北京大学人民医院乳腺中心 王殊
前情提要
一直以来，我们对于乳腺癌的治疗决策均是基于肿瘤分期和分子分型，随着高通量基因检测技术的进步，以个体化医疗为基础的“精准医疗”时代正向我们走近，这不仅体现在为乳腺癌患者选择更为有针对性的治疗，也体现在为无法从化疗中获益的患者做“减法”。近期的TAILORx前瞻性研究结果显示，在激素受体阳性、HER2阴性、腋窝淋巴结阴性的浸润性乳腺癌患者中，复发评分（RS）≤10分者仅接受辅助内分泌治疗，其5年无远处复发率及总生存（OS）率分别为99.3%和98.0%。该研究提示在分子本质上低风险的患者或许可以避免化疗的应用，而PlanB研究也得到了类似的结果。然而，这两项研究目前报道的都是单臂试验结果，这让我们不禁对刚刚发表的MINDACT研究的前瞻性随机对照结果充满期待。
MINDACT研究入组了来自欧洲112个肿瘤中心的6693例患者，分别应用70-基因和Adjuvant! Online（v8.0）评估患者的复发风险。当基因评估和临床评估同时显示低风险时，患者仅接受内分泌治疗；当基因评估和临床评估同时显示高风险时，患者则接受化疗；当基因评估和临床评估不一致时，随机分组按照基因或临床评估的结果决定化疗的应用。
研究的主要目标是评估临床高风险而基因评估低风险的患者若不接受化疗，其远期生存非劣于接受化疗的患者（5年的无远处转移生存率界定为92%）。这组患者中，48%淋巴结阳性，93%组织学分级2～3级，34%相对年轻（≤50岁），这些均是传统意义上的高危因素。结果显示，临床高风险而基因评估低风险的1550例（23.2%）患者中，未接受化疗的患者无远处转移生存率为94.7%（95% CI：92.5%～96.2%），达到预设标准。按照基因风险决定化疗与否或按照临床风险决定化疗与否，最终的生存预后无明显差别，但基于基因风险的决策明显有更少的患者接受化疗。结论提示临床高风险的患者中大约有46%可能无需化疗。
可能引起争议的结果是，在ITT人群中，临床高风险而基因评估低风险的患者，接受化疗者的无远处转移生存率、无疾病生存（DFS）率及OS率与未接受化疗者的绝对差异分别为1.5%、2.8%和1.4%；而在PP人群中，也有一致性的结果，接受化疗者的无远处转移生存率、DFS率及OS率与未接受化疗者的绝对差异分别为1.9%、3%和1.5%――尽管这些差异均没有统计学效力，却也不能完全忽视其潜在的临床意义。这有可能意味着基因评估可能会把部分本可能从化疗获益的临床高风险患者分配到低风险组。在临床低风险而基因评估高风险的患者中，接受化疗也未见明显的生存获益。因此，研究者并不推荐在临床低风险人群中应用基因风险评估的化疗建议。
另外，由于入组的绝大部分患者是Luminal型，5年以上的复发风险持续存在，故后续10年的随访结果值得关注。
试图摒弃被广泛认可的治疗方式其实是非常具有挑战性的，但是这在乳腺癌的治疗史上并不罕见，从改良根治到保乳手术、从腋窝清扫到前哨活检都是成功的先例。化疗的“减法”是必然趋势，然而MINDACT研究的结果并非完美，能否转化到临床实践中来见仁见智，我们还需要更多的数据，期待TAILORx研究在中危患者的探索结果能给我们带来更多的信息。
N Engl J Med. 2016 Aug 25;375(8):717-729.
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.
Cardoso F, Van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, Pierga JY, Brain E, Causeret S, DeLorenzi M, Glas AM, Golfinopoulos V, Goulioti T, Knox S, Matos E, Meulemans B, Neijenhuis PA, Nitz U, Passalacqua R, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Sotiriou C, Stork L, Straehle C, Thomas G, Thompson AM, van der Hoeven JM, Vuylsteke P, Bernards R, Tryfonidis K, Rutgers E, Piccart M; MINDACT Investigators.
