Wen-Ming Cao

Background: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer represents the most prevalent molecular subtype but demonstrates pronounced biological and clinical heterogeneity. Homologous recombination deficiency (HRD) and tumor-infiltrating lymphocytes (TILs) have recently emerged as key determinants of prognosis and immune activity, but their interplay in this subtype remains understudied. Objectives: To assess the relationship between HRD, TILs, and clinical outcomes in HR+/HER2− breast cancer and validate the prognostic value of HRD. Design: Retrospective multicenter cohort study. Methods: A total of 365 patients (332 with available TILs data) from three institutions were enrolled. HRD was quantified using Shallow HRD algorithm on low-depth whole-genome sequencing (threshold: score ⩾6). TILs were evaluated by the MD Anderson system (⩾10% classified as high). Spearman correlation, Kaplan–Meier survival analysis, and multivariable Cox regression were performed. Results: HRD scores were inversely correlated with TILs (Spearman rho = −0.13, p = 0.031). HRD-high patients had significantly inferior 10-year survival (invasive disease-free survival (IDFS): 31.0% vs 57.9%, hazard ratio (HR) = 2.36; distant recurrence-free survival (DRFS): 34.1% vs 61.1%, HR = 2.48; overall survival (OS): 48.7% vs 79.0%, HR = 2.79; p < 0.0001). HRD was confirmed as an independent prognostic predictor (IDFS HR = 2.03, DRFS HR = 2.16, OS HR = 2.15; p < 0.01). No significant survival benefit from anthracycline-based chemotherapy was observed in HRD-high tumors (HR = 1.32, p = 0.451). High TILs showed no significant association with survival outcomes in this cohort. Conclusion: HRD represents a reliable independent prognostic biomarker in HR+/HER2− breast cancer in this cohort, with an inverse association with TILs suggesting immune evasion. Its potential impact on prognosis and treatment requires further validation in prospective clinical trials.

In the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative, and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increased HIF1A transcription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate triple-negative breast cancer angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediating HIF1A transcription. Furthermore, we discovered that STAMBPL1 regulates GRHL3 transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer.

In the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increased HIF1A transcription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate TNBC angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediating HIF1A transcription. Furthermore, we discovered that STAMBPL1 regulates GRHL3 transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer.

Long‐term survival varies among hormone receptor‐positive (HR+) and human epidermal growth factor receptor 2‐negative (HER2−) breast cancer patients and is seriously impaired by metastasis. Chromosomal instability (CIN) was one of the key drivers of breast cancer metastasis. Here we evaluate CIN and 10‐year invasive disease‐free survival (iDFS) and overall survival (OS) in HR+/HER2−– breast cancer. In this large‐scale, multiple‐site, retrospective study, 354 HR+/HER2− breast cancer patients were recruited. Of these, 204 patients were used for internal training, 70 for external validation, and 80 for cross‐validation. All medical records were carefully reviewed to obtain the disease recurrence information. Formalin‐fixed paraffin‐embedded tissue samples were collected, followed by low‐pass whole‐genome sequencing with a median genome coverage of 1.86X using minimal 1 ng DNA input. CIN was then assessed using a customized bioinformatics workflow. Three or more instances of CIN per sample was defined as high CIN and the frequency was 42.2% (86/204) in the internal cohort. High CIN correlated significantly with increased lymph node metastasis, vascular invasion, progesterone receptor negative status, HER2 low, worse pathological type, and performed as an independent prognostic factor for HR+/− breast cancer. Patients with high CIN had shorter iDFS and OS than those with low CIN [10‐year iDFS 11.1% versus 82.2%, hazard ratio (HR) = 11.12, p < 0.01; 10‐year OS 45.7% versus 94.3%, HR = 14.17, p < 0.01]. These findings were validated in two external cohorts with 70 breast cancer patients. Moreover, high CIN could predict the prognosis more accurately than Adjuvant! Online score (10‐year iDFS 11.1% versus 48.6%, HR = 2.71, p < 0.01). Cross‐validation analysis found that high consistency (83.8%) was observed between CIN and MammaPrint score, while only 45% between CIN and Adjuvant! Online score. In conclusion, high CIN is an independent prognostic indicator for HR+/HER2− breast cancer with shorter iDFS and OS and holds promise for predicting recurrence and metastasis.

In the clinic, anti-tumor angiogenesis is commonly employed for treating recurrent, metastatic, drug-resistant triple-negative and advanced breast cancer. Our previous research revealed that the deubiquitinase STAMBPL1 enhances the stability of MKP-1, thereby promoting cisplatin resistance in breast cancer. In this study, we discovered that STAMBPL1 could upregulate the expression of the hypoxia-inducible factor HIF1α in breast cancer cells. Therefore, we investigated whether STAMBPL1 promotes tumor angiogenesis. We demonstrated that STAMBPL1 increased HIF1A transcription in a non-enzymatic manner, thereby activating the HIF1α/VEGFA signaling pathway to facilitate TNBC angiogenesis. Through RNA-seq analysis, we identified the transcription factor GRHL3 as a downstream target of STAMBPL1 that is responsible for mediating HIF1A transcription. Furthermore, we discovered that STAMBPL1 regulates GRHL3 transcription by interacting with the transcription factor FOXO1. These findings shed light on the role and mechanism of STAMBPL1 in the pathogenesis of breast cancer, offering novel targets and avenues for the treatment of triple-negative and advanced breast cancer.

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.

Anti-angiogenesis is a crucial therapeutic strategy for triple-negative breast cancer (TNBC), but the current targeted drugs are insufficient to meet clinical requirements. Our study has discovered that silencing the deubiquitinating enzyme STAMBPL1 can effectively inhibit the growth and angiogenesis of TNBC xenografts in nude mice. STAMBPL1 promotes the expression of HIF1α/VEGFA in TNBC through a non-enzymatic-dependent mechanism. STAMBPL1 interacts with the transcription factor FOXO1, which binds to the promoter of the GRHL3 gene, thereby positively regulating its transcription. Subsequently, GRHL3 binds to the HIF1α gene promoter to promote its transcription and angiogenesis. Moreover, we have demonstrated that the combination of FOXO1 inhibitor AS1842856 and VEGFR inhibitor Apatinib significantly inhibited the growth of transplanted tumors in nude mice. These findings indicate that the STAMBPL1/FOXO1/GRHL3/HIF1α/VEGFA axis provides potential therapeutic targets in TNBC.

BRCA2-mutated carriers have a high lifetime risk of breast cancer (BC), an early age of onset, and an increased risk of other cancers (including ovarian, pancreatic, and prostate cancer). Almost 70–80% of BRCA2-mutated BC are estrogen receptor (ER)-positive, which is a particular type of ER-positive BC that differs from sporadic ER-positive BC. This article reviews the clinicopathological features, treatment, and prognosis of ER-positive and BRCA2-mutated BC to provide a reference for clinical decision-making.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation’s effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers ( p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64–1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61–1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.