早期三阴性乳腺癌能否避免化疗？

　　三阴性乳腺癌与激素受体阳性或HER2阳性乳腺癌相比，对内分泌治疗或HER2靶向治疗通常无效，即使肿瘤切除后，复发率和死亡率仍然较高。因此，指南推荐对大多数早期三阴性乳腺癌患者进行术后（辅助）或术前（新辅助）全身化疗，并根据肿瘤大小和有无淋巴结转移选择化疗药物的种类和数量。不过，全身化疗毕竟毒性反应较大，需要寻找指导全身治疗最佳方案同时避免过度治疗的生物标志物。三阴性乳腺癌复发风险较低相关预后标志物可以帮助确定哪些患者能够通过较低强度治疗实现高治愈率。其中，肿瘤浸润淋巴细胞是人体自身抗肿瘤免疫反应活跃与否的标志。早期三阴性乳腺癌组织肿瘤浸润淋巴细胞水平较高与较低的患者相比，辅助化疗后生存时间显著较长，新辅助化疗后病理完全缓解率显著较高。对不到500例患者进行的小样本研究表明，即使术前或术后未化疗，肿瘤浸润淋巴细胞水平较高也与生存改善显著相关。可是，三阴性乳腺癌肿瘤浸润淋巴细胞丰度对于未化疗女性乳腺癌复发和死亡的影响仍然缺乏大样本研究证据。

　　2024年4月2日，国际四大医学期刊之一、创刊140周年的《美国医学会杂志》正刊在线发表美国梅奥医学中心（妙佑医疗国际）、法国巴黎萨克雷大学古斯塔夫鲁西研究院、里昂贝拉德癌症中心、巴黎文理大学居里研究院、比利时安特卫普医院、澳大利亚墨尔本大学彼得麦卡伦癌症中心、荷兰癌症研究所、乌得勒支大学医学中心、鹿特丹大学癌症研究院、加拿大艾伯塔大学、不列颠哥伦比亚大学、意大利米兰大学欧洲肿瘤研究院、热那亚大学圣马蒂诺综合医院、帕多瓦大学威尼托肿瘤研究院、瑞典哥德堡大学萨尔格伦斯卡医院、日本国立癌研究中心医院、韩国蔚山大学医学院首尔峨山医院的国际肿瘤免疫生物标志物工作组研究报告，对早期三阴性乳腺癌术前或术后未化疗患者肿瘤浸润淋巴细胞水平与复发和生存之间的关系进行了大数据分析。

　　该国际多中心回顾研究对北美（美国罗切斯特，加拿大温哥华）、欧洲（法国巴黎、里昂和维勒瑞夫，荷兰阿姆斯特丹和鹿特丹，意大利米兰、帕多瓦和热那亚，瑞典哥德堡）和亚洲（日本东京，韩国首尔）13个研究中心1979年1月至2017年11月被诊为三阴性乳腺癌进行局部治疗（手术±放疗）但未进行术前或术后化疗并随访至2021年9月27日的1966例患者个体水平数据进行汇总分析。主要指标为来自原发肿瘤切除标本乳腺组织肿瘤浸润淋巴细胞丰度。主要结局为无浸润癌生存。次要结局为无复发生存、远处无复发生存和总生存。采用多因素比例风险回归模型对患者年龄、肿瘤大小、淋巴结状态、组织学分级、是否放疗等其他影响因素进行校正，并按研究中心进行分层。

　　结果，1966例患者年龄中位56岁（四分位39～71岁），I期三阴性乳腺癌占55%，肿瘤浸润淋巴细胞水平中位15%（四分位5%～40%）。

　　417例患者（21%）肿瘤浸润淋巴细胞水平≥50%（年龄中位41岁，四分位36～63岁）。

　　1300例患者（66%）肿瘤浸润淋巴细胞水平<30%（年龄中位59岁，四分位41～72岁）。

　　对于I期三阴性乳腺癌患者，肿瘤浸润淋巴细胞水平≥50%与<30%相比：

• 5年远处无复发生存率：94%比78%（95%置信区间：91%～96%、75%～80%）
• 5年总生存率：95%比82%（95%置信区间：92%～97%、79%～84%）

　　中位随访18年，对患者年龄、肿瘤大小、淋巴结状态、组织学分级、是否放疗进行校正后，肿瘤浸润淋巴细胞每增加10%：

• 浸润癌或死亡风险：低8%（风险比：0.92，95%置信区间：0.89～0.94）
• 复发或死亡风险：低10%（风险比：0.90，95%置信区间：0.87～0.92）
• 远处复发或死亡风险：低13%（风险比：0.87，95%置信区间：0.84～0.90）
• 总死亡风险：低12%（风险比：0.88，95%置信区间：0.85～0.91）
• 似然比检验：P<0.000001

