High HRD score

We provide the largest mutational landscape of IBC. Only a few subtle differences were identified with non-IBCs. The most clinically relevant one was the higher HRD score in TN IBCs than in TN non-IBCs, whereas the most intriguing one was the smaller intratumor heterogeneity of IBCs.

Furthermore, functional experiments demonstrated that silencing CARD11 and GATA2 impairs HR repair efficiency and enhances the sensitivity of tumor cells to olaparib treatment. In summary, in the absence of mutations in the HR genes, the sensitivity of tumor cells to PARP inhibitors and platinum-based chemotherapy may be enhanced in a subset of breast cancer patients with LNGC somatic mutations.

Higher HRD scores were associated with poorer PFI outcomes, particularly in people with HR+/HER2-low. Varied HRD states exhibited distinctions in HRRGs and the tumor immune landscape. These insights have the potential to assist clinicians in promptly identifying high-risk groups and tailoring personalized treatments for patients with HER2-low EBC, aiming to enhance long-term outcomes.

Collectively, the existing data from established cancer cell lines do not reflect the expected association between HRD status and drug response to platinum agents and PARP inhibitors in clinical tumors. This discrepancy may extend to other tumor characteristics, highlighting the importance of recognizing potential limitations in cell line data for researchers.

PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.

Our prognostic signature which integrates hypoxia and m6A/m5C/m1A-regulated genes, provides valuable insights for clinical prediction and treatment guidance for liver cancer patients.

Among Japanese mHSPC patients, IDC-P demonstrates significant associations with an elevated incidence of genetic alterations and increased HRD score, emphasizing its potential clinical significance.

Methylation profiling identified two distinct breast cancer clusters with significant differences in HRD score. The association among methylation, HRD score, and PAM50 subtype indicates that methylation could be a useful tool for breast cancer subtyping and treatment.

Conclusions HRD positive, defined as GIS score >9, may be an appropriate threshold to predict the likelihood of response to PARPi in prostate cancer. Prospective, and large sample clinical trials will be needed to confirm our findings.

Conclusions In conclusion, we found that high TMB and B-cell related enrichment were associated with good efficacy while HRD was associated with poor efficacy of eribulin plus nivolumab in patients with HER-2 negative metastatic breast cancer. The implications from our study would need to be considered when designing the clinical trial in terms of biomarker enrichment and inclusion/exclusion criteria.

Finally, scRNA-seq analyses confirmed that the immune-related signaling pathways were upregulated in HRD-positive patients. In conclusion, the present study not only demonstrated that a high HRD score is a valid prognostic biomarker in KIRC patients, but also revealed the TME in HRD-positive tumors.

A proportion of noncanonical primary tumors have biallelic loss and evidence of HRD. Our data suggest that assessment of biallelic loss and HRD could supplement identification of germline BRCA1/2 mutations in selection of patients for platinum or PARP inhibitor therapy.

This could also be underlined by the significant lower levels of JARID1B expression in cancers with high HRD scores. In order to further investigate the role of JARID1B in OC analyses on its interplay with CCL14 are ongoing.

Olaparib responsive tumors were sensitive to oxaliplatin as well. However, familial history of cancer, the absence of RAD51 foci in tumor cells and a high HRD score suggest a deleterious effect of this mutation in gastric cancer. ConclusionPARP inhibition is a potential strategy for treating gastric cancer patients with mutated BRCA2 or homologous repair deficiency, including familial intestinal gastric cancer patients, for whom BRCA2 germline testing should be recommended.

Olaparib responsive tumors were sensitive to oxaliplatin as well. In conclusion, PARPis could represent an effective therapeutic option for BRCA2-mutated and/or high HRD score patients with GEA, including patients with familial intestinal gastric cancer. PARP inhibition is a potential strategy for treating patients with gastric cancer with mutated BRCA2 or homologous repair deficiency, including patients with familial intestinal gastric cancer, for whom BRCA2 germline testing should be recommended.

Different BRCA1/2 statuses lead to different HRD characterization in OC patients. OC patients with BRCA1/2 CNV (with/without BRCA1/2 SNV) showed higher HRD score than patients with BRCA1/2 SNV. These patients may deserve opportunity for PARPi treatment besides patients with germline or somatic BRCA1/2 mutation, especially for PARPi with specific requirements for patients, such as Olaparib.

In the 6 patients who received HRD-related treatments (including cisplatin based chemotherapy or olaparib), 1 of the 2 patients with low HRD score had PSA progression after 251 days (the other one was lost to follow up), while no PSA progression was observed in the 4 patients with high HRD score with a median follow-up of 107 days (range: 40-274 days). A mCRPC case with high HRD score (37) and HRR wild-type who received second line docetaxel+cisplatin even achieved undetectable PSA... To our knowledge, this is the first study in China reporting the association of HRD score and platinum-based treatments in PCa. Our results supported the possibility that HRD score could be predictive for the efficacy of platinum-based chemotherapy.

Based on multi-scale transcriptomics, our findings comprehensively reveal differences in the TME between HRD and non-HRD samples. Combining HRD with the prediction model or other methods for assessing immune cell content, may better predict response to ICIs in TNBC.

Based on bioinformatic analysis, we fully explored the therapeutic and prognostic potential of HRD in BRCA. A novel HRD-related gene signature (MELK) were identified through the combination of WGCNA and GPSA analysis. In addition, we detailed the TME landscape in BRCA and identified four unique TME subtypes in group with high or low HRD score group. Moreover, Clofibrate were screened out to improve oncological outcomes in BRCA by reversing the increase of high HRD score. Thus, our study contributes to the development of personalized clinical management and treatment regimens of BRCA.

Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy.

The HRD status can be identified as an independent significance in Chinese HGSOC patients treated with first-line platinum-based chemotherapy.

Our study delineates the associations of tumor immune contexture with molecular features, recurrence after radical prostatectomy, and the efficacy of ADT and immunotherapy. The TICS may improve the existing risk stratification systems and serve as a patient-selection tool for ADT and immunotherapy in prostate cancer.

Sixteen models found to carry HRR mutations, with ATM and BRCA1 mutations being the most common ones, being found in 9 and 5 of 25 models, respectively. Although HRRm positive (HRRm+) models have higher HRD score for both Myriad HRD score and HRD score generated with CNVkit/scarHRD approach, the association between HRR (HRRm+/HRRm-) and Myriad HRD (HRD+/HRD- defined by HRD threshold of 42) is not statistically significant (Fisher’s exact test p value = 0.1998, odds ratio=3.5), likely due to small cohort sizes.These results suggest that combination of CNVkit and scarHRD for HRD score calculation may be an alternative approach for HRD identification in preclinical PDX models.

HRD is a potential predictive biomarker for clinical benefit from neoadjuvant carboplatin-based chemotherapy and provides a possibility for screening the optimum chemotherapy backbone to combine with immunotherapy.

This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation.

CK-AML/MDS cases with TP53 mutations have a significantly higher HRD score compared to those with wild-type TP53. HRD score is an independent prognostic biomarker with a potential therapeutic opportunity for treatment using DNA damaging drugs.

BARD1 and RAD51D behave as classic BRCA-like genes with bi-allelic inactivation but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of bi-allelic inactivation does not provide definitive evidence against the gene's involvement in BC predisposition.

Patients with primary HER2-negative breast cancer, HRD and indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and TNBC or cT1c and Ki-67 >20%) were randomly assigned to receive either P 80 mg/m2 weekly plus O 100 mg twice daily for 12 weeks or P plus Cb area under the curve 2 (AUC2) weekly for 12 weeks, both followed by four cycles of either 2-weekly or 3-weekly epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2. In patients with HER2-negative and HRD breast cancer the use of olaparib instead of carboplatinum although showing comparable pCR rates, tended to result in an overall inferior outcome. This was mainly driven by the patients without a g/tBRCA mutation. In patients with a g/t BRCA mutation no difference between olaparib and carboplatinum was seen.

Furthermore, consensus clustering analysis was employed to divide patients with EOC into three clusters based on the expression of the five HRRlncRNAs, which exhibited a significant difference in checkpoints' expression levels and the tumor microenvironment (TME) status. Taken together, the results of this project supported that the five HRRlncRNA models might function as a biomarker and prognostic indicator with respect to predicting the PARP inhibitor and immune treatment in EOC.

Comprehensive genomic profiling of ER+/HER2- LABC patients revealed that altered NOTCHand NFR2 pathway genes were associated with poor survival outcomes. An analysis involvingresidual cancer burden (RCB) is currently ongoing.

M1, high Gleason score, and IDC-P pathology represent higher HRD scores in PCa. Tumors with IDC-P might have different driven mechanisms for high HRD scores than non-IDC-P. HRD score displayed prognostic value in this aggressive prostate cancer cohort.

Moreover, HRD score can be predicted by a linear function contributed by five DNA helicase genes. In conclusion, our study revealed a close relation between the overexpression of certain DNA helicase genes and the deficiency of homologous recombination repair in breast cancer.

Overall, this big data study determined the threshold of HRD score in LGG, identified HRD-related genes, developed a risk model based on HRD-related genes, and determined the molecular and immunological characteristics of the risk model. This provides potential new targets for future targeted therapies and facilitates the development of individualized immunotherapy to improve prognosis.

The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.

This study revealed some genomic characteristics of rare malignant ovarian tumors, including NETs and CCC.

High HRD scores were associated with an immunologically activated tumor microenvironment only in a minority of cancer types. Our data favor the combination of genetic markers, complex genomic markers (including HRDsum and TMB), and other molecular markers (including proliferation scores) for a precise and comprehensive read-out of the tumor biology and an individually tailored treatment.

Using an in-house HRD evaluation method, our findings show that overall HRR gene mutations account for a significant part of HRD in the absence of BRCA1/2 aberrations, and suggest that HRD positive status might be a predictive biomarker of Pt-chemotherapy.

Our 7-mRNA signature could accurately predict recurrence risks of early-stage TNBCs. This model may facilitate personalized therapy decision-making for early-stage TNBCs individuals.

HRD-H is associated with poor outcome in HNSCC patients. Those patients may benefit from PARPi treatment rather than ICIs treatment for its non-inflamed tumor microenvironment.

Background: We recently performed the NeoCART trial to compare six cycles of docetaxel plus carboplatin (DCb) with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel (EC-D) in the neoadjuvant setting of triple-negative breast cancer (TNBC). PCR in TNBC patients correlated with a higher HRD score, higher stromal TILs, and a higher Ki67 index on carboplatin-based neoadjuvant chemotherapy regardless of BRCA status.

HRD correlates with platinum sensitivity in epithelial ovarian tumors, which has clinical significance as a predictor of sensitivity to PARPi. During treatment, tissue samples are obtained at different times points and sources, some at diagnosis/surgical debulking and some after neoadjuvant therapy. After neoadjuvant treatment, tumor volume is reduced.