AcornHRD: an HRD algorithm which was highly associated with anthracycline-based neoadjuvant chemotherapy in Chinese breast cancer
Abstract Background Homologous recombination deficiency (HRD) can result from BRCA dysfunction and is associated with platinum sensitivity, PARP inhibitor, and other DNA-damaging drugs. There are many commercial HRD detection assays, but there is still no uniform standard in China. This study aimed to develop and validate an HRD scoring algorithm. Methods Ninety-six in-house BC samples and 6 HRD positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed a algorithm named AcornHRD for HRD score based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. The sensitivity and specificity were compared between our algorithm and the ShallowHRD. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. Results A 100kb-window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD positive threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve 95% sensitivity. The sensitivity and specificity of AcornHRD were both 100%, while those of the ShallowHRD were 40% and 100%, respectively. Meanwhile, AcornHRD sensitivity was superior to ShallowHRD (87% vs 13%) in the clinical cohort. BRCA status was significantly associated with HRD status by AcornHRD and ShallowHRD (P = 0.00838 and P = 0.00284, respectively). However, AcornHRD had a higher positive concordance rate than the ShallowHRD algorithm (70% vs 60%). In the clinical cohort of neoadjuvant treatment, the HRD positive group was more likely to respond to anthracycline-based chemotherapy than the HRD negative group, with outcomes of pCR (OR = 9.5, 95% CI: 1.11–81.5, p = 0.04) and residual cancer burden score of 0 or 1 (RCB0/1) (OR = 10.29, 95% CI: 2.02–52.36, p = 0.005). Among 35 patients lacking BRCA mutations, the HRD positive group tended to have RCB0/1 responses compared to the HRD negative group (OR = 6.0, 95% CI: 1.00–35.91, p = 0.05). Conclusion Here, we developed a stable algorithm for the HRD score. A promising assay for clinical application to predict the sensitivity of DNA-damaging drugs..
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Preprint| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
ResearchSquare.com - (2022) vom: 03. Aug. Zur Gesamtaufnahme - year:2022 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pan, Jia-Ni [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.21203/rs.3.rs-1770144/v1 |
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| PPN (Katalog-ID): |
XRA036373109 |
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| 520 | |a Abstract Background Homologous recombination deficiency (HRD) can result from BRCA dysfunction and is associated with platinum sensitivity, PARP inhibitor, and other DNA-damaging drugs. There are many commercial HRD detection assays, but there is still no uniform standard in China. This study aimed to develop and validate an HRD scoring algorithm. Methods Ninety-six in-house BC samples and 6 HRD positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed a algorithm named AcornHRD for HRD score based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. The sensitivity and specificity were compared between our algorithm and the ShallowHRD. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. Results A 100kb-window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD positive threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve 95% sensitivity. The sensitivity and specificity of AcornHRD were both 100%, while those of the ShallowHRD were 40% and 100%, respectively. Meanwhile, AcornHRD sensitivity was superior to ShallowHRD (87% vs 13%) in the clinical cohort. BRCA status was significantly associated with HRD status by AcornHRD and ShallowHRD (P = 0.00838 and P = 0.00284, respectively). However, AcornHRD had a higher positive concordance rate than the ShallowHRD algorithm (70% vs 60%). In the clinical cohort of neoadjuvant treatment, the HRD positive group was more likely to respond to anthracycline-based chemotherapy than the HRD negative group, with outcomes of pCR (OR = 9.5, 95% CI: 1.11–81.5, p = 0.04) and residual cancer burden score of 0 or 1 (RCB0/1) (OR = 10.29, 95% CI: 2.02–52.36, p = 0.005). Among 35 patients lacking BRCA mutations, the HRD positive group tended to have RCB0/1 responses compared to the HRD negative group (OR = 6.0, 95% CI: 1.00–35.91, p = 0.05). Conclusion Here, we developed a stable algorithm for the HRD score. A promising assay for clinical application to predict the sensitivity of DNA-damaging drugs. | ||
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| 700 | 1 | |a Wang, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Ming-Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Xiao-Wen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Tao |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hui-Na |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yun-Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Li-Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Wei-Wu |e verfasserin |4 aut | |
| 700 | 1 | |a Lou, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiao-Jia |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Wen-Ming |e verfasserin |4 aut | |
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