第一部分第一章

背景：乳腺癌是全球最常见的恶性肿瘤之一。随着全身治疗和放疗技术的进步，乳腺癌保乳术（breast-conserving surgery，BCS）已成为早期乳腺癌的首选治疗方法。然而我国在BCS与乳房切除术的生存预后比较研究领域仍存在不足。现有研究尚未充分阐明影响患者手术方式选择的关键因素，且对不同术式在长期生存预后、生活质量及医疗经济负担等方面的差异缺乏系统性评估。因此，亟需深入探讨手术方式选择的决策因素，并全面评估不同术式对患者预后及卫生经济学的影响。

方法：本研究是一项基于中国国家癌症中心肿瘤信息系统数据库的一项回顾性队列研究，纳入 2013 至 2022 年期间接受手术治疗的114,094例早期女性乳腺癌患者，根据手术方式分为BCS组和乳房切除术组。采用卡方检验比较两组患者的临床病理特征、死亡原因构成比以及医疗费用的差异性。通过多因素Logistic回归分析评估影响手术方式选择的关键因素。同时，采用Kaplan-Meier法绘制生存曲线，比较两组患者的总生存期和乳腺癌特异性生存期，并运用Cox比例风险回归模型分析影响预后的独立危险因素，以全面评估不同手术方式对患者生存结局的影响。

结果：本研究共纳入114,094例早期乳腺癌女性患者，其中20.6%接受BCS，79.4%接受乳房切除术。年龄在25岁以下（OR=7.89，95%CI： 6.30-9.95，p<0.001）、激素受体阴性（OR=1.27，95%CI：1.23-1.31，p<0.001）以及接受新辅助治疗（OR=1.19，95%CI：1.12-1.26，p<0.001）的患者更倾向选择BCS。与乳房切除术相比，BCS组的5年总生存期（97.9% vs. 95.3%，p<0.001）和5年乳腺癌特异性生存期（99.0% vs. 97.4%，p<0.001）均显著提高。在死因构成比比较中，乳腺癌相关死因在BCS组的比例低于乳房切除术组（49.6% vs 57.3%，p<0.001），而心血管疾病相关死因的比例在BCS组更高（13.4% vs 12.3%，p<0.001）。在医疗花费分析中，BCS组的平均医疗费用高于乳房切除术组（78,610.63元 vs. 68,995.82元，p<0.001）。

结论：在 2013 至 2022 年间我国早期乳腺癌保乳率总体呈上升趋势。尽管BCS患者存在较高比例的心血管疾病相关死亡风险及更高的治疗成本，但其5年总生存期和乳腺癌特异性生存期均显著优于接受乳房切除术的患者。

第一部分第二章

背景：乳腺癌是全球女性发病率和死亡率较高的恶性肿瘤之一，多灶/多中心性乳腺癌（multifocal/multicentric breast cancer，MMBC）作为常见类型，其治疗策略备受关注。随着医学技术发展及对生活质量重视度提升，保乳术（breast conserving surgery，BCS）联合放疗的治疗模式逐渐受到关注，但MMBC的多灶性特征使得手术方式选择存在争议。

方法：本研究回顾性纳入 2016-2023 年于本中心接受手术的924例MMBC患者，根据手术方式分为BCS组（117例）与乳房切除组（807例）。通过Kaplan-Meier生存分析评估两组患者的总生存期（overall survival，OS）及无病生存期（disease-free survival，DFS），并运用Cox比例风险模型进行单变量和多变量分析，同时对年龄分组、病灶分布特征、AJCC分期及分子分型等进行亚组分析，探讨不同因素对预后的影响。

结果：BCS组及乳房切除组OS虽未达统计学显著性（p=0.051），但乳房切除术组长期生存趋势存在潜在优势，其1年、3年及5年OS分别为100%、98.7%和94.9%，而BCS组分别为98.3%、93.4%和89.9%；DFS分析显示乳房切除术组显著优于BCS组（p=0.019），其1年、3年及5年DFS分别为98.9%、96.3%和95.0%，而BCS组分别为99.1%、90.2%和86.0%。亚组分析显示，年轻患者（＜40岁）更易从乳房切除术中获益，多灶性乳腺癌患者BCS预后不劣于乳房切除术，而多中心性患者乳房切除术预后更优，三阴性乳腺癌亚组患者乳房切除术在DFS上显著优于BCS。单因素及多因素Cox回归分析揭示了影响MMBC患者OS和DFS的相关因素，如手术方式、年龄、月经状况、多灶/多中心性、脉管癌栓、分子分型、T分期、N分期及AJCC分期等。

