乳腺癌术前单药免化疗内分泌治疗

　　对于肿瘤较大难以手术或术后复发风险较高的早期乳腺癌，术前新辅助治疗可提高手术的可行性和成功率。不过，对于HER2阳性早期乳腺癌，无论激素受体是否阳性，术前新辅助化疗都是标准治疗。恩美曲妥珠单抗（T-DM1）是HER2抗体与化疗药的缀合物，对HER2阳性早期乳腺癌疗效极好；不过，对于未常规化疗的患者，T-DM1新辅助治疗的长期生存数据极少。2012年5月、2013年6月、2014年3月，西德研究协作组（WSG）先后启动3项ADAPT研究，分别对HER2阳性激素受体阳性乳腺癌、三阴性乳腺癌、HER2阳性激素受体阴性早期乳腺癌术前新辅助治疗效果及其预测指标进行探讨。

WSG-ADAPT (NCT01779206): Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer
WSG-ADAPT-TN (NCT01815242): Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer
WSG-ADAPT-HER2+/HR- (NCT01817452): A Prospective, Randomized Multicenter, Open-label Comparison of Preoperative Combination of Trastuzumab and Pertuzumab With or Without Concurrent Taxane Chemotherapy Given for Twelve Weeks in Patients With Operable HER2+/HR- Breast Cancer Within the ADAPT Protocol

　　2023年2月21日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表WSG-ADAPT-TP研究结果，报告了激素受体阳性HER2阳性早期乳腺癌术前未化疗患者T-DM1±内分泌治疗与曲妥珠单抗＋内分泌治疗的5年生存结局。

　　该多中心非盲随机对照二期伞式研究于2012年10月～2015年3月从48个研究中心入组375例经过集中复核为激素受体阳性HER2阳性早期（临床I～III期）乳腺癌术前患者，按1∶1∶1的比例随机分为3组接受12周新辅助治疗：

A组119例：每3周T-DM1＋内分泌治疗
B组127例：每3周T-DM1单药
C组129例：每3周曲妥珠单抗＋内分泌治疗

　　该研究主要终点为病理完全缓解，病理完全缓解患者术后允许免化疗。该研究次要终点包括无浸润癌生存、无远处癌生存、总生存和生物学标志物分析。通过生存时间曲线法、双侧对数秩统计法、淋巴结和绝经状态分层多因素比例风险回归模型对接受至少一次研究治疗的患者进行分析。P值<0.05被认为有统计学意义。

　　结果，A组、B组、C组相比：

5年无浸润癌生存率相似：88.9%、85.3%、84.6%（对数秩P=0.447）
5年无远处癌生存率相似：91.6%、92.3%、88.9%（对数秩P=0.567）
5年总生存率相似：97.2%、96.4%、96.3%（对数秩P=0.671）

　　病理完全缓解与否相比：

5年无浸润癌生存率显著较高：92.7%比82.7%（风险比：0.40，95%置信区间：0.18～0.85，对数秩P=0.014）
5年无远处癌生存率显著较高（风险比：0.35，95%置信区间：0.14～0.91，对数秩P=0.024）

　　117例患者病理完全缓解，其中76例术后化疗患者与41例术后未化疗患者相比，5年无浸润癌生存率相似：93.0%比92.1%（风险比：1.15，对数秩P＝0.848）

　　转化研究表明，对于PIK3CA未突变、免疫学标志物PD-L1和/或CD8高表达、50基因管腔A型乳腺癌患者，T-DM1±内分泌治疗免化疗的无浸润癌生存率和无远处癌生存率显著较高。

　　因此，该多中心非盲随机对照二期临床研究结果表明，对于激素受体阳性HER2阳性早期乳腺癌患者，术前12周T-DM1±内分泌治疗免化疗后，病理完全缓解与否相比，5年无浸润癌生存率和5年无远处癌生存率显著较高；虽然T-DM1±内分泌治疗与曲妥珠单抗＋内分泌治疗相比，病理完全缓解率较高，但是由于未病理完全缓解后强制标准化疗，全部研究组生存结局相似；对于HER2阳性早期乳腺癌患者，此类免化疗研究可行且安全；根据生物学标志物或分子亚型进行患者筛选，可能提高T-DM1±内分泌治疗免化疗有效率。

　　此外，T-DM1本身已经缀合化疗药，免化疗本在情理之中。不过值得注意的是，对于此类患者，T-DM1±内分泌治疗相比，5年无浸润癌生存率、5年无远处癌生存率、5年总生存率也相似，能否说明T-DM1除了免化疗，还可免内分泌治疗？故有必要进一步开展更大样本研究、更长随访时间进行验证。

相关链接

J Clin Oncol. 2023 Feb 21. IF: 50.717

De-Escalated Neoadjuvant Trastuzumab-Emtansine With or Without Endocrine Therapy Versus Trastuzumab With Endocrine Therapy in HR+/HER2+ Early Breast Cancer: 5-Year Survival in the WSG-ADAPT-TP Trial.

