曲妥珠单抗联合帕妥珠单抗治疗 HER2 阳性乳腺癌的疗效与 HER2 富集亚型和 ERBB2 表达的关系
HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade.
机构信息
Department of Medical Oncology, Hospital Clínic de Barcelona, Spain.
Translational Genomics and Targeted Therapeutics in Solid Tumors Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
出版信息
J Natl Cancer Inst. 2020 Jan 1;112(1):46-54. doi: 10.1093/jnci/djz042.
BACKGROUND
Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy.
METHODS
A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated.
RESULTS
A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01).
CONCLUSIONS
Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
背景
识别具有高抗 HER2 敏感性的 HER2 阳性乳腺癌有助于降低化疗强度。在此，我们测试了一种临床适用的 RNA 检测方法，该方法将 ERBB2 和 HER2 富集（HER2-E）内在亚型结合在接受双 HER2 阻断治疗而不进行化疗的 HER2 阳性疾病中。
方法
在来自五项 II-III 期临床试验（SOLTI-PAMELA、TBCRC023、TBCRC006、PER-ELISA、EGF104090）的 422 例 HER2 阳性肿瘤中应用了基于研究的 PAM50 检测方法。在 SOLTI-PAMELA、TBCRC023、TBCRC006 和 PER-ELISA 中，所有患者均患有早期疾病，并接受了新辅助拉帕替尼或曲妥珠单抗联合培妥珠单抗治疗 12-24 周。主要结局是病理完全缓解（pCR）。在 EGF104900 中，296 例晚期疾病患者随机接受拉帕替尼单药或拉帕替尼联合曲妥珠单抗治疗。评估了无进展生存期（PFS）、总缓解率（ORR）和总生存期（OS）。
结果
共分析了 305 例早期和 117 例晚期 HER2 阳性疾病患者。在早期疾病中，HER2-E 分别代表 ERBB2-高和 ERBB2-低肿瘤的 83.8%和 44.7%。在接受拉帕替尼和曲妥珠单抗治疗后，与其余患者相比，HER2-E 和 ERBB2（HER2-E/ERBB2）高组的 pCR 率更高（44.5%，95%CI=35.4%至 53.9%比 11.6%，95%CI=6.9%至 18.0%；调整后的优势比[OR]=6.05，95%CI=3.10 至 11.80，P<0.001）。在新辅助曲妥珠单抗和培妥珠单抗治疗中也观察到了类似的发现（HER2-E/ERBB2 高组的 pCR 率为 66.7%，95%CI=22.3%至 95.7%比其他组的 14.7%，95%CI=4.9%至 31.1%；调整后的 OR=11.60，95%CI=1.66 至 81.10，P=0.01）。在晚期环境中，HER2-E/ERBB2 高组与更长的 PFS 独立相关（风险比[HR]=0.52，95%CI=0.35 至 0.79，P<0.001）；更高的 ORR（16.3%，95%CI=8.9%至 26.2%比 3.7%，95%CI=0.8%至 10.3%，P=0.02）；以及更长的 OS（HR=0.66，95%CI=0.44 至 0.97，P=0.01）。
结论
将 HER2-E 亚型和 ERBB2 mRNA 结合到单个检测中可识别出对 HER2 靶向治疗具有高反应性的肿瘤。该生物标志物可帮助约 40%的 HER2 阳性乳腺癌患者降低化疗强度。
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