结论：BCS在特定条件下可获得不劣于乳房切除术的预后，但需综合多方面因素选择手术方式，尤其对三阴性或高龄患者应慎行保乳术，未来也需进一步扩大样本来验证相关结论并优化手术方式的选择。

第二部分

背景：乳腺癌是全球女性健康的重大威胁，其进展与肿瘤微环境和基因调控密切相关。乳酸化修饰作为一种关键的表观遗传机制，在乳腺癌中的作用尚未完全阐明。本研究旨在探讨乳酸化相关基因，特别是PRDX1的调控机制及其在乳腺癌中的预后价值。

方法：本研究综合了包括全基因组关联研究（汇总统计、单细胞RNA测序、空间转录组学以及来自癌症基因组图谱和基因表达综合数据库的批量RNA测序数据）。通过基于汇总数据的孟德尔随机化分析（Summary-based Mendelian Randomization，SMR），识别与乳腺癌相关的乳酸化相关基因，并对PRDX1的表达模式、细胞间通信网络和空间异质性进行分析。此外，本研究基于PRDX1阳性单核细胞的基因表达谱构建并验证了一个预后模型，通过Cox回归和LASSO回归分析对其进行了评估。

结果：PRDX1被确定为与乳腺癌风险显著相关的关键乳酸化相关基因（p_SMR = 0.0026）。单细胞RNA测序分析显示PRDX1在单核细胞中的表达显著上调，PRDX1阳性单核细胞与成纤维细胞之间的细胞间通信增强。空间转录组学分析揭示了PRDX1在肿瘤巢区域的异质性表达，突显了PRDX1阳性单核细胞与成纤维细胞之间的空间相互作用。基于PRDX1阳性单核细胞基因表达谱构建的预后模型在训练队列和验证队列中均显示出高准确性，用于预测患者生存。高风险患者表现出免疫抑制微环境特征，包括免疫细胞浸润减少和免疫检查点基因表达上调。分子生物学实验揭示PRDX1基因在乳腺癌侵袭迁移中发挥着重要作用。

结论：本研究揭示了PRDX1在乳腺癌进展中的关键作用，其主要是通过调节肿瘤微环境和免疫逃逸机制。基于PRDX1的生存预测模型为个性化治疗策略提供了新的见解。

PartI Chapter I

Background: Breast cancer remains one of the most common malignancies globally. With advancements in systemic therapies and radiation, breast-conserving surgery (BCS) has emerged as a preferred option for early-stage breast cancer. However, there are still deficiencies in the field of survival prognosis of BCS compared with mastectomy in China. Existing studies have inadequately elucidated key determinants influencing surgical decision-making, and moreover, there remains a lack of comprehensive evaluations regarding disparities in long-term survival outcomes, quality of life, and healthcare economic burdens associated with different surgical approaches. Therefore, there is an urgent need to investigate decision-making factors for surgical modality selection and to systematically evaluate the prognostic and healthcare economic implications of distinct surgical strategies.

Method: This retrospective cohort study utilized data from the National Cancer Center Cancer Information System database in China. A total of 114,094 female patients with early-stage breast cancer who underwent surgical treatment between 2013 and 2022 were included and stratified into two groups based on surgical approach: the BCS group and the mastectomy group. Clinicopathological characteristics, cause-specific mortality profiles, and medical expenditure distributions were compared between groups using the Chi-square test. Multivariate logistic regression analysis was implemented to identify critical determinants influencing surgical decision-making. Survival outcomes were evaluated through Kaplan-Meier curves for overall survival (OS) and breast cancer-specific survival (BCSS), with statistical significance assessed by the log-rank test. Cox proportional hazards regression models were further employed to identify independent prognostic factors. This comprehensive analytical framework aimed to elucidate survival disparities attributable to distinct surgical interventions.

Results: This study included 114,094 female breast cancer patients, with 20.6% undergoing BCS and 79.4% for mastectomy. Patients who were younger than 25 years old (OR=7.89, 95%CI: 6.30-9.95, p<0.001), hormone receptor-negative (OR=1.27, 95%CI, 1.23-1.31, p<0.001), and who received neoadjuvant therapy (OR=1.19, 95%CI, 1.12-1.26, p<0.001) were more likely to choose BCS. 5-year overall survival (97.9% vs. 95.3%, p<0.001) and 5-year breast cancer-specific survival (99.0% vs. 97.4%, p<0.001) were significantly higher in the BCS group compared to mastectomy. In the comparison of cause of death component ratios, the proportion of breast cancer-related deaths was lower in the BCS group than in the mastectomy group (49.6% vs. 57.3%, p<0.001), while the proportion of cardiovascular disease-related deaths was higher in the BCS group (13.4% vs. 12.3%, p<0.001). In the medical spending analysis, mean medical costs were higher in the BCS group than in the mastectomy group (78,610.63RMB vs. 68,995.82RMB, p<0.001).

