Hofmann Daniel, Nitz Ulrike, Gluz Oleg, Kates Ronald E, Schinkoethe Timo, Staib Peter, Harbeck Nadia
West German Study Group, Ludwig-Weber-Str, 15b, 41061 Moenchengladbach, Germany.
Trials. 2013 Aug 19;14:261. doi: 10.1186/1745-6215-14-261.
Adjuvant treatment decision-making based on conventional clinical/pathological and prognostic single molecular markers or genomic signatures is a therapeutic area in which over-/under-treatment are still key clinical problems even though substantial and continuous improvement of outcome has been achieved over the past decades. Response to therapy is currently not considered in the decision-making procedure.ADAPT is one of the first new generation (neo)adjuvant trials dealing with individualization of (neo)adjuvant decision-making in early breast cancer and aims to establish early predictive surrogate markers, e.g., Ki-67, for therapy response under a short induction treatment in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment.
METHODS/DESIGN: The prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III ADAPT trial has an innovative "umbrella" protocol design. The "umbrella" is common for all patients, consisting of dynamic testing of early therapy response. ADAPT will recruit 4,936 patients according to their respective breast cancer subtype in four distinct sub-trials at 80 trial sites in Germany; 4,000 patients with hormone receptor positive (HR+) and HER2 negative disease will be included in the ADAPT HR+/HER2- sub-trial, where treatment decision is based on risk assessment and therapy response to induction therapy, and 380 patients will be included in ADAPT HER2+/HR+. A further 220 patients will be included in ADAPT HER2+/HR- and 336 patients will be recruited for ADAPT Triple Negative. These three sub-trials focus on identification of early surrogate markers for therapy success in the neoadjuvant setting. Patients will be allocated to the respective sub-trial according to the result of their diagnostic core biopsy, as reported by local/central pathology for HR and HER2 status.
Recent trials, such as the GeparTrio, have shown that response-guided therapy using clinical response may improve outcome. For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome. For endocrine therapy, response to short induction treatment - as defined by decrease in tumor cell proliferation - strongly correlates with outcome. ADAPT now aims to combine static prognostic and dynamic predictive markers, focusing not just on single therapeutic targets, but also on general markers of proliferation and cell death. Biomarker analysis will help to optimize selection of subtype-specific treatment.
ClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN:NCT01815242.
基于传统临床/病理及预后单分子标志物或基因组特征进行辅助治疗决策，是一个治疗领域，尽管在过去几十年中治疗效果有了显著且持续的改善，但过度治疗/治疗不足仍是关键的临床问题。目前，治疗反应在决策过程中未被考虑。ADAPT是首批处理早期乳腺癌（新）辅助决策个体化的新一代（新）辅助试验之一，旨在建立早期预测替代标志物，如Ki-67，用于短期诱导治疗下的治疗反应，以最大程度地实现治疗个体化，并避免无效治疗带来的不必要毒性。
方法/设计：前瞻性、多中心、对照、非盲、随机、研究者发起的II/III期ADAPT试验采用了创新的“伞形”方案设计。“伞形”对所有患者通用，包括早期治疗反应的动态检测。ADAPT将在德国的80个试验地点，根据各自的乳腺癌亚型，在四个不同的子试验中招募4936名患者；4000名激素受体阳性（HR+）且HER2阴性疾病的患者将纳入ADAPT HR+/HER2-子试验，该试验中治疗决策基于风险评估和诱导治疗的治疗反应，380名患者将纳入ADAPT HER2+/HR+试验。另外220名患者将纳入ADAPT HER2+/HR-试验，336名患者将被招募进入ADAPT三阴性试验。这三个子试验专注于在新辅助治疗环境中识别治疗成功的早期替代标志物。患者将根据当地/中心病理报告的HR和HER2状态，依据诊断性核心活检结果分配到各自的子试验中。
近期的试验，如GeparTrio试验，表明使用临床反应进行反应导向治疗可能改善治疗效果。对于化疗或HER2靶向治疗，新辅助治疗环境下的病理完全缓解是治疗效果的极佳预测指标。对于内分泌治疗，短期诱导治疗的反应（以肿瘤细胞增殖减少来定义）与治疗效果密切相关。ADAPT现在旨在将静态预后标志物和动态预测标志物相结合，不仅关注单一治疗靶点，还关注增殖和细胞死亡的一般标志物。生物标志物分析将有助于优化亚型特异性治疗的选择。
ClinicalTrials.gov：ADAPT伞形试验：NCT01781338；ADAPT HR+/HER2-试验：NCT01779206；ADAPT HER2+/HR+试验：NCT01745965；ADAPT HER2+/HR-试验：NCT01817452；ADAPT三阴性试验：NCT01815242。
