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Background: Elderly breast cancer (BC) patients (pts) have been reported to have worse BC-related outcome than younger pts, even within clinical trials such as TEAM. Shak et al. recently showed in a large SEER data analysis that in the high 21-gene recurrence score (RS) group, older pts (>70y) receive less chemotherapy (CT) and have a worse BC-specific mortality than younger pts. Here, we therefore aimed to see whether there are age-related outcome disparities according to RS groups in pts receiving state-of-the-art CT in the prospective WSG PlanB trial. Material and Methods: PlanB compared 6 cycles of anthracycline-free TC vs. standard anthracycline-taxane based CT (4xECà4xDoc) in patients with high risk pN0 (T2-4, G2-3, Results: In all pts with luminal cancer and RS results (n=2577), there was an age-related significant difference in RS risk group assignment (p25; in pts 40-69 years, 18.3% had RS≤11, 61% RS 12-25, and 20.7%% RS>25; in elderly pts (>70y), 19.5% had RS≤11, 55.3% RS 12-25, and 25.2% RS>25. Among patients receiving chemotherapy, RS>25 vs. RS25, there were no significant differences in DFS between any two of these three age groups. Conclusion: A substantial percentage of elderly patients (> 70y) presents with high-risk luminal disease; these patients are candidates for CT. In PlanB, about 25% of elderly luminal BC patients had high-risk (RS>25) tumors. Nevertheless, after receiving modern adjuvant CT, their DFS was comparable to that of non-elderly pts with high-risk RS tumors. Consequently, older BC pts with high-risk luminal tumors who are fit enough to receive adjuvant CT should be treated according to guidelines in order to overcome age-dependent survival disparities which have been observed in registries for high-RS tumors. Citation Format: Harbeck N, Gluz O, Wuerstlein R, Clemens M, Malter W, Reimer T, Nuding B, Stefek A, Pollmanns A, Augustin D, Uleer C, Lorenz-Salehi F, Shak S, Chao C, Christgen M, Kates R, Kreipe H, Nitz U. No age-related outcome disparities according to 21-gene recurrence score groups in early breast cancer patients treated by adjuvant chemotherapy in the prospective WSG PlanB trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-06-06.

Background: Optimal treatment, particularly use of anthracyclines in aggressive triple-negative breast cancer (TNBC), is still a controversial issue in early BC management. However, TNBC exhibits substantial molecular heterogeneity: for example, the immune phenotype seems to be associated with better outcome. An important clinical issue in early TNBC is to quantify the impact of subtypes as well as individual genes on survival and especially on anthracycline benefit. Methods: In PlanB, patients with ER and PR Results: RNA expression results were available in n=394 (203 TC vs. 191 EC-Doc): PAM-50 subtype: basal-like 82%; HER2-enriched 7%; luminal (A or B) 3.5%; normal-like 7.4%. Median age was 54; 78% were node-negative. In patients with “discordant” tumors (HR positive by local or central assessment), 76% were still basal-like, compared to 86% in “concordant” TNBC. Of 27 patients with HER2-enriched subtype, HER2 status was positive by central assessment in only five cases (18%). Within this TN cohort, 5y DFS was similar in TC (83%) and EC-Doc (79%) arms; positive nodal status and tumor size >2 cm were (unfavorable) clinical-pathological prognostic markers. Prognostic or predictive impacts of molecular subtype, risk of recurrence subgroups, or proliferation indices were not seen. Twelve genes (incl. CD8, EGFR, GPR160, SPINT2) showed potential multivariate prognostic impact by entering the “forwards stepwise” multivariate Cox model for DFS. The upper half of patients according to the resulting “twelve-gene signature” had well over 90% 5y-DFS, whereas the lowest quartile had under 60% 5-y DFS. Several genes (incl. ERBB2, FOXC1) showed potential for a predictive impact regarding TC vs. EC-Doc by interaction analysis. Further details and perspectives for testing the robustness of these potential impacts will be presented at the meeting. Conclusions To our knowledge, these are the first results from a prospective, adjuvant taxane-based trial regarding molecular predictors of anthracycline efficacy and PAM-50-based prognostic factors in early TNBC. ERBB2 expression, but not HER2-enriched subtype, was predictive for A-benefit in HER2-negative BC. Molecular heterogeneity of TNBC beyond basal-like vs. non-basal-like subtype is clinically relevant and should be considered for patient stratification in ongoing trials with combination therapy. The identified prognostic gene signature should be validated in the WSG-ADAPT-TN and other TNBC trials. Citation Format: Gluz O, Liedtke C, Prat A, Christgen M, Gebauer D, Kates R, Pelz E, Clemens M, Warm M, Aktas B, Kuemmel S, Pare L, Krabisch P, Kreipe HH, Wuerstlein R, Nitz U, Harbeck N. Genomic markers but not molecular subtypes provide prognostic impact and predict anthracycline efficacy in early triple-negative breast cancer: Results from the prospective WSG PlanB trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-03.

