2024年12月12日，全球最大的乳腺癌研究会议第47届圣安东尼奥乳腺癌研讨会第二场全体大会和国际四大医学期刊之一《新英格兰医学杂志》同时公布低风险早期乳腺癌患者保乳术后免除前哨淋巴结活检等腋窝淋巴结手术的INSEMA研究结果。对此，美国纽约纪念医院斯隆凯特林癌症中心乳腺外科主任、康奈尔大学威尔医学院外科学教授莫妮卡·莫罗发表同期评论：早期乳腺癌前哨淋巴结活检过时？ 腋窝淋巴结手术对于乳腺癌治疗的作用已经发生变化。其中，腋窝前哨淋巴结活检被用于确定淋巴结转移，但是该方法并无治疗作用，再加上全身治疗决策更强调肿瘤生物学特征，于是已有随机对照试验对早期乳腺癌免除前哨淋巴结活检开展研究。 两项对临床淋巴结阴性乳腺癌患者是否免除腋窝淋巴结手术治疗的随机对照试验现已经提供结局数据：2023年9月21日，《美国医学会杂志》肿瘤学分册首先发表意大利、瑞士、西班牙、智利的SOUND研究；2024年12月12日，《新英格兰医学杂志》随后发表德国和奥地利的INSEMA研究。两项试验都入组了计划进行保乳手术的患者，并且都需要腋窝超声检查，但是未根据受体亚型或者是否绝经进行限制。SOUND研究入组了临床T1期（肿瘤≤2厘米）淋巴结阴性乳腺癌患者；INSEMA研究还入组了临床T2期（肿瘤>2厘米至≤5厘米）淋巴结阴性乳腺癌患者。虽然入组标准比较宽泛，但是两项研究大约95%的女性为激素受体阳性且人类表皮生长因子受体HER2阴性乳腺癌，大约90%为绝经后患者。这些研究选择的管腔型乳腺癌老年患者，这反映了淋巴结状态对于选择HER2阳性或三阴性乳腺癌以及绝经前激素受体阳性HER2阴性乳腺癌全身治疗方案时的重要性。 INSEMA和SOUND研究表明，就生存结局而言，不进行前哨淋巴结活检并不逊色于进行前哨淋巴结活检。对于超声检查结果正常的临床T1期淋巴结阴性乳腺癌患者，病理N2期（4至9枚腋窝淋巴结阳性）比例不到1%。虽然SOUND研究和INSEMA研究分别有大约9%和11%的前哨淋巴结活检患者出现1至3枚腋窝淋巴结宏转移，但是仅分别有0.4%和1.0%的未进行腋窝淋巴结手术患者出现腋窝复发。 对于治疗T2期乳腺癌患者时免除前哨淋巴结活检的安全问题仍然存在：INSEMA研究仅19.2%的患者为病理T2期（肿瘤中位2.5厘米）。随着肿瘤增大，淋巴结转移可能性和数量都可增加；20.8%的T2期患者有宏转移，而T1期患者为10.6%，该发现引起人们对于如果较大的T2期肿瘤采用该方法可能增加腋窝复发率的担忧。对于治疗高风险乳腺癌患者时免除前哨淋巴结活检（包括3级肿瘤患者，仅占INSEMA研究患者总数的3.6%，代表性不足）可能导致术后治疗推荐意见达不到最佳标准。 美国国家综合癌症网络（NCCN）指南鼓励对腋窝淋巴结转移1至3枚患者考虑进行区域淋巴结放疗，根据SOUND和INSEMA研究的数据，该方法可能导致大约9%至11%未进行前哨淋巴结活检的患者治疗不足。相比之下，T期1肿瘤患者通常适合乳房局部快速放疗；然而，目前乳房局部快速放疗的指南规定患者淋巴结组织学为阴性，该标准导致许多临床医师面临淋巴结状态无法确定时寻求全乳放疗。单组前瞻研究LUMINA和IDEA的数据表明，对于激素受体阳性、HER2阴性、生物学低风险乳腺癌绝经后女性，可以完全免除全乳放疗。该理念正在进行随机对照试验，但是LUMINA和IDEA研究全部入组患者淋巴结均为组织学阴性；将来，我们需要确定应该优先考虑的降级治疗。 细胞周期蛋白依赖性蛋白激酶（CDK）4和6抑制剂可能治疗不足也引起类似担忧。阿贝西利是首个获准用于术后治疗的CDK4/6抑制剂，其依据为monarchE研究无病生存率提高，该研究除了入组高风险患者，还入组了1至3枚淋巴结阳性和T1或T2、1级或2级肿瘤患者；该研究引发人们对免除前哨淋巴结活检情况下失去阿贝西利获益的担忧。随着术后治疗药物瑞波西利获准用于淋巴结阴性和淋巴结阳性乳腺癌，该担忧有所缓解，减少了对淋巴结状态的依赖。由于CDK4/6抑制剂并非没有额外毒性，而且与单用内分泌治疗相比，其成本相当高，因此对于极低风险乳腺癌患者（例如INSEMA研究入组患者）而言，其价值可能很小。 INSEMA和SOUND研究（以及另外两项正在进行但是结果尚未公布的NAUTILUS和BOOG 2013-08研究）让我们得以一窥未来。前哨淋巴结活检并发症虽然较少，但是仍然存在，免除该手术可以减轻患者的治疗负担。不过，如果免除该手术影响术后治疗的推荐意见，并导致对符合乳房局部快速放疗指征者进行全乳放疗，或由于对淋巴结状态无法确定而取消CDK4/6抑制剂治疗，那么这是最合适的做法吗？任何治疗方法成功降级都需要多学科考虑其对整个治疗计划的影响；INSEMA和SOUND研究数据为考虑如何将免除前哨淋巴结活检纳入实践提供了坚实的基础。目前，1级或2级临床T1期乳腺癌患者是该方法的理想候选者。如果手术病理检查发现较大的T2期肿瘤、肿瘤级别较高或侵犯淋巴血管，这些因素可增加淋巴结转移可能性，并提示预后较差，患者可以进行前哨淋巴结活检。该方法将避免大多数患者进行腋窝淋巴结手术，同时最大限度减少治疗不足。随着我们越来越多地面临放弃哪些治疗方法的选择，还需要患者报告结局确定患者更愿意减少哪些治疗方法。N Engl J Med. 2024 Dec 12. IF: 96.2Axillary Surgery in Breast Cancer - Primary Results of the INSEMA Trial.2024 SABCS GS2-07: No axillary surgery versus axillary sentinel lymph node biopsy in patients with early invasive breast cancer and breast-conserving surgery: Final primary results of the Intergroup-Sentinel-Mamma (INSEMA) trial.Reimer T, Stachs A, Veselinovic K, Kühn T, Heil J, Polata S, Marmé F, Müller T, Hildebrandt G, Krug D, Ataseven B, Reitsamer R, Ruth S, Denkert C, Bekes I, Zahm DM, Thill M, Golatta M, Holtschmidt J, Knauer M, Nekljudova V, Loibl S, Gerber B.University of Rostock, Rostock, Germany; University Hospital Ulm, Ulm, Germany; Hospital Esslingen, Esslingen, Germany; University Hospital Heidelberg, Heidelberg, Germany; Sankt Elisabeth Hospital, Heidelberg, Germany; Evang. Waldkrankenhaus Spandau, Berlin; University of Heidelberg, Mannheim, Germany; Hanau City Hospital, Hanau, Germany; University Hospital Rostock, Rostock, Germany; University Hospital Hamburg-Eppendorf, Hamburg, Germany; University Medical Center Schleswig-Holstein, Kiel, Germany; Medical School and