背景:作为新发现的与预后较差相关的HER2阴性肿瘤亚型,评估潜在的预后和预测因素仍然至关重要,特别是非侵入性生物标志物,对于患有人类表皮生长因子2(HER2)低早期乳腺癌(EBC)的个体。多项研究强调,HER2阴性的EBC患者表现出高同源重组缺陷(HRD)评分,对新辅助化疗(NAC)的病理完全反应(PCR)率较低。然而,迄今为止,尚无研究探讨HER2低的EBC患者HRD与长期预后之间的相关性.
方法:本回顾性观察研究的重点是来源于癌症基因组图谱数据集(TCGA)的原发性EBC。它揭示了低HER2表达的EBC中的基因突变景观,并阐明了不同HRD状态下的肿瘤免疫景观。利用生物信息学分析和Cox比例模型,连同Kaplan-Meier方法,该研究评估了HRD状态与疾病特异性生存期(DSS)之间的相关性,无病间隔(DFI),和无进展间期(PFI)。进行亚组分析以确定HRD与预后之间关联的潜在差异。
结果:在低HER2乳腺癌患者中,具有同源重组相关基因(HRRGs)缺陷的患者的HRD评分约为没有相关基因突变的患者的两倍,并且获得ARID1A的风险更高,ATM,和BRCA2突变。我们还发现,在高HRD的EBC肿瘤中,大多数免疫细胞丰度明显高于低HRD或HRD-medium的EBC肿瘤。特别是血浆B细胞丰度,CD8T细胞丰度,和M1巨噬细胞。此外,这些HRD高的肿瘤似乎也有更高的肿瘤免疫评分和更低的间质评分.然后,分析不同HRD状态与预后的关系。低HRD组和高HRD组的DSS和PFI差异有统计学意义(分别为P=.036和P=.046)。HRD高EBC患者的生存结局相对较差.中等HRD评分(危险比,HR=2.15,95%CI:1.04-4.41,P=0.038)是PFI的重要危险因素。激素受体阳性是获得中高HRD评分和不良预后的重要因素。
结论:较高的HRD评分与较差的PFI结局相关,特别是在HR+/HER2低的人群中。不同的HRD状态在HRRG和肿瘤免疫景观中表现出差异。这些见解有可能帮助临床医生及时识别高危人群,并为低HER2EBC患者定制个性化治疗方法。旨在提高长期成果。
BACKGROUND: As a newly identified subtype of HER2-negative tumors associated with a less favorable prognosis, it remains crucial to evaluate potential prognostic and predictive factors, particularly non-invasive biomarkers, for individuals with human epidermal growth factor 2 (HER2) low early-stage breast cancer (EBC). Multiple investigations have highlighted that HER2-negative patients with EBC exhibiting high homologous recombination deficiency (HRD) scores display lower rates of pathological complete response (PCR) to neoadjuvant chemotherapy (NAC). Nevertheless, no study to date has explored the correlation between HRD and the long-term prognosis in HER2-low patients with EBC.
METHODS: This retrospective observational study focuses on primary EBC sourced from The Cancer Genome Atlas dataset (TCGA). It reveals the gene mutation landscape in EBC with low HER2 expression and elucidates the tumor immune landscape across different HRD states. Utilizing bioinformatics analysis and Cox proportional models, along with the Kaplan-Meier method, the study assesses the correlation between HRD status and disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Subgroup analyses were conducted to identify potential variations in the association between HRD and prognosis.
RESULTS: In the patients with HER2-low breast cancer, patients with homologous recombination related genes (HRRGs) defects had an HRD score about twice that of those without related genes mutations, and were at higher risk of acquiring ARID1A, ATM, and BRCA2 mutations. We also found that most immune cell abundances were significantly higher in EBC tumors with high HRD than in EBC tumors with low HRD or HRD-medium, particularly plasma B-cell abundance, CD8 T-cell abundance, and M1 macrophages. In addition, these tumors with HRD-high also appear to have significantly higher tumor immune scores and lower interstitial scores. Then, we analyzed the relationship between different HRD status and prognosis. There was statistical significance (P = .036 and P = .046, respectively) in DSS and PFI between the HRD-low and HRD-high groups, and patients with HRD-high EBC showed relatively poor survival outcomes. A medium HRD score (hazard ratio, HR = 2.15, 95% CI: 1.04-4.41, P = .038) was a significant risk factor for PFI. Hormone receptor positivity is an important factor in obtaining medium-high HRD score and poor prognosis.
CONCLUSIONS: 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.