This abstract was withdrawn by the authors.

Background Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis. Patients and methods Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC → P) q3w. Event-free survival (EFS) was the primary end point. Results A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC →P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63–0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60–0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC → P arm, respectively. Conclusion The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC → P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up.

Background: Immune and apoptosis biomarkers are potential prognostic/predictive markers in HER2+ EBC. High PD-L1 expression was shown to be predictive for lower pCR after chemotherapy+trastuzumab+/-pertuzumab, particularly in HER2+, ER- disease. Yet, HER2+ EBC co-expressing hormone receptors is a distinct entity. The ADAPT HER2+/HR+ phase II trial (n=376) compared 12 weeks of neoadjuvant T-DM1 + ET vs. trastuzumab (T)+ET and demonstrated pCR rates of about 41% in both (well tolerated) T-DM1 arms. Methods: In order to identify potential early predictors for pCR (i.e. no invasive tumor in breast and lymph nodes), immune markers (PDL1 on infiltrating immune cells (IIC) and on tumor cells (TC); CD8 in invasive margin and in tumor center) and apoptosis markers (bcl-2; mcl-2) were determined by immunohistochemistry (IHC; H-scores) in core biopsy sections obtained at primary diagnosis and at cycle 2. For multivariate logistic regression, each biomarker (separately), clinical factors (Ki-67, cT, cN) and therapy were entered. All analyses were exploratory. Results:Biomarkers were available in up to 326 patients (pts) at baseline and up to 170 pts at 3 weeks (due to low tumor content in 2nd core biopsy). Baseline IIC-PDL1 was associated with pCR in the T-DM1 arm (OR 2.89; 95%CI: 1.11-7.51); IIC-PDL1 at cycle 2 was not associated with pCR. PD-L1 expression in TC was rare (2%); cycle-2 TC-PD-L1 was associated with pCR in all pts and in the pooled TDM-1 arms. High baseline CD8 in tumor center was associated with pCR in the whole cohort (OR 2.4; CI: 1.04 – 5.5) and in the T+ET arm (OR=10.1; CI: 1.12 - 91.6) and at cycle 2 in all pts (OR=9.52; CI: 2.17 – 41), in pooled TDM-1 arms (OR=15.7; CI: 2.49 – 99), and in TDM-1+ET (OR=25.05; CI: 2.12 – 295). Increases in this marker also predicted pCR in all pts, pooled TDM-1, and in TDM-1+ET. Association of cycle-2 CD8 in tumor center with pCR persisted in multivariate models. Lower baseline CD8 in invasive margin was associated with pCR in the T-DM1 arm (OR=0.09; CI: 0.01-0.69), but at cycle 2 in all pts (OR=18.1; CI: 1.60 – 204) and in pooled TDM-1 arms (OR=23.5; CI: 1.1 - 500). This positive impact persisted in multivariate models. Bcl-2 expression at baseline was associated with non-pCR in all pts (OR=0.28, CI: 0.12 - 0.66), in the pooled T-DM1 arms (OR=0.216, CI: 0.08 - 0.61), and particularly in the T-DM1+ET arm (OR=0.14; CI: 0.03 - 0.71). This association persisted in multivariate analysis. At cycle 2, lower bcl-2 had OR=0.16 (CI: 0.03 - 0.96) in the pooled T-DM1 arms. No association with efficacy was seen for mcl-1. Conclusions: The WSG-ADAPT HER2+/HR+ phase II trial is the first international trial to focus on HER2+/HR+ EBC alone and the first to show substantial pCR rates of > 40% after only 12 weeks of T-DM1 -- without standard chemotherapy. Expression of bcl-2 may affect resistance