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过去，对于早期乳腺癌患者，如果腋窝淋巴结阳性，必须进行腋窝淋巴结清扫术，但是术后上肢淋巴水肿、麻木以及肩部活动受限等并发症较多，对患者生活质量影响较大。近年来，SENOMAC等研究证实，对于临床检查淋巴结阴性患者，如果前哨淋巴结活检发现转移不超过2枚，可以安全地避免腋窝淋巴结清扫术。
不过，对于占全部乳腺癌7成左右的雌激素受体阳性HER2阴性乳腺癌，指南推荐如果腋窝淋巴结转移超过3枚，必须进行全身治疗，而这只能通过腋窝淋巴结清扫术确定。monarchE研究证实阿贝西利联合内分泌治疗对激素受体阳性HER2阴性淋巴结阳性高风险早期乳腺癌有效，也需要通过腋窝淋巴结清扫术确定是否符合适应证。MINDACT研究证实70基因检测可以指导雌激素受体阳性HER2阴性乳腺癌能否避免化疗，同样需要通过腋窝淋巴结清扫术确定腋窝淋巴结转移数量。此外，对于腋窝淋巴结转移数量较多的乳腺癌，还要考虑筛查远处转移以及扩大局部区域放疗靶区。因此，腋窝淋巴结转移数量可能改变术后治疗决策，不做腋窝淋巴结清扫术可能导致治疗不足，故有必要采取替代措施准确预测腋窝淋巴结转移数量，避免不必要的乳腺癌腋窝淋巴结清扫术，减少患者面临上肢长期并发症风险。
2024年9月25日，全球外科期刊影响因子排名第一的《美国医学会杂志》外科分册在线发表瑞典隆德大学斯科讷医院、思特尔数据科技、卡罗林大学医院、圣乔治医院、乌普萨拉大学西曼兰医院、萨尔格伦斯卡大学医院，哥德堡大学萨尔格伦斯卡学院、于默奥大学、丹麦奥胡斯大学医院、哥本哈根大学根措夫特医院、意大利圣拉斐尔生命健康大学医院、希腊雅典大学莱科医院、德国乌尔姆大学、菲尔德医院、罗斯托克大学、芬兰赫尔辛基大学医院的SENOMAC研究预设二次分析报告，探讨了如何准确预测前哨淋巴结阳性激素受体阳性HER2阴性乳腺癌（全部组织学类型以及其中比例最高的乳腺小叶癌）腋窝淋巴结转移数量是否≥4枚（N2期）以避免不必要的腋窝淋巴结清扫术。
该国际多中心非劣效研究于2015年1月31日至2021年12月31日从瑞典、丹麦、德国、希腊、意大利5个国家67家医院入组临床淋巴结阴性、T1至T3期（肿瘤最大直径：T1期≤20毫米、T2期21～50毫米、T3期>50毫米）并且1或2枚前哨淋巴结宏转移（转移灶最大直径>2毫米）原发乳腺癌患者2540例，按1∶1随机分成两组：单纯活检组1335例前哨淋巴结活检后免腋窝淋巴结清扫术、活检清扫组1205例前哨淋巴结活检后予腋窝淋巴结清扫术。结果发现：单纯活检与活检清扫相比，5年无复发生存率相似。
本次分析于2023年6月至2024年4月进行，仅选择其中激素受体阳性HER2阴性乳腺癌完成腋窝淋巴结清扫术患者1010例（年龄34～90岁，中位61岁；女性1006例，占99.6%；男性4例，占0.4%）随机分为训练集（80%）和测试集（20%），淋巴结转移数量相似。通过多因素逻辑回归对全部患者队列和乳腺小叶癌亚组开发预测模型，构建列线图。对激素受体阳性乳腺癌预测模型进行判别和校准评定。
结果，其中138例（13.7%）腋窝淋巴结转移数量≥4枚，212例（21.0%）为乳腺小叶癌。
训练集（804例）模型包括前哨淋巴结宏转移数量、前哨淋巴结微转移与否、前哨淋巴结比例、前哨淋巴结包膜外浸润与否以及肿瘤大小（不包括于乳腺小叶癌亚组）。
对测试集（201例）进行验证后，受试者操作特征（真假阳性率比值）曲线下面积达0.74（95%置信区间：0.62～0.85），校准度令人满意。灵敏度临界值≥80%时，除了5例低风险患者，全部患者都被准确分类，对应阴性预测值达94%。乳腺小叶癌亚组预测模型达到线下面积达0.74（95%置信区间：0.66～0.83）。
因此，该研究预设二次分析结果表明，预测模型和列线图可能有助于高风险早期乳腺癌患者术后强化全身治疗决策，并减少患者面临不必要的腋窝淋巴结清扫术而导致上肢并发症风险，故有必要进一步开展外部验证。
对此，美国康奈尔大学威尔医学院发表特邀评论：不同临床研究协作组之间合作的重要性，建议SENOMAC研究协作组可以与OTOASOR、AMAROS、IBCSG 23-01、ACOSOG Z0011等类似研究协作组负责人取得联系，开展合作外部验证工作，让更多患者获益。
JAMA Surg. 2024 Sep 25. IF: 15.7Prediction of High Nodal Burden in Patients With Sentinel Node-Positive Luminal ERBB2-Negative Breast Cancer.Skarping I, Bendahl PO, Szulkin R, Alkner S, Andersson Y, Bergkvist L, Christiansen P, Filtenborg Tvedskov T, Frisell J, Gentilini OD, Kontos M, Kühn T, Lundstedt D, Vrou Offersen B, Olofsson Bagge R, Reimer T, Sund M, Rydén L, de Boniface J.Lund University, Skane University Hospital, Lund, Sweden; Cytel Inc, Sweden; Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Capio St Goran's Hospital, Stockholm, Sweden; Uppsala University, Vastmanland Hospital, Vasteras, Sweden; Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Umea University, Umea, Sweden; Aarhus University Hospital, Aarhus University, Faculty of Health, Aarhus, Denmark; Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Università Vita-Salute San Raffaele, Milano, Italy; IRCCS Ospedale San Raffaele, Milano, Italy; National and Kapodistrian University of Athens, Laiko Hospital, Athens, Greece; University of Ulm, Ulm, Germany; Breast Center Die Filderklinik, Filderstadt, Germany; University of Rostock, Rostock, Germany; University of Helsinki and Helsinki University Hospital, Helsinki, Finland.QUESTION: Can high nodal burden (≥4 axillary metastases/≥N2) be predicted without completion axillary lymph node dissection (CALND) in patients with luminal ERBB2-negative tumors and, separately, in those with invasive lobular carcinoma, and 1 or 2 sentinel lymph node (SLN) macrometastases?FINDINGS: In this diagnostic/prognostic study including the CALND arm (n = 1010) of the randomized SENOMAC