. Meanwhile, a total of 23 pts carried non-gBRCA1/2m. The germline HRR mutations mainly occurred on BRCA1/2, indicating the strong pathogenicity of gBRCA1/2m. But the HRR mutations detected in different cancers are variable, the sensitivity of these pts to PARP inhibitors needs to be further studied. Table: 1838P
Counts of mutations in multi-cancers
| Cancer/Gene | ATM | BARD1 | BRCA1 | BRCA2 | BRIP1 | PALB2 | RAD51C | RAD51D | N/Total, % |
| Brain | 0 | 1 | 7 | 5 | 4 | 0 | 2 | 1 | 20/9287, 0.22% |
| Breast | 0 | 0 | 9 | 1 | 1 | 1 | 0 | 0 | 12/596, 2.01% |
| Bile duct | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 2/1117, 0.18% |
| Colorectal | 1 | 0 | 2 | 3 | 0 | 1 | 0 | 0 | 7/5669, 0.12% |
| Esophagus | 0 | 0 | 1 | 3 | 0 | 0 | 0 | 0 | 4/423, 0.95% |
| Lung | 1 | 0 | 9 | 12 | 3 | 0 | 2 | 0 | 27/26901, 0.10% |
| Ovary | 0 | 0 | 18 | 0 | 0 | 0 | 0 | 0 | 18/276, 6.52% |
| Pancreas | 0 | 0 | 2 | 3 | 0 | 0 | 0 | 1 | 6/973, 0.62% |
| Prostate | 1 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 3/144, 2.08% |
| Stomach | 1 | 0 | 4 | 1 | 1 | 1 | 0 | 0 | 8/1997, 0.40% |
| Thymus | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1/102, 0.98% |
| Tongue | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1/40, 2.50% |
| Urothelial | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1/183, 0.55% |
Conclusions
This study revealed the landscape of germline mutations in HRR pathway in Chinese cancer pts, which might result in more effective personalized diagnoses and therapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.