to T-DM1. High immune activity at baseline and/or cycle 2 seems to be associated with pCR. The association of CD8 expression and its changes with therapy efficacy is complex and could depend on ET. Further biomarker analyses are ongoing and will be presented at the meeting. Citation Format: Harbeck N, Nitz UA, Matthias C, Kates R, Braun M, Kümmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, Liedtke C, Grischke E-M, de Haas SL, Deurloo R, Schumacher J, Wuerstlein R, Kreipe HH, Gluz O. The role of immune and apoptosis markers for prediction of pCR in the WSG-ADAPT HER2+/HR+ phase II trial evaluating 12-weeks of neoadjuvant TDM1 ± endocrine therapy (ET) versus T + ET in HER2-positive hormone-receptor-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-05.

Background: In luminal early breast cancer (EBC) with limited nodal involvement, current guidelines recommend to use multigene assays in addition to conventional clinicopathological factors for decision making regarding adjuvant chemotherapy (CT). The WSG PRIME Study prospectively evaluated the impact of the 70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) on clinical therapy decisions in EBC. Methods: WSG PRIME recruited 452 consecutive patients (pts) in 34 centers with ER+ and/or PR+ HER- pN0-1 EBC (04/15-03/16). Of the 430 evaluable pts, 309 had pN0 and 121 pN1 disease; median age was 58 years (68% post-menopausal). MammaPrint®, TargetPrint®, and BluePrint® results were provided prospectively, after therapy decisions based on clinicopathological factors and/or local IHC (ER/PR/Ki67) had been ascertained. Results: The WSG PRIME study observed a switch in CT decisions based on the multigene test results of 28.4 % (95% CI 23.3-33.4%). In 57 pts (13.3%), the decision switched from CT to no-CT, in 65 (15.1%) from no-CT to CT; in 107 (24.9%) pts a CT decision and in 201 (46.7%) a no-CT decision was maintained. Physicians strongly adhered to test results, most notably when initial CT recommendation was discordant with the test: 62/72 (86.1%) switched from no-CT to CT following MammaPrint® high risk, with 84.7% in N0 and 92.3% in N1. For MammaPrint® low risk, 56/80 (70%) switched from CT to no-CT; this percentage was similar in pN0 and pN1. Overall adherence (all pts) was 92.9% (CT) for high risk and 90.1% (no-CT) for low risk. Regarding subtype, 1/430 tumors was classified as HER2-enriched by BluePrint®; of the 6 basal-like tumors by IHC, 2 were molecularly re-classified as luminal A and 4 as luminal B. Of the 424 luminal-A/-B-like tumors by IHC, only 283 (66.7%) were subtyped concordantly by BluePrint®; 40% (61/152) of the luminal-B-like tumors were re-classified as luminal A and 29% (79/272) of the luminal-A-like tumors were re-classified as luminal B. Switches in CT decisions were strongly impacted by molecular subtype, with 142/152 (93.4%) of molecular luminal B pts eventually scheduled for CT and 247/272 (90.8%) of molecular luminal A pts for no-CT. After the test results, physicians' confidence in their therapy decision increased in 141 (32.9%) of the cases. Conclusions: In a decision impact study, the true percentage of CT saved by a prognostic test depends on cohort characteristics. Yet, the WSG PRIME study showed that the70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) strongly impacted clinical therapy decisions in EBC with up to 3 involved lymph nodes. There was a substantial discordance between clinical and molecular luminal subtypes. After receiving the test