Nadia Harbeck, Ulrike A. Nitz, Matthias Christgen, Sherko Kümmel, Michael Braun, Claudia Schumacher, Jochem Potenberg, Joke Tio, Bahriye Aktas, Helmut Forstbauer, Eva-Maria Grischke, Iris Scheffen, Wolfram Malter, Raquel von Schumann, Marianne Just, Christine zu Eulenburg, Claudia Biehl, Cornelia Kolberg-Liedtke, Regula Deurloo, Sanne de Haas, Katarzyna Józwiak, Michael Hauptmann, Ronald Kates, Monika Graeser, Rachel Wuerstlein, Hans H. Kreipe, Oleg Gluz; WSG-ADAPT investigators.

West German Study Group, Moenchengladbach, Germany; LMU University Hospital, Munich, Germany; Ev. Hospital Bethesda, Moenchengladbach, Germany; Medical School Hannover, Hannover, Germany; Kliniken Essen-Mitte, Essen, Germany; Charité—Universitatsmedizin Berlin, Berlin, Germany; Rotkreuz Clinics Munich, Munich, Germany; St Elisabeth Hospital Cologne, Cologne, Germany; Ev. Waldkrankenhaus Berlin, Berlin, Germany; University Hospital Münster, Münster, Germany; University Clinics Essen, Essen, Germany; University Clinics Leipzig, Women's Clinic, Leipzig, Germany; Oncology Practice Network Troisdorf, Troisdorf, Germany; University Clinics Tuebingen, Tuebingen, Germany; University Hospital, Cologne, Germany; Oncological Practice, Bielefeld, Germany; University Medical Center Hamburg, Hamburg, Germany; Westphalian Brest Center Dortmund, Dortmund, Germany; F. Hoffmann-La Roche Ltd, Basel, Switzerland; Brandenburg Medical School Theodor Fontane, Neuruppin, Germany; University Medical Center Hamburg, Hamburg, Germany; University Clinics Cologne, Cologne, Germany.

PURPOSE: 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.

PATIENTS AND METHODS: 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. P values < .05 were considered statistically significant.

RESULTS: T-DM1, T-DM1 + ET, and trastuzumab + ET induced similar 5-year invasive disease-free survival (iDFS; 88.9%, 85.3%, 84.6%; Plog-rank = .608) and overall survival rates (97.2%, 96.4%, 96.3%; Plog-rank = .534). Patients with pCR versus non-pCR had improved 5-year iDFS rates (92.7% v 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; Plog-rank = .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.

CONCLUSION: 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.

KEY OBJECTIVE: No survival data are available for de-escalated antibody-drug conjugate-based neoadjuvant therapy without conventional chemotherapy in human epidermal growth factor receptor 2-positive (HER2+) early breast cancer. Here, we report the survival and biomarker analysis of the WSG-ADAPT-TP (ClinicalTrials.gov identifier: NCT01779206) neoadjuvant phase II trial comparing short (12-week), de-escalated (conventional chemotherapy-free) antibody-drug conjugate trastuzumab-emtansine (T-DM1) versus T-DM1 + endocrine therapy (ET) versus trastuzumab + ET.

KNOWLEDGE GENERATED: De-escalated neoadjuvant T-DM1, T-DM1 + ET, and trastuzumab + ET followed by standard adjuvant anti-HER2 therapy and standard chemotherapy in all patients without pathologic complete response (pCR) led to a comparable invasive (invasive disease-free survival [iDFS]), distant disease-free survival and overall survival. pCR, higher programmed cell death ligand 1 and CD8 expression, PIK3CA wild type, and luminal-A tumors were associated with better iDFS and/or distant disease-free survival. Omission of adjuvant chemotherapy in patients with pCR did not compromise iDFS.

RELEVANCE: Pathologic complete response predicts long-term outcome in patients treated with standard cytotoxic regimens, but data on long-term outcome in patients who achieved pCR with less intensive regimens were lacking. Would how you reached pCR matter? The WSG-ADAPT-TP trial begins to answer that question, paving the way for chemotherapy-free treatment for some patients with ER+/HER2+ disease.

DOI: 10.1200/JCO.22.01816

SUPPORT: F. Hoffmann-la Roche Ltd.

CLINICAL TRIAL INFORMATION: NCT01779206

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