七十基因主要对老年乳腺癌有意义？

　　70基因（MammaPrint）由荷兰癌症研究院研发，有助于判断早期乳腺癌术后患者能否避免化疗。2016年，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》公布的欧洲癌症研究治疗组织MINDACT研究结果表明，对于临床风险高而70基因风险低的早期乳腺癌术后患者，即使不化疗，5年无远处转移生存率也高达94.7%（95%置信区间：92.5～96.2）与化疗患者相比仅相差1.5个百分点（校正后风险比：0.78，95%置信区间：0.50～1.21，P=0.27）。不过，对于早期乳腺癌患者而言，5年随访时间相对较短，可能不足以发现较多的远处转移或死亡事件进行统计学分析。此外，该研究采用的临床风险评分方法并未考虑年龄等影响因素。

前情提要

　　2021年3月12日，英国《柳叶刀》肿瘤学分册在线发表比利时布鲁塞尔自由大学、欧洲癌症研究治疗组织、那慕尔大学医院、国际乳腺癌协作组、美国旧金山加利福尼亚大学、贝勒医学院、德克萨斯大学健康科学中心、法国古斯塔夫鲁西研究所、巴黎大学居里学院、乔治弗朗索瓦勒克莱尔中心、荷兰西北医院集团、阿里尼医院、耶罗恩博世医院、荷兰癌症研究院、意大利米兰大学欧洲肿瘤研究院、意大利临床肿瘤学协作组、热那亚大学圣马蒂诺综合医院、欧洲乳腺癌联盟、瑞士生物信息学研究院、洛桑大学、西班牙纳瓦拉大学、德国埃森中心医院、斯洛文尼亚肿瘤研究院、葡萄牙尚帕利莫基金会临床中心的MINDACT研究将近9年长期随访结果，并按年龄和淋巴结状态对激素受体阳性HER2阴性乳腺癌患者进行了探索性分析。

MINDACT (Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy): A Prospective, Randomized Study Comparing the 70-Gene Signature With the Common Clinical-Pathological Criteria in Selecting Patients for Adjuvant Chemotherapy in Breast Cancer With 0 to 3 Positive Nodes (NCT00433589, EudraCT 2005-002625-31, EORTC-10041, BIG-3-04)

　　该国际多中心非盲随机对照三期临床研究于2007年2月8日～2011年7月11日从9个欧洲国家或地区112家学术或社区医院入组年龄18～70岁、经组织学证实为原发乳腺浸润癌、T1～T2期或可手术T3期、阳性淋巴结≤3枚、无远处转移、世界卫生组织体力状态评分为0～1的女性患者6693例，对70基因风险和临床风险（根据 Adjuvant! Online 修订版）进行评分：

• 临床风险低且70基因风险低的2634例患者：放弃化疗

• 临床风险高且70基因风险高的1872例患者：接受化疗（主要为蒽环类和/或紫杉类方案）

• 临床风险低而70基因风险高的 690例患者：按1∶1随机分为化疗组344例、不化疗组346例

• 临床风险高而70基因风险低的1497例患者：按1∶1随机分为化疗组749例、不化疗组748例

　　利用最小化技术集中进行随机化，并按医院、风险分组、临床病理特征进行分层。治疗分配非盲。主要终点为临床风险高而70基因风险低的不化疗患者5年无远处转移生存率下限是否低于95%置信区间：高于预设非劣效临界值92%。

　　本文对随访结果进行更新，并按年龄和淋巴结状态对激素受体阳性HER2阴性患者进行探索性分析。上述分析对全部意向治疗患者进行。入组工作已经完成，正在进一步长期随访。

　　结果，截至2020年2月26日，中位随访8.7年（四分位：7.8～9.7）。

四组患者无远处转移生存比较

　　对于临床风险高而70基因风险低的748例不化疗组患者，剔除其中21例风险评分变化、85例实际接受化疗、1例不知是否化疗，其余644例患者的5年无远处转移生存率更新为95.1%（95%置信区间：93.1～96.6），高于预设非劣效临界值92%，支持此前分析并证实MINDACT研究降级治疗结果为阳性。

　　对于临床风险高而70基因风险低的1497例意向治疗患者，化疗组749例与不化疗组748例相比，推算8年无远处转移生存率为92.0%比89.4%（95%置信区间：89.6～93.8、86.8～91.5；绝对差2.6个百分点，标准误：1.6，95%置信区间：-0.5～5.7；风险比：0.66，95%置信区间：0.48～0.92）。

　　对于临床风险高而70基因风险低的1358例（90.7%）激素受体阳性HER2阴性意向治疗患者进行探索性亚组分析，化疗组676例与不化疗组682例相比，推算8年无远处转移生存率：

• 464例年龄≤50岁女性：93.6%比88.6%（95%置信区间：89.3～96.3、83.5～92.3；绝对差5.0个百分点，标准误：2.8，95%置信区间：-0.5～10.4）

• 894例年龄>50岁女性：90.2%比90.0%（95%置信区间：86.8～92.7、86.6～92.6；绝对差0.2个百分点，标准误：2.1，95%置信区间：-4.0～4.4）

