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                        HRD Reference Standard
                        2020-12-11 [1313]

                        DNA homologous recombination repair (HRR) is an important way to repair DNA double-strand damage. HRR is a complex signal pathway involving multiple steps, among which the key proteins are BRCA1 and BRCA2. If the BRCA gene mutations cause the BRCA1 and BRCA2 proteins to lose their function, it will cause HRD. It has been confirmed that HRD can cause "genome scar" phenomena, including loss of genome heterozygosity, telomere allele imbalance, and large fragment migration.


                        In terms of mechanism of action, tumor cells with HRD are more sensitive to platinum drugs or PARP inhibitors. In ovarian cancer, BRCA gene mutations, HRR gene mutations, gene promoter methylation, and other reasons can all cause HRD. It can be seen that if only BRCA gene mutations are detected, some HRD-positive patients will miss the opportunity of PARP inhibitor maintenance treatment. HRD testing may provide opportunities for benefit for BRCA-negative patients. HRD positive is a reasonable biomarker for choosing maintenance therapy with PARP inhibitors.


                        In April 2018, the US FDA approved Rubraca® (rucaparib) tablets for the maintenance treatment of patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. These patients had complete or partial remission after receiving platinum chemotherapy. The FDA also approved the supplementary diagnostic test FoundationFocus CDx BRCA LOH to determine the homologous recombination defect (HRD) status of tumor samples, and Rubraca monotherapy for advanced ovarian cancer with BRCA mutations (germline and/or somatic) from accelerated Approval turned into formal approval. The corresponding technical documents.


                        In October 2019, the US FDA approved Niraparib (Zejula) for the treatment of patients with advanced ovarian cancer, fallopian tube cancer or primary peritoneal cancer who have received ≥3 chemotherapy regimens, and these cancers are all homologous recombination Defective disorder (HRD) is positive. At the same time, the FDA also approved Myriad myChoice CDx test as a companion diagnostic method for identifying eligibility to use niraparib (the use of niraparib must be based on the FDA-approved companion diagnosis). The corresponding technical documents, please click to read the original download.


                        At the beginning of 2020, we found that more and more genetic testing companies (no less than 10) in China have begun to deploy HRD testing. Many companies are rushing to develop IVD kits. An embarrassing thing at the time is that there is no standard. No matter what method is used for testing, it is impossible to evaluate the performance of its own method (accuracy, precision, detection limit, etc.). At that time, FoundationFocus CDx BRCA LOH and Myriad myChoice CDx test did not have agents in China and could not directly benchmark data. Most companies developed their own test products by referring to the methods of two foreign companies. At the same time, several pharma companies are also leading domestic clinical trials and developing companion diagnostics. Whether it is retrospective or forward-looking, everyone has made a lot of investment in HRD testing.


                        As a diagnostic standard product development company,  We  will start the layout of HRD standard product research and development in early 2020. The following are our views and progress on HRD standard product development for everyone to discuss and communicate.


                        We understand that domestic companies that develop HRD testing products are mainly based on WES/WGS testing, SNP testing, and HRR-related gene testing as product development routes. Each has its own advantages and disadvantages. Many companies also developed several methods at the same time. , And some will be upgraded on the original panel products.


                        We believe that the development of HRD standards can be evaluated from three dimensions:


                        1. The accuracy and consistency of the test data of each company;

                        2. After the data comes out, analyze the information and get the value of LOD, TAI, LST;

                        3. Consistency analysis of HRD score and drug sensitivity;


                        We understand that when domestic companies select samples, most of them are tested for paired samples. Some companies can test single samples at the same time. Few companies only test single samples. Therefore, we chose 22 pairs of paired samples and 4 single samples. To develop the standard products of HRD Score-High, HRD Score-Median, and HRD Score-Low, a pair is set up as a paired sample and a single sample to evaluate the difference of data analysis.


                        First of all, because the normal samples in the paired samples need to be established, they involve immortalization operations and virus infections, which may cause certain changes to the overall genome. Therefore, we select better ones by testing the matching degree of Tumor and Normal. Paired samples.


                        Secondly, for the detection accuracy of each sample, we chose the WES method. Obviously, the WGS method can detect a large number of SNPs in introns, which is better than WES, but the intron probe design experience is not The cost is more expensive, and the capture efficiency is difficult to guarantee. Therefore, we did not develop WGS. When the subsequent product upgrades are involved, you can upgrade.


                        Thirdly, due to the differences in the detection methods of each company and the differences in bio-credit analysis, the final value of the test for the same sample, HRD score=LOH+TAI+LST, is also significantly different. In the case that the FoundationFocus CDx BRCA LOH and Myriad myChoice CDx test cannot be detected in China, we initiated a joint cooperation for HRD testing at the beginning of the year and invited multiple HRD testing companies to perform calibration on the same sample together and count the test values of each company. Share with cut-off anonymously and also used for internal self-evaluation of each company.


                        Finally, considering the relationship between HRD score and PARPi, we performed in vitro proliferation inhibition tests on multiple pairs of samples, and selected olaparib (AZD2281), and obtained drug sensitivity data through the drug sensitivity test on the samples, and then observed Whether there is a clear correlation with HRD score.


                        Because the entire project has been underway for more than 9 months, the testing of each company is constantly upgrading, so we found that there are still big differences between the testing data of many. Not only are the differences in the number of HRD scores, but there are also qualitative and clear inconsistencies. The cut-offs of each company are too the same. At the same time, it is also found that there are obvious differences in the HRD scores in the data of the same sample and the single sample . It can be said that domestic HRD testing is still quite confusing.


                        In addition, in the drug susceptibility data, we did not find a clear correlation between the data and the HRD score. The possible reason is that the model is not appropriate. It is estimated that many samples are still multi-drive tumors and are not sensitive to a single PARPi.


                        In the multiple data, we selected several samples. These samples are relatively consistent in the accuracy of data detection and the qualitative and quantitative HRD score, and the data quality is high.


                        We welcome everyone's trial, communication, and work together to make the HRD test accurate.





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