West German Study Group, Moenchengladbach, Germany.
Department of Gynecology and Obstetrics and CCCMunich, Breast Center, LMU University Hospital, Munich, Germany.
J Clin Oncol. 2023 Aug 1;41(22):3796-3804. doi: 10.1200/JCO.22.01816. Epub 2023 Feb 21.
Neoadjuvant chemotherapy is standard of care in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC), irrespective of the hormone receptor status. Trastuzumab-emtansine (T-DM1), antibody-drug conjugate, is highly effective in HER2+ EBC; however, no survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy.
In the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) phase II trial, 375 centrally reviewed patients with hormone receptor-positive (HR+)/HER2+ EBC (clinical stage I-III) were randomly assigned to 12 weeks of T-DM1 with or without endocrine therapy (ET) or trastuzumab + ET once every 3 weeks (ratio 1:1:1). Adjuvant chemotherapy (ACT) omission was allowed in patients with pathologic complete response (pCR). In this study, we report the secondary survival end points and biomarker analysis. Patients who received at least one dose of study treatment were analyzed. Survival was analyzed using the Kaplan-Meier method, two-sided log-rank statistics, and Cox regression models stratified for nodal and menopausal status. values < .05 were considered statistically significant.
T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; = .608) and overall survival rates (97.2%, 96.4%, 96.3%; = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% 82.7%; hazard ratio, 0.40 [95% CI, 0.18 to 0.85]). Among the 117 patients with pCR, 41 did not receive ACT; 5-year iDFS rates were similar in those with (93.0% [95% CI, 84.0 to 97.0]) and without ACT (92.1% [95% CI, 77.5 to 97.4]; = .848). Translational research revealed that tumors with PIK3CA wild type, high immune marker expression, and luminal-A tumors (by PAM50) had an excellent prognosis with de-escalated anti-HER2 therapy.
The WSG-ADAPT-TP trial demonstrated that pCR after 12 weeks of chemotherapy-free de-escalated neoadjuvant therapy was associated with excellent survival in HR+/HER2+ EBC without further ACT. Despite higher pCR rates for T-DM1 ± ET versus trastuzumab + ET, all trial arms had similar outcomes because of mandatory standard chemotherapy after non-pCR. WSG-ADAPT-TP demonstrated that such de-escalation trials in HER2+ EBC are feasible and safe for patients. Patient selection on the basis of biomarkers or molecular subtypes may increase the efficacy of systemic chemotherapy-free HER2-targeted approaches.
新辅助化疗是人表皮生长因子受体 2 阳性（HER2+）早期乳腺癌（EBC）的标准治疗方法，无论激素受体状态如何。曲妥珠单抗-美坦新偶联物（T-DM1）是一种高效的 HER2+EBC 抗体-药物偶联物；然而，对于没有常规化疗的降级抗体-药物偶联物为基础的新辅助治疗，尚无生存数据。
在 WSG-ADAPT-TP（临床试验.gov 标识符：NCT01779206）的 II 期试验中，375 名经中心审查的 HR+/HER2+EBC（临床分期 I-III）患者被随机分为 12 周 T-DM1 加或不加内分泌治疗（ET）或曲妥珠单抗+ET 每 3 周一次（比例为 1:1:1）。在病理完全缓解（pCR）的患者中允许省略辅助化疗（ACT）。在这项研究中，我们报告了次要生存终点和生物标志物分析。至少接受一剂研究治疗的患者被纳入分析。采用 Kaplan-Meier 法、双侧对数秩检验和 Cox 回归模型进行生存分析，分层分析淋巴结和绝经状态。 值<0.05 被认为具有统计学意义。
T-DM1、T-DM1+ET 和曲妥珠单抗+ET 诱导的 5 年浸润性无病生存率（iDFS；88.9%、85.3%、84.6%；=0.608）和总生存率（97.2%、96.4%、96.3%；=0.534）相似。pCR 患者与非 pCR 患者的 5 年 iDFS 率更高（92.7%比 82.7%；风险比，0.40[95%CI，0.18 至 0.85]）。在 117 例 pCR 患者中，有 41 例未接受 ACT；无 ACT 组的 5 年 iDFS 率相似（93.0%[95%CI，84.0 至 97.0]）和有 ACT 组（92.1%[95%CI，77.5 至 97.4]；=0.848）。转化研究表明，PIK3CA 野生型、高免疫标志物表达和 luminal-A 型肿瘤（通过 PAM50）的肿瘤在 HR+/HER2+EBC 中，降级抗 HER2 治疗后 pCR 与极好的生存相关，无需进一步 ACT。尽管 T-DM1±ET 与曲妥珠单抗+ET 的 pCR 率较高，但由于非 pCR 后强制性标准化疗，所有试验组的结局相似。WSG-ADAPT-TP 表明，在 HER2+EBC 中进行此类降级试验对患者是可行和安全的。基于生物标志物或分子亚型的患者选择可能会提高无系统化疗的 HER2 靶向治疗的疗效。
