乳腺癌六种预后方法的直接比较

　　目前，乳腺癌治疗的结局预测（预后）方法主要有6种：临床治疗评分（CTS）、4指标免疫组化评分（IHC4）、21基因复发评分（Oncotype DX，RS）、7基因乳腺癌指数（BCI）、50基因复发风险（PAM50，Prosigna，ROR）、11基因内分泌预测临床（EndoPredict-clin，EPC）。其中，CTS包括肿瘤大小、分级、淋巴结状态、患者年龄、内分泌治疗，ROR包括肿瘤大小，EPC包括肿瘤大小、阳性淋巴结数量，其他3种不包括临床病理学信息，仅仅根据分子学信息进行评分。那么，这些方法对于雌激素受体（ER）阳性HER2阴性早期乳腺癌总体（0～10年）和后期（5～10年）远处复发预估和风险分层的效果如何？此前缺乏可以指导患者选择的直接比较信息。

　　2018年2月15日，《美国医学会杂志》肿瘤学分册在线发表英国伦敦玛丽王后大学、皇家马斯登医院、伦敦大学癌症研究院、格拉斯哥大学、奥地利维也纳医科大学、瑞士圣安娜医院、德国西维堂诊断（11基因）、柏林大学医学院、德国癌症联盟、美国纳米串（50基因）、麻省总医院、美国生物诊疗（7基因）、美国基因组健康（21基因）的随机临床研究数据生物标志二次分析报告，直接比较了6种方法对ER阳性HER2阴性早期乳腺癌患者接受5年内分泌治疗的预后价值。结果发现，多基因表达检测＋临床病理学信息可以提高对于淋巴结阳性乳腺癌女性远处复发和风险分层的预后价值，对于后期远处复发的预后价值可见显著差异。因此，对于ER阳性HER2阴性乳腺癌的远处复发和风险分层，尤其对于淋巴结阳性乳腺癌女性，临床病理学＋分子学信息可以提高预后价值。

　　该生物标志回顾分析为预先计划的二次转化研究，利用2009年1月～2015年4月多中心随机双盲临床研究（ATAC）774例ER阳性HER2阴性早期乳腺癌绝经后女性（平均年龄64.1±8.1岁，其中591例淋巴结阴性患者平均年龄63.4±7.9岁、肿瘤平均大小17.6±8.5mm，183例1～3个淋巴结阳性患者平均年龄66.4±8.3岁、肿瘤平均大小24.2±12.2mm；其中不包括44例≥4个淋巴结阳性患者）接受5年内分泌辅助治疗（阿那曲唑、他莫昔芬、阿那曲唑＋他莫昔芬）10年随访数据，对6种方法（CTS、IHC4、RS、BCI、ROR、EPC）的预后价值进行多中心之间患者比较。主要结局衡量指标为这些方法与CTS相比对乳腺癌诊断后0～10年和5～10年远处复发的预后价值。使用χ²检验和C指数进行似然比统计，评定各个方法的预后价值。

　　结果，774例ER阳性HER2阴性早期乳腺癌绝经后女性平均年龄64.1±8.1岁，其中：

• 591例淋巴结阴性患者平均年龄63.4±7.9岁、肿瘤平均大小17.6±8.5mm

• 183例淋巴结阳性患者平均年龄66.4±8.3岁、肿瘤平均大小24.2±12.2mm

　　6种方法对于591例淋巴结阴性患者总体（0～10年）远处复发风险的预后价值依次为：

• ROR（风险比：2.56，95%：1.96～3.35）

• BCI（风险比：2.46，95%：1.88～3.23）

• EPC（风险比：2.14，95%：1.71～2.68）

• CTS（风险比：1.99，95%：1.58～2.50）

• IHC（风险比：1.95，95%：1.55～2.45）

• RS（风险比：1.69，95%：1.40～2.03）

　　6种方法对于535例淋巴结阴性患者后期（5～10年）远处复发风险的预后价值依次为：

• ROR（风险比：2.77，95%：1.93～3.96）

• BCI（风险比：2.30，95%：1.61～3.30）

• EPC（风险比：2.19，95%：1.62～2.97）

• CTS（风险比：1.95，95%：1.43～2.65）

• IHC（风险比：1.59，95%：1.16～2.16）

• RS（风险比：1.46，95%：1.09～1.96）

　　6种方法对于183例淋巴结阳性患者0～10年复发风险的预后价值均较低，其中仅BCI和EPC稍高于CTS（Δ似然比χ²分别为9.2和7.4）。

　　6种方法对于154例淋巴结阳性患者5～10年复发风险的预后价值均较低，其中仅ROR和EPC稍高于CTS（Δ似然比χ²分别为3.3和6.1）。

　　因此，对于淋巴结阴性的女性，50基因ROR、7基因BCI、11基因EPC临床对总体和后期远处复发的预后价值显著较高；对于1～3个淋巴结阳性的女性，上述任何方法独立获得的信息有限，需要密切结合临床。这些数据可能有助于肿瘤专科医师和患者考虑使用化疗±延长内分泌治疗时选择最合适的检测方法。

JAMA Oncol. 2018 Feb 15. [Epub ahead of print]

Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor-Positive Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Sestak I, Buus R, Cuzick J, Dubsky P, Kronenwett R, Denkert C, Ferree S, Sgroi D, Schnabel C, Baehner FL, Mallon E, Dowsett M.

