AcornHRD: an HRD algorithm highly associated with anthracycline-based neoadjuvant chemotherapy in breast cancer in
Jia-Ni Pan1,2,3, Pu-Chun Li1,4, Meng Wang5
1Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
Insights
We developed AcornHRD, a novel algorithm for detecting homologous recombination deficiency (HRD) in breast cancer using whole-genome sequencing. AcornHRD accurately identifies HRD status and predicts response to anthracycline-based chemotherapy in Chinese patients.
Area of Science:
- Genomics
- Oncology
- Biotechnology
Background:
- Homologous recombination deficiency (HRD) is a key factor in breast cancer development and treatment response.
- Accurate HRD detection is crucial for personalized therapy selection.
Purpose of the Study:
- To develop and validate a homologous recombination deficiency (HRD) scoring algorithm, AcornHRD, specifically for the Chinese breast cancer population.
- To assess the performance of AcornHRD using whole-genome sequencing (WGS) data at low coverage.
- To evaluate the association between AcornHRD-determined HRD status and treatment outcomes in breast cancer patients.
Main Methods:
- Whole-genome sequencing (WGS) of 96 in-house breast cancer (BC) samples and 6 HRD-positive standard cells.
- Down-sampling of 122 TCGA BCs to ~1X WGS for algorithm development.
- Construction of the AcornHRD algorithm to estimate large-scale copy number alteration (LCNA) events.
- Validation in a clinical cohort of 50 BCs to assess HRD status and treatment response.
Main Results:
- AcornHRD demonstrated 100% agreement in HRD status compared to 60% for ShallowHRD in standard cells.
- AcornHRD showed superior BRCA-positive agreement rates (87% vs. 13%) in the clinical cohort.
- High HRD score by AcornHRD correlated significantly with favorable treatment outcomes (RCB0/1) and predicted better response to anthracycline-based chemotherapy.
Conclusions:
- The AcornHRD algorithm exhibits high performance for HRD detection in breast cancer.
- LCNA genomic signatures are effective for HRD assessment.
- AcornHRD holds promise for guiding treatment decisions in breast cancer patients.
Purpose:
Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population.
Methods And Materials:
Ninety-six in-house breast cancer (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 an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. 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 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]).
Conclusion:
Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.