University Medical Center OWL, Bielefeld University, Klinikum Lippe, Detmold, Germany; Salzburg Regional Hospital, Salzburg, Austria; Johanniter-Hospital Genthin-Stendal, Genthin, Germany; Philipps-University Marburg and University Hospital Marburg, Marburg, Germany; Breast Center St. Gallen, Kantonsspital, St. Gallen, Switzerland; SRH Wald-Klinikum Gera, Gera, Germany; Agaplesion Markus Hospital, Frankfurt am Main, Germany; German Breast Group, Neu-Isenburg, Germany; Tumor and Breast Center Eastern Switzerland, St. Gallen, Switzerland.BACKGROUND: Whether surgical axillary staging as part of breast-conserving therapy can be omitted without compromising survival has remained unclear.METHODS: In this prospective, randomized, noninferiority trial, we investigated the omission of axillary surgery as compared with sentinel-lymph-node biopsy in patients with clinically node-negative invasive breast cancer staged as T1 or T2 (tumor size, ≤5 cm) who were scheduled to undergo breast-conserving surgery. We report here the per-protocol analysis of invasive disease-free survival (the primary efficacy outcome). To show the noninferiority of the omission of axillary surgery, the 5-year invasive disease-free survival rate had to be at least 85%, and the upper limit of the confidence interval for the hazard ratio for invasive disease or death had to be below 1.271.RESULTS: A total of 5502 eligible patients (90% with clinical T1 cancer and 79% with pathological T1 cancer) underwent randomization in a 1:4 ratio. The per-protocol population included 4858 patients; 962 were assigned to undergo treatment without axillary surgery (the surgery-omission group), and 3896 to undergo sentinel-lymph-node biopsy (the surgery group). The median follow-up was 73.6 months. The estimated 5-year invasive disease-free survival rate was 91.9% (95% confidence interval [CI], 89.9 to 93.5) among patients in the surgery-omission group and 91.7% (95% CI, 90.8 to 92.6) among patients in the surgery group, with a hazard ratio of 0.91 (95% CI, 0.73 to 1.14), which was below the prespecified noninferiority margin. The analysis of the first primary-outcome events (occurrence or recurrence of invasive disease or death from any cause), which occurred in a total of 525 patients (10.8%), showed apparent differences between the surgery-omission group and the surgery group in the incidence of axillary recurrence (1.0% vs. 0.3%) and death (1.4% vs. 2.4%). The safety analysis indicates that patients in the surgery-omission group had a lower incidence of lymphedema, greater arm mobility, and less pain with movement of the arm or shoulder than patients who underwent sentinel-lymph-node biopsy.CONCLUSIONS: In this trial involving patients with clinically node-negative, T1 or T2 invasive breast cancer (90% with clinical T1 cancer and 79% with pathological T1 cancer), omission of surgical axillary staging was noninferior to sentinel-lymph-node biopsy after a median follow-up of 6 years.Funded by the German Cancer AidINSEMA ClinicalTrials.gov number, NCT02466737DOI: 10.1056/NEJMoa2412063N Engl J Med. 2024 Dec 12. IF: 96.2
Sentinel-Lymph-Node Biopsy in Early-Stage Breast Cancer - Is It Obsolete?
Morrow M.
Memorial Sloan Kettering Cancer Center, New York.
PMID: 39665673
DOI: 10.1056/NEJMe2414899