Queen Mary University of London, London, England; Royal Marsden, London, England; Institute of Cancer Research, London, England; Medical University of Vienna, Austria; Klinik St Anna, Luzern, Switzerland; Sividon Diagnostics, GmbH, Koln, Germany; Charité Universitatsmedizin and German Cancer Consortium, Berlin, Germany; NanoString Technologies, Seattle, Washington; Massachusetts General Hospital, Boston, Massachusetts; Biotheranostics, San Diego, California; GenomicHealth, Redwood City, California; University of Glasgow, Glasgow, Scotland.

This secondary analysis of a randomized clinical trial evaluates the prognostic value of 6 multigene signatures in women with early estrogen receptor-positive breast cancer who have received 5 years of endocrine therapy.

QUESTION: What is the comparative performance of prognostic multigene signatures for estimation and risk stratification of overall and late distant recurrence in estrogen receptor-positive ERBB2-negative breast cancer?

FINDINGS: In this biomarker analysis of data from a randomized clinical trial, a combination of multigene expression tests with clinical information was associated with improved prognostic value for distant recurrences and risk stratification specifically in women with node-positive disease. Differences in the prognostic value for late distant recurrence were observed.

MEANING: The combination of clinical and molecular information may enhance the prognostic value for distant recurrence and risk stratification in estrogen receptor-positive, ERBB2-negative breast cancer, particularly for women with node-positive disease.

IMPORTANCE: Multiple molecular signatures are available for managing estrogen receptor (ER)-positive breast cancer but with little direct comparative information to guide the patient's choice.

OBJECTIVE: To conduct a within-patient comparison of the prognostic value of 6 multigene signatures in women with early ER-positive breast cancer who received endocrine therapy for 5 years.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective biomarker analysis included 774 postmenopausal women with ER-positive ERBB2 (formerly HER2)-negative breast cancer. This analysis was performed as a preplanned secondary study of data from the Anastrozole or Tamoxifen Alone or Combined randomized clinical trial comparing 5-year treatment with anastrozole vs tamoxifen with 10-year follow-up data. The signatures included the Oncotype Dx recurrence score, PAM50-based Prosigna risk of recurrence (ROR), Breast Cancer Index (BCI), EndoPredict (EPclin), Clinical Treatment Score, and 4-marker immunohistochemical score. Data were collected from January 2009, through April 2015.

MAIN OUTCOMES AND MEASURES: The primary objective was to compare the prognostic value of these signatures in addition to the Clinical Treatment Score (nodal status, tumor size, grade, age, and endocrine treatment) for distant recurrence for 0 to 10 years and 5 to 10 years after diagnosis. Likelihood ratio (LR) statistics were used with the χ² test and C indexes to assess the prognostic value of each signature.

RESULTS: In this study of 774 postmenopausal women with ER-positive, ERBB2-negative disease (mean [SD] age, 64.1 [8.1] years), 591 (mean [SD] age, 63.4 [7.9] years) had node-negative disease. The signatures providing the most prognostic information were the ROR (hazard ratio [HR], 2.56; 95% CI, 1.96-3.35), followed by the BCI (HR, 2.46; 95% CI, 1.88-3.23) and EPclin (HR, 2.14; 95% CI, 1.71-2.68). Each provided significantly more information than the Clinical Treatment Score (HR, 1.99; 95% CI, 1.58-2.50), the recurrence score (HR, 1.69; 95% CI, 1.40-2.03), and the 4-marker immunohistochemical score (HR, 1.95; 95% CI, 1.55-2.45). Substantially less information was provided by all 6 molecular tests for the 183 patients with 1 to 3 positive nodes, but the BCI (ΔLR χ²=9.2) and EPclin (ΔLR χ²=7.4) provided more additional prognostic information than the other signatures.

CONCLUSIONS AND RELEVANCE: For women with node-negative disease, the ROR, BCI, and EPclin were significantly more prognostic for overall and late distant recurrence. For women with 1 to 3 positive nodes, limited independent information was available from any test. These data might help oncologists and patients to choose the most appropriate test when considering chemotherapy use and/or extended endocrine therapy.

TRIAL REGISTRATION: ISRCTN.com Identifier: ISRCTN18233230

PMID: 29450494

DOI: 10.1001/jamaoncol.2017.5524