对于雌激素受体阳性淋巴结阳性早期乳腺癌，确定哪些患者术后单用内分泌辅助治疗复发风险极低而化疗获益不大，仍然是重要的临床难题。理想情况下，选择标准应该结合预后风险预测有利、化疗获益微乎其微并对内分泌治疗高度敏感。如果两项检测结果独立且互补，那么两项检测结果结合可能避免淋巴结阳性乳腺癌过度治疗。
21基因复发评分已被证实对淋巴结阴性和淋巴结阳性雌激素受体阳性乳腺癌女性的化疗获益具有预测和预后作用。然而，淋巴结状态仍然独立影响预后。RxPONDER研究对1～3枚淋巴结受累且复发评分≤25的患者术后内分泌辅助治疗±化疗的作用进行了比较，绝经后女性对化疗未见显著获益，不过该研究效力不足以确定非劣效。
内分泌治疗敏感指数SET2,3是针对福尔马林固定石蜡包埋肿瘤组织的定制检测，同一实验室和不同实验室都能产生可重复结果，为患者接受内分泌治疗提供预后信息。SET2,3结合雌孕激素受体相关转录内分泌治疗敏感指数SETER/PR、基线预后指数BPI，后者来自病理肿瘤大小、淋巴结受累和RNA4（ESR1、PGR、ERBB2、AURKA）分子亚型。既往研究证实，无论SETER/PR还是BPI都可独立补充预后信息。SET2,3多因素比例风险回归模型分析表明，BPI的RNA4可被当代预后分子特征取代，但是SETER/PR不能被取代。SET2,3评分较高的患者内分泌治疗敏感且结局较好，而SET2,3评分较低的患者内分泌治疗耐药且结局较差。
美国西南肿瘤学组（SWOG）S8814研究将1558例绝经后淋巴结阳性雌激素受体阳性早期乳腺癌术后患者随机分为三组：单用5年他莫昔芬、化疗→5年他莫昔芬、化疗＋5年他莫昔芬。其中367例原发肿瘤标本进行21基因复发评分，结果发现复发评分＞31可预测蒽环类化疗方案（环磷酰胺＋多柔比星＋氟尿嘧啶）获益。那么，SET2,3能否为复发评分补充预后信息？SET2,3较低患者能否对化疗获益？SET2,3两个组成指数（SETER/PR、BPI）对预后的贡献如何？
SWOG-8814 (NCT00929591): Tamoxifen With or Without Combination Chemotherapy in Postmenopausal Women Who Have Undergone Surgery for Breast Cancer (Phase III Comparison of Adjuvant Chemoendocrine Therapy With CAF and Concurrent or Delayed Tamoxifen to Tamoxifen Alone in Postmenopausal Patients With Involved Axillary Lymph Nodes and Positive Receptors)
2023年1月17日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表密歇根大学、德克萨斯大学MD安德森癌症中心、SWOG统计数据管理中心、精密科学、堪萨斯大学医学中心、耶鲁大学癌症中心、芝加哥洛约拉大学斯特里奇医学院红衣主教伯纳丁癌症中心、贝勒医学院的S8814研究回顾分析报告，探讨了21基因复发评分＋SET2,3能否改善预后评定，以及SET2,3能否预测蒽环类化疗方案获益。
该研究对S8814其中两个随机治疗组（单用5年他莫昔芬、化疗→5年他莫昔芬）进行盲法回顾临床验证，利用已经检测21基因复发评分的283例患者肿瘤标本全转录组RNA测序进行SET2,3测定和校准，主要终点为无病生存。
结果，中位8.99年随访期间，发生106例无病生存事件，仅前5年满足比例风险假设。
SET2,3与21基因复发评分不相关（r=-0.04）并且独立预后：
SET2,3：每单位风险比0.48（95%置信区间：0.34～0.68，P<0.001）
复发评分：每10单位风险比1.28（95%置信区间：1.14～1.44，P<0.001）
SET2,3指数并未预测化疗获益（交互作用P=0.77）
53%的复发评分≤25（低风险）患者SET2,3较高，5年无病生存率为97%
51%的复发评分＞25（高风险）患者SET2,3较低，5年无病生存率为53%
SET2,3的两个组成部分针对复发评分校正后都有预后意义：
SETER/PR：风险比0.65（95%置信区间：0.46～0.92）
BPI：风险比0.45（95%置信区间：0.31～0.64）
因此，该研究结果表明，内分泌治疗敏感指数SET2,3独立于21基因复发评分，对于预后具有补充作用，并且对于S8814亚组患者并未预测化疗获益，SET2,3的两个组成部分SETER/PR和BPI都可为复发评分补充预后信息。
相关链接
J Clin Oncol. 2023 Jan 17. IF: 50.717
Evaluation of the Sensitivity to Endocrine Therapy Index and 21-Gene Breast Recurrence Score in the SWOG S8814 Trial.
