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Randomized Controlled Trial
. 2019 Jul;24(7):893-900.
doi: 10.1634/theoncologist.2018-0407. Epub 2019 Jan 24.

Everolimus plus Exemestane for Hormone Receptor-Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO-2

Aleix Prat  1   2 , Jan Christoph Brase  3 , Yuan Cheng  3 , Paolo Nuciforo  4 , Laia Paré  5   2 , Tomás Pascual  5   2 , Débora Martínez  5   2 , Patricia Galván  5   2 , Maria Vidal  5   2 , Barbara Adamo  5   2 , Gabriel N Hortobagyi  6 , José Baselga  7 , Eva Ciruelos  8
Affiliations
Randomized Controlled Trial

Everolimus plus Exemestane for Hormone Receptor-Positive Advanced Breast Cancer: A PAM50 Intrinsic Subtype Analysis of BOLERO-2

Aleix Prat et al. Oncologist. 2019 Jul.

Abstract
in English, Chinese

Background: The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]-enriched and basal-like) subtypes within advanced hormone receptor-positive (HR+) breast cancer is currently unknown.

Materials and methods: This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO-2 study; BOLERO-2 randomized 724 patients with advanced HR+/HER2-negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression-free survival (PFS) were evaluated.

Results: Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2-enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal-like (n = 37), and 1.9% basal-like (n = 5); HER2-enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47-0.94; p = .020) and HER2-enriched and non-HER2-enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07-2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2-enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .034); however, the association between HER2-enriched tumors and everolimus benefit was nonsignificant (p = .433).

Conclusion: The HER2-enriched subtype was identified in a substantial proportion of advanced HR+/HER2-negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2-enriched tumors in the advanced HR+/HER2-negative breast cancer setting.

Implications for practice: Using 261 tumor samples from the BOLERO-2 phase III clinical trial, this study shows that a substantial proportion (20%-30%) of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2-negative breast cancer.

摘要

背景。目前尚不清楚激素受体阳性 (HR+) 的晚期乳腺癌中两种非管腔 [人表皮生长因子受体 2 (HER2) ‐ 过表达和基底细胞样]亚型的预后和预测价值。

材料和方法。本研究回顾性分析了 BOLERO‐2 研究中的 261 例肿瘤(80.7% 原发；19.3% 转移)；BOLERO‐2 将 724 例晚期 HR +/HER2 阴性的晚期乳腺癌患者随机分配至依维莫司加依西美坦或安慰剂加依西美坦。使用 PAM50 亚型预测因子对肿瘤进行分类。多变量 Cox 回归分析检验了 PAM50 的独立预后意义，并评估了 PAM50 亚型与治疗无进展生存期 (PFS) 之间的关联。

结果。亚型分布为 46.7% 管腔 A 型(n = 122)，21.5% HER2 过表达(n = 56)，15.7% 管腔 B 型(n = 41)，14.2% 正常样型(n = 37)，以及 1.9% 基底细胞样型(n = 5)；HER2 过表达的亚型在转移性肿瘤中较原发性肿瘤更常见(32.0% vs. 18.7%；p = 0.038)。中位 PFS方面，管腔型和非管腔型之间[6.7 vs. 5.2 个月；校正风险比，0.66；95% 置信区间 (CI)，0.47‐0.94；p = 0.020]以及 HER2 过表达和非 HER2 过表达亚型之间(5.2 vs. 6.2个月；校正风险比，1.53；95%CI，1.07‐2.19；p = 0.019)的差异明显。在 HER2 过表达的肿瘤患者中，依维莫司加依西美坦与安慰剂加依西美坦相比显著改善了中位 PFS(5.8 vs. 4.1 个月；校正风险比，0.49；95%CI，0.26‐0.90；p = 0.034)；然而，HER2 过表达肿瘤与依维莫司治疗受益之间的关联并不显著(p = 0.433)。

结论。 HER2 过表达亚型在晚期 HR +/HER2 阴性乳腺肿瘤中占有相当大比例，并且是预后不良的一致性生物标志物。因此，对于晚期 HR +/HER2 阴性乳腺癌患者中 HER2 过表达的肿瘤需要个体化定制疗法。

实践意义:使用来自 BOLERO‐2 III 期临床试验的 261 份肿瘤样本，本研究显示相当大部分(20% ‐ 30%)激素受体阳性 (HR+)/人表皮生长因子受体 2 (HER2)‐阴性的晚期乳腺癌不具有管腔 A 型或 B 型基因表达谱。无论在依西美坦治疗中是否加入依维莫司，这组患有非管腔型肿瘤的患者的生存结果都很差。这是第二项证实了该生物标志物的预后价值的研究。总体而言，这些研究结果表明有必要设计针对 HR +/HER2 阴性非管腔型乳腺癌的新型临床试验。

Keywords: Advanced breast cancer; Everolimus; Exemestane; Intrinsic subtype; Mammalian target of rapamycin.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1.
Figure 1.
Consolidated Standards of Reporting Trials‐style diagram of the BOLERO‐2 PAM50 study. Abbreviations: FFPE, formalin‐fixed paraffin‐embedded; HER2, human epidermal growth factor receptor 2.
Figure 2.
Figure 2.
Intrinsic subtype distribution in BOLERO‐2 tumor samples. (A): All patients (n = 261). (B): Primary tumors (n = 209). (C): Metastatic tumors (n = 50)*. *, Biopsy source unknown for two patients. Abbreviation: HER2, human epidermal growth factor receptor 2.
Figure 3.
Figure 3.
Prognosis based on subtype classification. (A): PFS in HER2‐enriched versus non‐HER2‐enriched subgroups. (B): PFS in luminal (including normal‐like) versus nonluminal subgroups. Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; PFS, progression‐free survival.
Figure 4.
Figure 4.
Everolimus PFS benefit based on subtype classification. (A): HER2‐enriched versus non‐HER2‐enriched subgroups. (B): Luminal (including normal‐like) versus nonluminal subgroups. Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; PFS, progression‐free survival.
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