Research ArticleOriginal Article

Association between homologous recombination deficiency and outcomes with platinum and platinum-free chemotherapy in patients with triple-negative breast cancer

Yimeng Chen, Xue Wang, Feng Du, Jian Yue, Yiran Si, Xiaochen Zhao, Lina Cui, Bei Zhang, Ting Bei, Binghe Xu and Peng Yuan
Cancer Biology & Medicine February 2023, 20 (2) 155-168; DOI: https://doi.org/10.20892/j.issn.2095-3941.2022.0525

Article Figures & Data

Figures

  • Correlation of HRD with molecular and clinical features. (A) Pathogenic alterations in tumor-associated genes and HRD scores, detected by next-generation sequencing of tumor DNA from 149 patients with TNBC. Patients with an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2 were classified as HRD-positive, whereas patients with an HRD score < 30 and BRCA1/2-intact status were defined as HRD-negative. Mutated genes are listed in descending order from most to least frequently altered. The clinical features include, from top to bottom, patient age, Ki67 expression, disease stage, histologic grade, and pathological subtype. B, HRD scores of BRCA-wild-type tumors and tumors with either germline or somatic BRCA1/2 mutations. C, HRD scores of tumors with HRR gene mutations. HRD scores were determined with 3D-HRD assays. Differences in groups were calculated with either Wilcoxon or t-tests, as appropriate. P < 0.05 was considered statistically significant.
    Correlation of HRD with molecular and clinical features. (A) Pathogenic alterations in tumor-associated genes and HRD scores, detected by next-generation sequencing of tumor DNA from 149 patients with TNBC. Patients with an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2 were classified as HRD-positive, whereas patients with an HRD score < 30 and BRCA1/2-intact status were defined as HRD-negative. Mutated genes are listed in descending order from most to least frequently altered. The clinical features include, from top to bottom, patient age, Ki67 expression, disease stage, histologic grade, and pathological subtype. B, HRD scores of BRCA-wild-type tumors and tumors with either germline or somatic BRCA1/2 mutations. C, HRD scores of tumors with HRR gene mutations. HRD scores were determined with 3D-HRD assays. Differences in groups were calculated with either Wilcoxon or t-tests, as appropriate. P < 0.05 was considered statistically significant.
    Figure 1

    Correlation of HRD with molecular and clinical features. (A) Pathogenic alterations in tumor-associated genes and HRD scores, detected by next-generation sequencing of tumor DNA from 149 patients with TNBC. Patients with an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2 were classified as HRD-positive, whereas patients with an HRD score < 30 and BRCA1/2-intact status were defined as HRD-negative. Mutated genes are listed in descending order from most to least frequently altered. The clinical features include, from top to bottom, patient age, Ki67 expression, disease stage, histologic grade, and pathological subtype. B, HRD scores of BRCA-wild-type tumors and tumors with either germline or somatic BRCA1/2 mutations. C, HRD scores of tumors with HRR gene mutations. HRD scores were determined with 3D-HRD assays. Differences in groups were calculated with either Wilcoxon or t-tests, as appropriate. P < 0.05 was considered statistically significant.

  • Association of progression-free survival (PFS) with HRD in metastatic TNBC. (A) Kaplan–Meier curves showing the PFS of metastatic patients with TNBC (n = 40) in each group, by chemotherapeutic regimen and HRD status. HRD+ was defined by an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2, whereas BRCA1/2-intact tumors with HRD scores < 30 were defined as HRD−. (B) PFS of BRCA1/2-wildtype TNBC treated with first-line platinum-containing or platinum-free chemotherapy (n = 35). Patients with HRD scores ≥ 30 were defined as HRD score high (HRD-H), whereas those with an HRD score < 30 were defined as HRD score low (HRD-L). (C) Subgroup analyses according to baseline characteristics including ECOG, age, HRD score, and mutations in BRCA1/2 and HRR genes. Forest plots showing the estimated hazard ratios (HR) for progression with a univariable Cox proportional hazards model; 95% confidence intervals (CI) of HRs are represented by horizontal bars. HRR, homologous recombination repair. HRD, homologous recombination deficiency. ECOG, Eastern Cooperative Oncology Group performance score.
    Figure 2

    Association of progression-free survival (PFS) with HRD in metastatic TNBC. (A) Kaplan–Meier curves showing the PFS of metastatic patients with TNBC (n = 40) in each group, by chemotherapeutic regimen and HRD status. HRD+ was defined by an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2, whereas BRCA1/2-intact tumors with HRD scores < 30 were defined as HRD−. (B) PFS of BRCA1/2-wildtype TNBC treated with first-line platinum-containing or platinum-free chemotherapy (n = 35). Patients with HRD scores ≥ 30 were defined as HRD score high (HRD-H), whereas those with an HRD score < 30 were defined as HRD score low (HRD-L). (C) Subgroup analyses according to baseline characteristics including ECOG, age, HRD score, and mutations in BRCA1/2 and HRR genes. Forest plots showing the estimated hazard ratios (HR) for progression with a univariable Cox proportional hazards model; 95% confidence intervals (CI) of HRs are represented by horizontal bars. HRR, homologous recombination repair. HRD, homologous recombination deficiency. ECOG, Eastern Cooperative Oncology Group performance score.