Conclusion: Breast-conserving ratio for early-stage breast cancer in China are generally on the rise between 2013 and 2022. Despite a higher proportion of cardiovascular disease-related deaths and higher treatment costs associated with BCS, patients undergoing this procedure still demonstrate superior overall survival and breast cancer-specific survival compared to those undergoing mastectomy.

PartI Chapter II

Background: Breast cancer is one of the most prevalent malignancies with high incidence and mortality rates among women globally. Multifocal/multicentric breast cancer (MMBC), as a common subtype, has drawn significant attention regarding its therapeutic strategies. With advancements in medical technology and increasing emphasis on quality of life, breast-conserving surgery (BCS) combined with radiotherapy has gained interest. However, the multifocal nature of MMBC raises controversies in surgical decision-making.

Methods: This retrospective study enrolled 924 MMBC patients who underwent surgery at our center between 2016 and 2023, categorized into the BCS group (n=117) and mastectomy group (n=807). Kaplan-Meier survival analysis was performed to evaluate overall survival (OS) and disease-free survival (DFS), supplemented by univariate and multivariate Cox proportional hazards models. Subgroup analyses stratified by age, lesion distribution characteristics, AJCC staging, and molecular subtypes were conducted to assess prognostic factors.

Results: Although OS did not reach statistical significance between groups (p=0.051), the mastectomy group showed a potential long-term survival advantage, with 1-, 3-, and 5-year OS rates of 100%, 98.7%, and 94.9%, respectively, compared to 98.3%, 93.4%, and 89.9% in the BCS group. DFS was significantly better in the mastectomy group (p=0.019), with 1-, 3-, and 5-year DFS rates of 98.9%, 96.3%, and 95.0% versus 99.1%, 90.2%, and 86.0% in the BCS group. Subgroup analysis revealed that younger patients (<40 years) derived greater benefits from mastectomy. BCS demonstrated non-inferior prognosis in multifocal cases, whereas mastectomy was superior in multicentric disease. Notably, triple-negative breast cancer (TNBC) patients had significantly improved DFS with mastectomy. Univariate and multivariate Cox regression identified prognostic factors for OS and DFS, including surgical approach, age, menopausal status, multifocal/multicentric features, lymphovascular invasion, molecular subtype, T/N staging, and AJCC stage.

Conclusion: BCS may achieve non-inferior prognosis compared to mastectomy under specific conditions, but surgical decisions should integrate multifactorial considerations. Caution is warranted for BCS in TNBC or elderly patients. Further large-scale studies are needed to validate these findings and optimize surgical strategies.

PartII

Background: Breast cancer is a major threat to women's health worldwide, and its progression is closely associated with the tumor microenvironment and gene regulation. Lactylation modification, as akey epigenetic mechanism in cancer biology, has not yet been fully elucidated in the context of breast cancer. This study aims to investigate the regulatory mechanisms of lactylation-related genes (LRGs), particularly PRDX1, and their prognostic value in breast cancer.

Methods: We integrated data from multiple databases, including Genome-Wide Association Study (GWAS) summary statistics, single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Using Summary-based Mendelian Randomization (SMR) analysis, we identified LRGs associated with breast cancer and conducted a comprehensive analysis of the expression patterns of PRDX1, cell-cell communication networks, and spatial heterogeneity. Furthermore, we constructed and validated a prognostic model based on the gene expression profile of PRDX1-positive monocytes, evaluating it through Cox regression and LASSO regression analyses.

Results: PRDX1 was identified as a key LRG significantly associated with breast cancer risk (p_SMR 0.0026). Single-cell RNA sequencing analysis revealed a significant upregulation of PRDX1 expression in monocytes, with enhanced cell-cell communication between PRDX1-positive monocytes and fibroblasts. Spatial transcriptomics analysis uncovered heterogeneous expression ofPRDX1 in the tumor nest regions, highlighting the spatial interaction between PRDX1-positive monocytes and fibroblasts. The prognostic model constructed based on the gene expression profile of PRDX1-positive monocytes demonstrated high accuracy in predicting patient survival in both the training and validation cohorts. High-risk patients exhibited immune-suppressive microenvironment characteristics, including reduced immune cell infiltration and upregulation of immune checkpoint gene expression. Molecular biology experiments reveal that PRDX1 gene plays an important role in breast cancer invasive migration.

Conclusion: This study reveals the key role of PRDX1 in breast cancer progression, particularly through the regulation of the tumor microenvironment and immune escape mechanisms. The survival prediction model based on PRDX1 demonstrates strong prognostic potential, providing new insights for personalized treatment strategies.