• 699例淋巴结阴性女性：91.7%比89.2%（95%置信区间：88.1～94.3、85.2～92.2；绝对差2.5个百分点，标准误：2.3，95%置信区间：-2.1～7.2）

• 658例淋巴结阳性女性：91.2%比89.9%（95%置信区间：87.2～94.0、85.8～92.8；绝对差1.3个百分点，标准误：2.4，95%置信区间：-3.5～6.1）

临床风险高而70基因风险低的激素受体阳性HER2阴性患者无远处转移生存比较（A、年龄≤50岁，B、年龄>50岁）

　　因此，该研究结果表明，根据将近9年的长期随访，70基因风险评分显示出区分临床风险较高女性的完整能力：70基因风险较低的早期乳腺癌术后患者即使单用内分泌治疗不化疗，无远处转移生存率也较高。对于这些女性，将化疗加入内分泌治疗的获益仅提高2.6个百分点，而且即使淋巴结阳性也未增加化疗获益。不过，根据样本量较小的探索性亚组分析，化疗获益似乎依赖于年龄，年龄≤50岁女性才可见化疗获益，达到有临床意义的临界值5.0个百分点。虽然这可能由于化疗所致卵巢功能抑制，但是应该成为知情告知、医患共同决策的一部分。由于探索性亚组分析的样本量缩水、说服力不足，对于可能需要加强内分泌治疗以放弃化疗的年轻女性，还需要开展进一步研究。

Lancet Oncol. 2021 Mar 12. Online ahead of print.

70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.

Martine Piccart, Laura J van 't Veer, Coralie Poncet, Josephine M N Lopes Cardozo, Suzette Delaloge, Jean-Yves Pierga, Peter Vuylsteke, Etienne Brain, Suzan Vrijaldenhoven, Peter A Neijenhuis, Sylvian Causeret, Tineke J Smilde, Giuseppe Viale, Annuska M Glas, Mauro Delorenzi, Christos Sotiriou, Isabel T Rubio, Sherko Kümmel, Gabriele Zoppoli, Alastair M Thompson, Erika Matos, Khalil Zaman, Florentine Hilbers, Debora Fumagalli, Peter Ravdin, Susan Knox, Konstantinos Tryfonidis, Aleksandra Peric, Bart Meulemans, Jan Bogaerts, Fatima Cardoso, Emiel J T Rutgers.

Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium; CHU Site Sainte-Elisabeth-UCL Namur, Namur, Belgium; Breast International Group Headquarters, Brussels, Belgium; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Baylor College of Medicine, Houston, TX, USA; University of Texas Health Sciences Center, San Antonio, TX, USA; Gustave Roussy, Villejuif, France; Institut Curie, Paris & Saint-Cloud, Université de Paris, Paris, France; Institut Curie–Hopital Rene Huguenin, Saint-Cloud, France; Centre George-Francois-Leclerc, Dijon, France; Noordwest Ziekenhuisgroep, Alkmaar, Netherlands; Alrijne Ziekenhuis, Leiderdorp, Netherlands; Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, Netherlands; Agendia, Amsterdam, Netherlands; Netherlands Cancer Institute, Amsterdam, Netherlands; University of Milan, Milan, Italy; European Institute of Oncology IRCCS, Milan, Italy; Gruppo Oncologico Italiano di Ricerca Clinica, Università degli Studi di Genova and IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Europa Donna-European Breast Cancer Coalition, Milan, Italy; Swiss Institute of Bioinformatics and University of Lausanne, Lausanne, Switzerland; Lausanne University Hospital CHUV, Lausanne, Switzerland; Clinica Universidad de Navarra, Madrid, Spain; Kliniken Essen-Mitte, Essen, Germany; Institute of Oncology, Ljubljana, Slovenia; Champalimaud Clinical Center, Champalimaud Foundation, Lisbon, Portugal.

BACKGROUND: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94.7% (95% CI 92.5-96.2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.

METHODS: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.

FINDINGS: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8.7 years (IQR 7.8-9.7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95.1% (95% CI 93.1-96.6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92.0% (95% CI 89.6-93.8) for chemotherapy versus 89.4% (86.8-91.5) for no chemotherapy (hazard ratio 0.66; 95% CI 0.48-0.92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93.6% (95% CI 89.3-96.3) with chemotherapy versus 88.6% (83.5-92.3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5.0 percentage points [SE 2.8, 95% CI -0.5 to 10.4]) and 90.2% (86.8-92.7) versus 90.0% (86.6-92.6) in 894 women older than 50 years (absolute difference 0.2 percentage points [2.1, -4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI 88.1-94.3) with chemotherapy and 89.2% (85.2-92.2) without chemotherapy in 699 node-negative patients (absolute difference 2.5 percentage points [SE 2.3, 95% CI -2.1 to 7.2]) and 91.2% (87.2-94.0) versus 89.9% (85.8-92.8) for 658 patients with one to three positive nodes (absolute difference 1.3 percentage points [2.4, -3.5 to 6.1]).

INTERPRETATION: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2.6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.

FUNDING: European Commission Sixth Framework Programme

DOI: 10.1016/S1470-2045(21)00007-3