Daniel Hofmann

WSG ADAPT - adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer: study protocol for a prospective, multi-center, controlled, non-blinded, randomized, investigator initiated phase II/III trial.

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.

Genomic Profiling in Luminal Breast Cancer

SummaryThe developments in gene expression analysis have made it possible to sub-classify hormone receptor-positive (luminal) breast cancer in different prognostic subgroups. This sub-classification is currently used in clinical routine as prognostic signature (e.g. 21-gene Onoctype DX®, 70-gene Mammaprint®). As yet, the optimal method for sub-classification has not been defined. Moreover, there is no evidence from prospective trials. This review explores widely used genomic signatures in luminal breast cancer, making a critical appraisal of evidence from retrospective/prospective trials. It is based on systematic literature search performed using Medline (accessed September 2013) and abstracts presented at the Annual Meeting of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium.

Abstract OT3-2-04: ADAPT - Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer

Background: Early therapy response is currently not regarded for further treatment decisions as standard of care in the treatment of breast cancer (BC). Predictive markers for the success of a certain therapy could support the physician’s choice of adequate and beneficial therapies by simultaneous reduction of unnecessary toxicity. Proliferation makers as Ki-67 seem to be a suitable tool, as dynamic changes of proliferation (as result of induction therapy) have been shown to be most important for outcome of neoadjuvant chemotherapy prediction in patients with pCR in distinct BC subtypes (luminal B, TNBC, HER2+). Methods: Trial design: ADAPT combines early assessment of prognosis by conventional markers (e.g. molecular classification, nodal status) with dynamic measurement of proliferation changes during a 3-week induction therapy, using baseline diagnostic core biopsy and a second biopsy after induction therapy. ADAPT consists of an umbrella trial and five different sub-trials (HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-, Elderly) and is set up as prospective, multi-center, controlled, non-blinded, randomized phase II/III trial. Subtype-specific treatment across the sub-trials is highly innovative and involves the following treatment strategies: • HR+/HER2-: endocrine therapy (ET) vs. chemotherapy (4xPac q2w – 4xEC q2w vs. 8xNab-Pac q1w – 4xEC q2w) + ET, depending on risk classification/early response. • HER2+/HR+: T-DM1 vs. T-DM1 + ET vs. trastuzumab + ET. • HER2+/HR-: Trastuzumab + Pertzumab ± Paclitaxel q1w. • TN: Nab-Paclitaxel + Gemcitabine vs. nab-Pac + Carboplatin. • Elderly: 2xMyocet + Cyclophosphamide q3w, depending on cPR/cCR or NC/toxicity the treatment will be continued for two more cycles or changed to 6xPac q1w. Adaptation/change in therapy regimens can be made by interim analysis after n=130 in each sub-trial. Eligibility criteria: Histologically confirmed unilateral primary invasive BC with known HR-/HER2-status (central pathology) for allocation to the respective sub-trial. Pts requiring chemo- or targeted (anti-HER2) therapy must have adequate laboratory values and organ function and must have no contraindications for the planned treatment. Primary endpoints: Evaluation of dynamic test for outcome prediction/prospective comparison of 5yr EFS in responders (intermediate risk (RS 12-25) / good response to short-term ET in HR+/HER2- or pts with pCR in HER2+/TN BC) compared to low risk HR+/HER2- (RS≤11, N0-1) pts (control group). Statistical methods: Assumption across sub-protocols: adjuvant CTx can be spared in HR+/HER2- or pCR be achieved in HER2+/TN in expected 1120 (HR+/HER2-) or 170 (HER2+/TN) pts, respectively. Outcome will be compared to the control group (expected n=640 HR+/HER2- pts: low risk (by RS), i.e. no CTx). Assuming 94% 5yr survival in control group, one-sided test of non-inferiority at 95% CI will have 80% power for survival non-inferiority margin of 3.2% (i.e. 90.8% survival). Present and target accrual: By June 2014, 73 active sites have recruited 1820 pts for ADAPT HR+/HER2-. Target accrual is 4000 pts. 190 of 380 pts were successfully randomized for ADAPT HER2+/HR+. ADAPT HER2+/HR- has included 17 of 220 pts and ADAPT Triple Negative has recruited 150 of 336 pts. Citation Format: Ulrike Nitz, Oleg Gluz, Raquel von Schumann, Daniel Hofmann, Ronald E Kates, Sherko Kuemmel, Michael Braun, Claudia Schumacher, Benno Nuding, Bahriye Aktas, Helmut Forstbauer, Nicolai Maass, Mahdi Rezai, Stefan Kraemer, Mathias Warm, Rachel Wuerstlein, Nadia Harbeck. ADAPT - Adjuvant Dynamic marker-Adjusted Personalized Therapy trial optimizing risk assessment and therapy response prediction in early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-04.