Speers CW, Symmans WF, Barlow WE, Trevarton A, The S, Du L, Rae JM, Shak S, Baehner R, Sharma P, Pusztai L, Hortobagyi GN, Hayes DF, Albain KS, Godwin A, Thompson A.
University of Michigan, Ann Arbor, MI; University of Texas MD Anderson Cancer Center, Houston, TX; SWOG Statistics and Data Management Center, Seattle, WA; Exact Sciences, Madison, WI; University of Kansas Medical Center, Kansas City, KS; Yale University Cancer Center, New Haven, CT; Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, IL; Baylor College of Medicine, Houston, TX.
PURPOSE: Chemotherapy has not demonstrated benefit over adjuvant endocrine therapy alone for postmenopausal patients with node-positive breast cancer with a 21-gene breast recurrence score (RS) of 25 or below (RS ≤ 25). We tested whether combined results from RS and the sensitivity to endocrine therapy (SET2,3) index of endocrine-related transcription (SETER/PR) adjusted for baseline prognostic index (BPI) improve prognostic assessment, and whether SET2,3 predicted benefit from anthracycline-based chemotherapy.
METHODS: A blinded retrospective clinical validation of SET2,3 in two randomized treatment arms from the SWOG S8814 trial comparing adjuvant anthracycline-based chemotherapy followed by tamoxifen endocrine therapy for 5 years, versus tamoxifen alone. SET2,3 assay was calibrated and measured using whole-transcriptome RNA sequence of tumor samples already tested for RS. The primary end point was disease-free survival (DFS).
RESULTS: There were 106 events in 283 patients over a median follow-up of 8.99 years. Proportional hazards assumptions were met during the first 5 years only. SET2,3 index and RS were not correlated (r = -0.04) and were independently prognostic (SET2,3: hazard ratio [HR], 0.48 per unit; 95% CI, 0.34 to 0.68; P < .001; RS: HR, 1.28 per 10 units; 95% CI, 1.14 to 1.44; P < .001). SET2,3 index did not predict chemotherapy benefit (interaction P = .77). SET2,3 was high in 93/175 (53%) patients with RS ≤ 25 (concordant low-risk), with 5-year DFS 97%. SET2,3 was low in 55/108 (51%) patients with RS > 25 (concordant high-risk), with 5-year DFS 53%. Both components of SET2,3 index were prognostic after adjustment for RS: SETER/PR (HR, 0.65; 95% CI, 0.46 to 0.92) and BPI (HR, 0.45; 95% CI, 0.31 to 0.64).
CONCLUSION: SET2,3 index was not correlated with RS, demonstrated additive prognostic performance, and was not chemopredictive in this subset of patients from S8814. The SETER/PR and BPI components of SET2,3 each added prognostic information to RS.
KEY OBJECTIVE: To determine whether an index measuring endocrine receptor-related transcription to predict sensitivity to endocrine therapy adjusted for baseline prognosis (SET2,3) improves the prognostic information from 21-gene breast recurrence score (RS) and whether cancers predicted to have low sensitivity to endocrine therapy preferentially benefit from adjuvant anthracycline-based chemotherapy.
KNOWLEDGE GENERATED: SET2,3 and RS were independent from each other and provided additive prognostic information when combined. SET2,3 index did not predict benefit from anthracycline-based chemotherapy in the S8814 trial.
RELEVANCE: The combination of two independent tests (SET2,3 and RS) added meaningfully to the prognostic assessment of postmenopausal patients with node-positive breast cancer, independent of anthracycline chemotherapy. There are multiple genomic assays already used in breast cancer. Different genomic assays can provide additive information. Further work is needed to determine when use of multiple assays might be appropriate.
TRIAL REGISTRATION: ClinicalTrials.gov NCT00929591
PMID: 36649570
DOI: 10.1200/JCO.22.01499
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