Abstract
BackgroundAdjuvant 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/designThe 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.DiscussionRecent 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.Trial registrationClinicalTrials.gov: ADAPT Umbrella: NCT01781338; ADAPT HR+/HER2-: NCT01779206; ADAPT HER2+/HR+: NCT01745965; ADAPT HER2+/HR-: NCT01817452; ADAPT TN:NCT01815242.
Highlights
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
For chemotherapy or HER2-targeted treatment, pathologic complete response in a neoadjuvant setting is an excellent predictor of outcome
The two most important questions in therapy of early breast cancer to be resolved over the decade are: Who can safely be spared adjuvant chemotherapy? and Who has the maximum benefit from chemo, endocrine and/or anti-HER2 therapy?
Summary
Adjuvant therapy indications in early HR+/ HER2- breast cancer are mainly based on the individual prognostic profile as determined by clinical-pathological factors (tumor size, nodal status, grade, age), prognostic genomic signatures (e.g., RS) or protein markers such as uPA/PAI-1 [20,21]. The ADAPT Umbrella trial brings together the results of dynamic testing acquired in the different subgroups It will allow identification of patients within all breast cancer subtypes, who have intermediate to poor prognosis according to conventional criteria, but excellent outcome due to high therapy efficacy. It will contribute to the goal of therapy individualization for each individual patient by maximizing treatment efficacy in early breast cancer at the same time The importance of this investigator initiated trial for clinical management is recognized by the fact that for the first time, payers in the German healthcare system are working together with an academic study group as well as partners from the diagnostic and pharmaceutical industry, in order to support the WSG ADAPT trial.
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