Abstract P6-05-11: Run-in phase of prospective WSG-ADAPT HR+/HER2- trial demonstrates feasibility of early endocrine sensitivity prediction by recurrence score and conventional parameters in clinical routine

Background: Despite promising evidence regarding outcome prediction, endocrine sensitivity, as determined by proliferation response to short-term preoperative endocrine therapy, is currently not included in adjuvant chemotherapy decisions in early HR+/HER2- breast cancer (BC). Methods: The prospective WSG-ADAPT HR+/HER2- trial includes early BC patients with 0-3 positive LN who are candidates for adjuvant chemotherapy based on clinical-pathological criteria alone; it aims to spare chemotherapy in a substantial proportion utilizing a combination of genomic assessment by Oncotype DX and endocrine sensitivity testing. All patients received 3-week preoperative endocrine induction therapy (ET): aromatase inhibitors (AI) if postmenopausal, tamoxifen if premenopausal. Patients with low (0-11) Recurrence Score (RS) or intermediate RS (12-25) and ET response (centrally tested, post-therapy Ki-67 Results: As of 6/2013, 380 patients from 30 study centers had been enrolled in the ADAPT HR+/HER2- trial. Median age was 54 years. At first pre-planned analysis (5/2013), paired Ki-67 measurements (pre-/post-therapy) were available in 241 patients; RS was available in 208 cases (201 with paired Ki-67). RS was low in 21.6%, intermediate in 57.7%, and high in 20.7%; the respective risk group responder percentages (post-treatment Ki 67 70% endocrine responders in the intermediate genomic risk group, who could potentially be spared adjuvant chemotherapy. Median Ki 67 level decreases (as percentage of pre-treatment value) were 25% in premenopausal patients (tamoxifen, n = 101) vs. 75% in postmenopausal patients (AI, n = 115) (p Conclusions: The Run-In Phase of the WSG ADAPT HR+/HER2- trial confirms trial design estimates of RS and proliferation response to induction ET. It indicates that the multicenter prospective ADAPT concept combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible. Proliferation response was strongly associated with therapy group (AI/post-menopausal vs. tamoxifen/pre-menopausal). Survival non-inferiority of intermediate Recurrence Score proliferation responders vs. low Recurrence Score patients (active control) will be tested in the ADAPT main phase to determine if adjuvant chemotherapy can be spared in 70% of patients with 0-3 positive LN classified as “intermediate risk” by conventional factors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-11.

Abstract P5-07-03: Prosigna® results impact on adjuvant decision making in early breast cancer (EBC): Final analysis of the prospective WSG study

Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in breast tumor tissue using nCounter® Technology (Nanostring Technologies, Inc.). It provides intrinsic subtype and risk of recurrence (ROR) score predicting 10-year recurrence probability. WSG prospectively evaluated Prosigna9s impact on therapy decisions in EBC and the quality assurance at its implementation in clinical routine. Methods: The study recruited 201 consecutive postmenopausal patients in 11 centers with ER+ HER- N0 EBC (10/2013 to 10/2014). Its primary objective was to assess the extent to which the Prosigna (Breast Cancer Intrinsic Subtype Test (BCIST)) affects the oncologists9 treatment recommendations regarding adjuvant chemotherapy (CT) and actual treatments received for EBC patients. Changes in treatment recommendations include (1) endocrine therapy alone, (2) endocrine therapy plus CT, and (3) changes in types of CT before/after the test and confidence in this treatment decision from physician and patient at a 6-month follow up. Secondary objectives included information on (1) physicians9 confidence in the recommendations before/after the test, and by cancer recurrence risk groups, (2) rate of CT related adverse events stratified by administration of CT, and (3) patients9 decisional conflict status, anxiety levels, and functional status before/after Prosigna9s results. As a secondary endpoint for quality assurance, we repeated Prosigna in a second decentralized pathology laboratory in Germany for inter-observation control. Results: In the total evaluable cohort (n=198), 114 (57.6%) of tumors were classified by Prosigna as Luminal A, 79 (39.9%) Luminal B, 3 (1.5%) Basal-like and 2 (1%) HER2-E. Median Prosigna ROR score was 45 (0-94). There was a 29.3% discordance in intrinsic subtyping between Prosigna and IHC. Concordance between central pathology and the second lab regarding molecular subtype was 95.5% with only 9 discordant samples, all within the luminal group. Concordance regarding ROR risk group classification was 92.9%; no clinically relevant differences (low-high or vice versa) were seen. Overall, there was a change of treatment choice (change in CT indication and change in regimens) in 18.2% compared to the pre-Prosigna decision. Post-Prosigna, 87.8% of physicians felt more confident with their prognostic assessment and 89.4% with their intended treatment. 94.8% of the patients expected to stick to their decision after discussing the Prosigna results. Six-month follow up (actual CT administered, its morbidity, perceptions by physicians and patients) will be presented at SABC. Conclusion: Overall, there was a change of treatment choice (change in CT indication and change in CT regimens) in 18.2% compared to the pre-Prosigna decision. Substantial discordance between Prosigna (PAM50) and local IHC underlines the importance of molecular subtyping prior adjuvant treatment decisions. High concordance of Prosigna results between central and decentralized lab testing were found. Results of WSG study can be pooled with two similar European studies and may thus help to improve our understanding of treatment decision making and adherence in EBC. Citation Format: Wuerstlein R, Sotlar K, Gluz O, Hofmann D, Otremba B, Von Schumann R, Witzel I, Schindlbeck C, Janni W, Schem C, Bauerfeind I, Hasmueller S, Tesch H, Paulenz A, Morel P, Cowens W, Hornberger J, Kates RE, Pelz E, Harbeck N. Prosigna® results impact on adjuvant decision making in early breast cancer (EBC): Final analysis of the prospective WSG study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-07-03.

Abstract P4-15-01: Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial

Background: HER2+, hormone receptor-positive (HR+) breast cancer is a distinct subtype associated with good prognosis but poor response to standard chemotherapy + anti-HER2 (single or dual blockade). Substantial overtreatment by poly-chemotherapy combined with anti-HER2 therapy is suspected in this subtype. Yet, the efficacy of combining endocrine therapy (ET) with anti-HER2 therapy or novel antibody drug conjugates like T DM1 without systemic chemotherapy remains unclear. Methods: ADAPT HER2+/HR+ is a phase II, randomized, neoadjuvant, 3-arm trial (12 weeks) in patients with cT1c-cT3, cN0/+ HER2+, ER+ and/or PR+ early BC. Arm A: T-DM1 (3.6 mg/kg) alone; Arm B: T DM1 + ET (premenopausal: tamoxifen, postmenopausal: AI); Arm C: trastuzumab + ET. Postoperative chemotherapy is recommended together with completion of one year of trastuzumab. Initial and serial core biopsies were obtained prior to therapy and after 3 weeks. First translational analysis of the trial run-in phase (n=130) focuses on dynamics of HER2, Ki67, ER and PR. Results: 162 tumors, HR+ and HER2+ by local pathology, were screened; n=130 were HR+ and HER2+ by central pathology and randomized at 40 trial sites in Germany between 11/2012 and 03/2014 (Arm A/B/C: 37/49/44). Median age was 49 years; 60% were cT2-3, 32% cN+, 75% central G3; median baseline Ki67 was 30%; 49 patients were treated by TAM and 44 postmenopausal patients by AI in ET containing arms. Three-week core biopsies were available in 117 patients (arm A/B/C: n=33/43/41), n=99 with invasive tumor tissue (61/76 (80%) in T-DM1 containing arms and 38/41(93%) in trastuzumab + ET arm). Three-week Ki67 could only be analyzed in n=73 (53% of patients in T-DM1-containing arms, 81% in the T+ET arm) due to a lacking amount of cells for counting ( Median fractional decrease in proliferation (Ki67) after 3 weeks of therapy was 40% in the T-DM1 + ET arm (B) as compared to 14% and 25% in the T-DM1 (A) and T+ET (C) arms, respectively. Among postmenopausal patients, the contrast (52% (B) vs. 0% (A) and 28% (B)) was significant. Mean PR expression change (absolute, measured in %) was -15 in the B Arm vs. 7 and -7 in the A and C arms, respectively (p=0.04) – particularly in postmenopausal women ( 25 vs. +13 and -10, respectively, p=0.04). Baseline ER expression was positively associated with early proliferation response (fractional Ki67 decrease), e.g., by logistic regression using 30% decrease as response criterion. Data on the impact of gene mutations and further molecular markers on proliferation response will be available for presentation at the meeting. Conclusions: In the unique neoadjuvant ADAPT HER2+/HR+ trial, the combination of T-DM1 with ET (particularly AI) seems to be associated with a strong early proliferation response and PR expression drop in anti-HER2 antibody (drug conjugate) +/- ET, without systemic pre-operative chemotherapy. Interim analysis is scheduled after 130 completely treated patients. The high percentage of non-invasive tissue biopsied after 3 weeks in the T-DM1 arms is intriguing, as it would be consistent with higher pathological complete response rates. Citation Format: Oleg Gluz, Ulrike Nitz, Kuemmel Sherko, Kraemer Stefan, Michael Braun, Claudia Schumacher, Bahriye Aktas, Helmut Forstbauer, Toralf Reimer, Peter Fasching, Jochem Potenberg, Daniel Hofmann, Ronald E Kates, Rachel Wuerstlein, Matthias Christgen, Hans H Kreipe, Nadia Harbeck. Distinct early proliferation response to neoadjuvant anti-HER2 antibody drug conjugate +/- endocrine therapy in early breast cancer in the WSG ADAPT HER2+/HR+ trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-01.