　　因此，该国际多中心大样本汇总分析回顾研究结果表明，对于早期三阴性乳腺癌仅局部治疗但术前或术后未全身化疗患者，乳腺癌组织肿瘤浸润淋巴细胞水平丰度较高与较低相比，生存结局显著较好，乳腺组织肿瘤浸润淋巴细胞丰度可以作为早期三阴性乳腺癌仅局部治疗未全身化疗患者预后因素。

　　不过，该研究虽然来自全球三大洲八国十三个地区、样本量较大、随访时间较长、数据缺失较少、肿瘤浸润淋巴细胞测定方法已标准化，但是需要注意：一、这是回顾研究，需要进一步开展前瞻研究进行验证；二、由于数据为观察性，故无法做出因果推论；三、患者越年轻，肿瘤浸润淋巴细胞水平越高，并且不能排除残留和未测量的混杂因素；四、未集中复核肿瘤浸润淋巴细胞，可能引入观察者差异；五、缺乏种系癌症易感突变数据，可能影响降低风险预防手术率，可能影响乳房和非乳房第二原发肿瘤风险；六、来自近45年前进行治疗患者的数据可能与如今的临床实践不太相关；七、缺少种族或民族的数据；八、肿瘤浸润淋巴细胞水平与预后呈线性相关，而预设≥50%和<30%为随意选择；九、在肿瘤浸润淋巴细胞量化可用于指导术前术后化疗决策之前，有必要进行临床试验进行前瞻评价。

JAMA. 2024 Apr 2;331(13):1135-1144. IF: 120.7

Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer.

Leon-Ferre RA, Jonas SF, Salgado R, Loi S, de Jong V, Carter JM, Nielsen TO, Leung S, Riaz N, Chia S, Jules-Clément G, Curigliano G, Criscitiello C, Cockenpot V, Lambertini M, Suman VJ, Linderholm B, Martens JWM, van Deurzen CHM, Timmermans AM, Shimoi T, Yazaki S, Yoshida M, Kim SB, Lee HJ, Dieci MV, Bataillon G, Vincent-Salomon A, André F, Kok M, Linn SC, Goetz MP, Michiels S; International Immuno-Oncology Biomarker Working Group.

Mayo Clinic, Rochester, Minnesota; Gustave Roussy, University Paris-Saclay, Villejuif, France; Léon Bérard Cancer Center, Lyon, France; Institut Curie, Paris, France; GZA-ZNA-Hospitals, Antwerp, Belgium; Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia; The Netherlands Cancer Institute, Amsterdam, the Netherlands; University Medical Center Utrecht, Utrecht, the Netherlands; Erasmus MC Cancer Institute, Rotterdam, the Netherlands; University of Alberta, Edmonton, Alberta, Canada; University of British Columbia, Vancouver, British Columbia, Canada; European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Milan, Italy; IRCCS Ospedale Policlinico San Martino, Genova, Italy; University of Genova, Genova, Italy; University of Padova, Padova, Italy; Veneto Institute of Oncology IOV-IRCCS, Padova, Italy; Sahlgrenska University Hospital, and Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden; National Cancer Center Hospital, Tokyo, Japan; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

This study of patients with early-stage triple-negative breast cancer not treated with adjuvant or neoadjuvant chemotherapy analyzes the association between tumor-infiltrating lymphocyte levels, cancer recurrence, and survival.

QUESTION: In patients with early-stage triple-negative breast cancer (TNBC) treated with locoregional therapy but without adjuvant or neoadjuvant chemotherapy, is a higher abundance of tumor-infiltrating lymphocytes (TIL) in breast cancer tissue associated with better survival?

FINDINGS: In this retrospective analysis of 1966 participants with early-stage TNBC treated with locoregional therapy but without adjuvant or neoadjuvant chemotherapy, survival rates were 90% for patients with a TIL level of 50% or greater, compared with 72% for patients with a TIL level of less than 30% at 5-year follow-up.

MEANING: In patients with early-stage TNBC treated with locoregional therapy only, higher TIL levels in breast cancer tissue were associated with improved survival.

IMPORTANCE: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear.

OBJECTIVE: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy.

DESIGN, SETTING, AND PARTICIPANTS: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy.

EXPOSURE: TIL abundance in breast tissue from resected primary tumors.

MAIN OUTCOMES AND MEASURES: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center.

RESULTS: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6).

CONCLUSIONS AND RELEVANCE: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.

PMID: 38563834

DOI: 10.1001/jama.2024.3056

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