  • Association of HRD with disease-free survival (DFS) among patients with TNBC receiving adjuvant chemotherapy in the surgical cohort. (A) DFS of HRD+/− patients with TNBC receiving platinum-containing in comparison to platinum-free chemotherapy. HRD+ was defined by an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2, whereas BRCA1/2-intact tumors with HRD scores < 30 were defined as HRD−. (B) DFS of BRCA1/2mut and BRCA1/2wt patients with TNBC treated with platinum-containing or platinum-free regimens.
    Figure 3

    Association of HRD with disease-free survival (DFS) among patients with TNBC receiving adjuvant chemotherapy in the surgical cohort. (A) DFS of HRD+/− patients with TNBC receiving platinum-containing in comparison to platinum-free chemotherapy. HRD+ was defined by an HRD score ≥ 30 and/or deleterious mutations in BRCA1/2, whereas BRCA1/2-intact tumors with HRD scores < 30 were defined as HRD−. (B) DFS of BRCA1/2mut and BRCA1/2wt patients with TNBC treated with platinum-containing or platinum-free regimens.

Tables

  • Table 1

    Correlation between clinicopathological features and HRD status in 189 triple-negative breast cancers

    CharacteristicsNo. (%)
    Total (n = 189)HRD+ (n = 93)HRD− (n = 96)P value
    Age, mean (standard deviation), years48.3 (9.5)46.6 (9.0)50.0 (9.7)0.01
    Menopausal status0.07
     Premenopausal102 (54.0)57 (61.3)45 (46.9)
     Postmenopausal87 (46.0)36 (38.7)51 (53.1)
    Ki67 proliferation index (%)
     Median (range)60 (5.0, 95.0)65 (10.0, 95.0)40 (5.0, 95.0)< 0.001
     N/A532
    Tumor stage0.13
     cT191 (48.4)38 (41.3)53 (55.2)
     cT292 (48.9)52 (56.5)40 (41.7)
     cT35 (2.7)2 (2.2)3 (3.1)
     N/A11
    Pathological status0.15
     Ductal182 (96.3)87 (93.5)95 (99.0)
     Medullary4 (2.1)3 (3.2)1 (1.0)
     Others3 (1.6)3 (3.2)0 (0.0)
    Histological grade0.09
     II52 (29.2)20 (22.7)32 (35.6)
     III126 (70.8)68 (77.3)58 (64.4)
     N/A1156
    Clinical stage0.15
     I50 (26.5)22 (23.7)28 (29.2)
     II91 (48.1)52 (55.9)39 (40.6)
     III8 (4.23)2 (2.20)6 (6.3)
     IV40 (21.2)17 (18.7)23 (24.0)
    PD-L1 IPS expression0.36
     <1%116 (77.9)62 (81.6)54 (74.0)
     ≥1%33 (22.1)14 (18.4)19 (26.0)
     N/A401723
    PD-L1 TPS expression1.00
     <1%133 (89.3)68 (89.5)65 (89.0)
     ≥1%16 (10.7)8 (10.5)8 (11.0)
     N/A401723
    BRCA 1/2< 0.001
     Mutant40 (21.2)40 (43.0)0 (0.00)
     Wild-type149 (78.8)53 (57.0)96 (100)
    HRR-associated genes< 0.001
     Mutant68 (36.0)49 (52.7)19 (19.8)
     Wild-type121 (64.0)44 (47.3)77 (80.2)

    HRD, homologous recombination deficiency. A tumor was defined as HRD+ on the basis of HRD scores ≥ 30 and/or deleterious mutation in BRCA1/2, whereas BRCA1/2-intact tumors with HRD scores < 30 were defined as HRD−. PD-L1, programmed death ligand 1; TPS, tumor proportion score, the proportion of viable tumor cells showing partial or complete membrane PD-L1 staining at any intensity; IPS, immune proportion score (IPS), the percentage of tumor-infiltrating immune cells with PD-L1 staining at any intensity; HRR, homologous recombination repair; N/A, not available.

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