trial, 2 prediction models for the identification of patients with ≥N2 were developed, including number of SLN macrometastases, additional SLN micrometastases, SLN ratio, extracapsular extension, and tumor size (only luminal model).MEANING: The prediction models may be used to identify patients at risk of high nodal burden eligible for intensified systemic treatment strategies without performing CALND.IMPORTANCE: In patients with clinically node-negative (cN0) breast cancer and 1 or 2 sentinel lymph node (SLN) macrometastases, omitting completion axillary lymph node dissection (CALND) is standard. High nodal burden (≥4 axillary nodal metastases) is an indication for intensified treatment in luminal breast cancer; hence, abstaining from CALND may result in undertreatment.OBJECTIVE: To develop a prediction model for high nodal burden in luminal ERBB2-negative breast cancer (all histologic types and lobular breast cancer separately) without CALND.DESIGN, SETTING, AND PARTICIPANTS: The prospective Sentinel Node Biopsy in Breast Cancer: Omission of Axillary Clearance After Macrometastases (SENOMAC) trial randomized patients 1:1 to CALND or its omission from January 2015 to December 2021 among adult patients with cN0 T1-T3 breast cancer and 1 or 2 SLN macrometastases across 5 European countries. The cohort was randomly split into training (80%) and test (20%) sets, with equal proportions of high nodal burden. Prediction models were developed by multivariable logistic regression in the complete luminal ERBB2-negative cohort and a lobular breast cancer subgroup. Nomograms were constructed. The present diagnostic/prognostic study presents the results of a prespecified secondary analysis of the SENOMAC trial. Herein, only patients with luminal ERBB2-negative tumors assigned to CALND were selected. Data analysis for this article took place from June 2023 to April 2024.EXPOSURE: Predictors of high nodal burden.MAIN OUTCOMES AND MEASURES: High nodal burden was defined as ≥4 axillary nodal metastases. The luminal prediction model was evaluated regarding discrimination and calibration.RESULTS: Of 1010 patients (median [range] age, 61 [34-90] years; 1006 [99.6%] female and 4 [0.4%] male), 138 (13.7%) had a high nodal burden and 212 (21.0%) had lobular breast cancer. The model in the training set (n = 804) included number of SLN macrometastases, presence of SLN micrometastases, SLN ratio, presence of SLN extracapsular extension, and tumor size (not included in lobular subgroup). Upon validation in the test set (n = 201), the area under the receiver operating characteristic curve (AUC) was 0.74 (95% CI, 0.62-0.85) and the calibration was satisfactory. At a sensitivity threshold of ≥80%, all but 5 low-risk patients were correctly classified corresponding to a negative predictive value of 94%. The prediction model for the lobular subgroup reached an AUC of 0.74 (95% CI, 0.66-0.83).CONCLUSIONS AND RELEVANCE: The predictive models and nomograms may facilitate systemic treatment decisions without exposing patients to the risk of arm morbidity due to CALND. External validation is needed.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02240472DOI: 10.1001/jamasurg.2024.3944JAMA Surg. 2024 Sep 25. IF: 15.7Importance of Cooperation Between Cooperative Group Clinical Trialists.Weill Cornell Medicine, New York, New York.DOI: 10.1001/jamasurg.2024.3926
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