Champalimaud Clinical Center-Champalimaud Foundation, Lisbon, Portugal; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco; European Organization for Research and Treatment of Cancer Headquarters, Breast International Group Headquarters, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Centre Hospitalier Universitaire Université Catholique de Louvain, Namur, Belgium; University of Milan and Istituto Europeo di Oncologia and Europa Donna-European Breast Cancer Coalition, Milan, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy; Gustave Roussy, Villejuif, Institut Curie Paris Sciences et Lettres, Université Paris Descartes, Sorbonne Paris Cité, Paris; Institut Curie-Hopital Rene Huguenin, Saint-Cloud, Centre Georges-Francois-Leclerc, Dijon, France; Swiss Institute of Bioinformatics and University of Lausanne, Lausanne, Switzerland; Agendia and the Netherlands Cancer Institute, Amsterdam, Alrijne Ziekenhuis, Rijnland Leiderdorp, Jeroen Bosch Hospital, 's-Hertogenbosch, Medisch Centrum Alkmaar, Alkmaar, Netherlands; Institute of Oncology, Ljubljana, Slovenia; Evangelisches Krankenhaus Bethesda, Duisburg, Germany; University of Texas Health Sciences Center, San Antonio; Hospital Universitario Vall d'Hebron, Barcelona; Imperial College London, London; University of Texas M.D. Anderson Cancer Center, Houston.
Background: The 70-gene signature test (MammaPrint) has been shown to improve prediction of clinical outcome in women with early-stage breast cancer. We sought to provide prospective evidence of the clinical utility of the addition of the 70-gene signature to standard clinical-pathological criteria in selecting patients for adjuvant chemotherapy.
Methods: In this randomized, phase 3 study, we enrolled 6693 women with early-stage breast cancer and determined their genomic risk (using the 70-gene signature) and their clinical risk (using a modified version of Adjuvant! Online). Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. The primary goal was to assess whether, among patients with high-risk clinical features and a low-risk gene-expression profile who did not receive chemotherapy, the lower boundary of the 95% confidence interval for the rate of 5-year survival without distant metastasis would be 92% (i.e., the noninferiority boundary) or higher.
Results: A total of 1550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of survival without distant metastasis in this group was 94.7% (95% confidence interval, 92.5 to 96.2) among those not receiving chemotherapy. The absolute difference in this survival rate between these patients and those who received chemotherapy was 1.5 percentage points, with the rate being lower without chemotherapy. Similar rates of survival without distant metastasis were reported in the subgroup of patients who had estrogen-receptor-positive, human epidermal growth factor receptor 2-negative, and either node-negative or node-positive disease.
Conclusions: Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy. Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy.
Funded by the European Commission Sixth Framework Program and others; ClinicalTrials.gov number, NCT00433589; EudraCT number, 2005-002625-31
PMID: 27557300
DOI: 10.1056/NEJMoa1602253
N Engl J Med. 2016 Aug 25;375(8):790-791.
Increasing Precision in Adjuvant Therapy for Breast Cancer.
Hudis CA, Dickler M.
American Society of Clinical Oncology, Alexandria, VA; Breast Medicine Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York.
Genomic testing of tumors can enable improved matching of individual patients or groups with treatments, but it can also identify situations where a specific intervention is not effective. In the recently reported results of the Trial Assigning Individualized Options for Treatment (TAILORx), investigators showed how one assay - the 21-gene recurrence score - could select a cohort of patients who had a 99% chance of 5-year survival without distant metastasis in whom currently available cytotoxic adjuvant chemotherapy could not be justified. A similar result was also seen in the West German Study Group PlanB trial. As we consider the practical . . .
PMID: 27557306
DOI: 10.1056/NEJMe1607947
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