Abstract OT3-2-03: Prospective observational study of clinical outcomes for the NanoString® technologies Prosigna™ test by the West German Study Group

Background: Current diagnostic tools for breast cancer (BC), including screening, diagnostic breast imaging and biopsy, do not provide information about subtype classification. However, the subtype classification is crucial for the assessment of the recurrence risk and for the choice of optimal adjuvant treatment. A vast amount of data from recent research, clinical trials, and peer reviewed publications support the value of intrinsic subtyping based on gene expression analyses to assess prognosis and treatment options for patients with early BC. Trial design: The multicenter (n=8), prospective study examines whether the Prosigna™ test influences physician and patient adjuvant treatment selection over and above currently used prognostic factors. It also examines the impact of the test results on patients’ reported outcomes including their decisional conflict status, anxiety levels, and functional status. Prosigna™ is a standardized test measuring the expression levels of 50 classifier genes in formalin-fixed, paraffin-embedded tissue samples and provides a subtype classification based on the fundamental biology of individual patient’s tumor (intrinsic subtyping), as well as a prognostic score (risk of recurrence (ROR) score) that predicts the probability of cancer recurrence over 10 years. Eligibility criteria: Postmenopausal women with resected N0, estrogen-receptor-positive (ER) (by immunohistochemistry (IHC); >1% of stained tumor cells is considered positive), HER2-negative (IHC and/or in-situ fluorescence hybridization by local laboratory), early-stage invasive BC (T1-T2, pN0 (i+/mol+), M0). Patients must be able to give consent and must be eligible for treatment with adjuvant chemotherapy (Ctx) (ECOG performance status ≤1). Patients with non-invasive (e.g. Paget’s disease, DCIS), ER-negative or HER2-positive BC must not be included. Metastatic disease and contraindications for adjuvant Ctx (age, ECOG >1, significant comorbidities) are exclusion criteria. Patients unable to complete patient reported outcome surveys will be excluded. Specific aims: Primary endpoint is the proportion of patients whose choice of treatment is changed as a result of receiving the Prosigna™ result. Secondary endpoints include the proportion of patients whose choice of treatment is changed stratified by ROR groups (low, intermediate, high) and who have cancer recurrence risk proximal to the cutoff points between risk strata (± 5% from cutoff point). Investigators’ confidence in treatment recommendations before/after Prosigna™ results and change in patients’ decisional conflict status, anxiety levels, and functional status, stratified by cancer recurrence risk strata, will be investigated. Rate and severity of treatment-related adverse events stratified by whether patient received adjuvant Ctx and agreement in molecular subtyping between Prosigna™ and local IHC will be evaluated. Statistical methods: Sample size of 200 produces a one-sided 95% lower-limit CI with a distance from the sample proportion to the lower limit that is equal to 0.05 when the sample proportion is 0.25. Present and target accrual: A total of 200 patients will be included, current accrual is n=111 as of 3rd June 2014. Citation Format: Rachel Wuerstlein, Karl Sotlar, Burkhard Otremba, Oleg Gluz, Enrico Pelz, Daniel Hofmann, Ronald E Kates, Isabelle Witzel, Christian Schindlbeck, Wolfgang Janni, Christian Schem, Hans Tesch, Nadia Harbeck. Prospective observational study of clinical outcomes for the NanoString® technologies Prosigna™ test by the West German Study Group [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-03.