Among DNA damage, the most serious damage is single-strand break and double-strand break, but single-strand break is more common. If these breaks cannot be repaired in time and accurately, the genome will become unstable, which will lead to cancer and even directly lead to cell death. For double-strand breaks, although rare, the situation is more serious. If it cannot be repaired in time, the DNA of the cell will become unstable and the cell will eventually die.
There are two main methods to repair double-stranded DNA breaks. One is the repair of non-homologous end ligation (NHEJ), which is more like an emergency fire chief. Whether the repair is correct or not, connect the broken DNA first. The main advantage of this method is its high speed, but it is very easy to make mistakes. Once there is a big problem, it may be a devastating blow to cells. The other is homologous recombination (HR) repair. There are many proteins involved in this repair, such as BRCA, ATM, RAD5 1 and so on. BRCA protein is the most famous. Just like surgery, this repair method is a high-fidelity and error-free repair method.
Homologous recombination repair (HRR) is an important DNA double-stranded repair mechanism. DNA double-strand breaks caused by ionizing radiation and other DNA damage factors are strong inducers of HRR, which can start the HRR process. Compared with other repair methods, HRR can obtain accurate repair effect by using the similarity of DNA sequences of paired chromosomes in cells. HRR is a complex signal path involving multiple steps, and several HR paths initiated by DSB have been clarified [1].
HRD usually refers to the state of HRR dysfunction at the cellular level. When HRD exists, DSB will excessively rely on alternative DNA damage repair pathways with low fidelity and high error-prone such as nonhomologous terminal ligation (NHEJ), microhomologous terminal ligation (MMEJ) and single strand annealing (SSA), which will most likely lead to insertion/deletion of nucleic acid sequence, abnormal copy number and chromosome cross-linking, thus leading to genome and chromosome instability [2 HRD can be caused by germline mutation or somatic mutation of HRR-related genes.
HRD will produce specific, quantifiable and stable genomic changes, including identifiable gene mutation, insertion/deletion pattern, abnormal chromosome structure, gene copy number variation and so on. This is also the theoretical basis for constructing the clinical detection method of HRD at present. Homologous recombination repair defect (HRD) has become a new biomarker for the clinical application of PARP inhibitors in patients with advanced ovarian cancer, and may also have guiding value for the clinical application of PARP inhibitors and platinum drugs in breast cancer, prostate cancer and other tumors.
The occurrence of HRD in malignant tumor is closely related to the location, histological type and detection method adopted. CHORD algorithm was used to analyze the whole genome sequencing (WGS) of metastatic (n=3504) and primary (n= 1854) pan-cancer population. The results showed that the incidence of HRD in metastatic cancer was 6%, with ovarian cancer (30%) and breast cancer, prostate cancer and pancreatic cancer (30%) having the highest incidence. The mutation frequency of HRR-related genes is 6%, among which ovarian cancer (30% ~ 50%) and breast cancer (12% ~ 24%) are the most common, followed by pancreatic cancer (7.3% ~ 13.0%) and prostate cancer (5.3% ~13).
HRD is a relatively stable molecular marker of malignant tumor. The HRD of 8 1 small biopsy specimens of 32 cases of early breast cancer was evaluated, and the HRD scores of different biopsy specimens of the same tumor were highly consistent (R 2 =0.98) [4]. The HRD status of primary and recurrent ovarian cancer tissues of 50 patients was analyzed by paired analysis, and it was found that the HRD scores of primary and recurrent tissues of the same patient also had high consistency (R 2 =0.93) [5].
The clinical detection methods of HRD can be divided into three categories: HRR-related gene mutation detection, genomic scar and mutation pedigree analysis, and HRD function detection. The following table summarizes some related studies [6-7].
At present, many kinds of PARP inhibitors have been approved for marketing in the world, such as Olaparib, Rucaparib, Niraparib and Talazoparib approved by FDA and Fluzoparib and Pamiparib approved by NMPA recently. Many indications have been approved in ovarian cancer, prostate cancer, breast cancer, pancreatic cancer and other tumors. At the same time, the clinical detection of HRD as an important prognostic indicator of PARP inhibitors has also developed rapidly.
In QUADRA study, the objective remission rate (ORR) of 98 patients with HRD positive cohort treated by NiRapali was 24%, and the median expected remission duration (DOR) was 8.3 months [8]. Paula. In the 1 study, the median PFS of HRD-positive patients who received first-line maintenance therapy with olapali plus bevacizumab or bevacizumab was 37.2 months and 17.7 months, respectively, while the median PFS of HRD-positive patients with BRCA mutation negative was 28. 1 month and16, respectively. In PRIMA study, the risk of disease progression or death in HRD-positive /BRCA mutant group was reduced by 60%, and that in HRD-positive /BRCA wild type group was reduced by 50%. Myriad myChoice was used in the above three studies. CDx confirmed the HRD status of tumor, and HRD positive was defined as BRCA 1/2 mutation and/or GIS score ≥42.
In ARIEL3 study, the loss of heterozygosity was detected by FoundationOne CDx(F 1CDx) to determine the HRD status, where the threshold of high loss of heterozygosity was ≥ 16%, and HRD positive was defined as BRCA mutant or BRCA wild-type high loss of heterozygosity. Exploratory analysis showed that the median survival time of patients with high heterozygosity loss in Lucapagli maintenance treatment group was longer than that of patients with low heterozygosity loss (9.7 months vs6.7 months, P=0.0338), while the median survival time of patients with high heterozygosity loss and low heterozygosity loss in placebo group was 5.4 months [1 1].
The results of in-depth study show that olapali can reduce the risk of disease progression or death of mCRPC patients with BRCA, ATM pathogenic or possibly pathogenic mutations by 66%. According to the evaluation of the Independent Review Committee, patients with other HRR gene pathogenic or possibly pathogenic mutations, such as BRCA, ATM, BARD 1, RIP 1, CDK 12, Chek12, FANCL, PALB2, RAD51.
In addition, currently based on Myriad myChoice? The clinical application of CDx, FoundationFocusTM CDx or similar methods for HRD status assessment of breast cancer and pancreatic cancer is still being explored.