results, physicians focused their indications for adjuvant CT on MammaPrint high-risk luminal-B-like tumors. Where test results were discordant with clinical assessment, physicians mostly omitted CT in MammaPrint low risk patients. Recently, the prospective MINDACT trial had shown that this did not compromise outcome.Background: In luminal early breast cancer (EBC) with limited nodal involvement, current guidelines recommend to use multigene assays in addition to conventional clinicopathological factors for decision making regarding adjuvant chemotherapy (CT). The WSG PRIME Study prospectively evaluated the impact of the 70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) on clinical therapy decisions in EBC. Methods: WSG PRIME recruited 452 consecutive patients (pts) in 34 centers with ER+ and/or PR+ HER- pN0-1 EBC (04/15-03/16). Of the 430 evaluable pts, 309 had pN0 and 121 pN1 disease; median age was 58 years (68% post-menopausal). MammaPrint®, TargetPrint®, and BluePrint® results were provided prospectively, after therapy decisions based on clinicopathological factors and/or local IHC (ER/PR/Ki67) had been ascertained. Results: The WSG PRIME study observed a switch in CT decisions based on the multigene test results of 28.4 % (95% CI 23.3-33.4%). In 57 pts (13.3%), the decision switched from CT to no-CT, in 65 (15.1%) from no-CT to CT; in 107 (24.9%) pts a CT decision and in 201 (46.7%) a no-CT decision was maintained. Physicians strongly adhered to test results, most notably when initial CT recommendation was discordant with the test: 62/72 (86.1%) switched from no-CT to CT following MammaPrint® high risk, with 84.7% in N0 and 92.3% in N1. For MammaPrint® low risk, 56/80 (70%) switched from CT to no-CT; this percentage was similar in pN0 and pN1. Overall adherence (all pts) was 92.9% (CT) for high risk and 90.1% (no-CT) for low risk. Regarding subtype, 1/430 tumors was classified as HER2-enriched by BluePrint®; of the 6 basal-like tumors by IHC, 2 were molecularly re-classified as luminal A and 4 as luminal B. Of the 424 luminal-A/-B-like tumors by IHC, only 283 (66.7%) were subtyped concordantly by BluePrint®; 40% (61/152) of the luminal-B-like tumors were re-classified as luminal A and 29% (79/272) of the luminal-A-like tumors were re-classified as luminal B. Switches in CT decisions were strongly impacted by molecular subtype, with 142/152 (93.4%) of molecular luminal B pts eventually scheduled for CT and 247/272 (90.8%) of molecular luminal A pts for no-CT. After the test results, physicians' confidence in their therapy decision increased in 141 (32.9%) of the cases. Conclusions: In a decision impact study, the true percentage of CT saved by a prognostic test depends on cohort characteristics. Yet, the WSG PRIME study showed that the70-gene signature (MammaPrint®) and the corresponding molecular subtype (BluePrint®) strongly impacted clinical therapy decisions in EBC with up to 3 involved lymph nodes. There was a substantial discordance between clinical and molecular luminal subtypes. After receiving the test results, physicians focused their indications for adjuvant CT on MammaPrint high-risk luminal-B-like tumors. Where test results were discordant with clinical assessment, physicians mostly omitted CT in MammaPrint low risk patients. Recently, the prospective MINDACT trial had shown that this did not compromise outcome. Citation Format: Wuerstlein R, Gluz O, Kates R, Persoon M, Wasmayr M, Knauer M, Koplmüller R, Grischke E-M, Schem C, Thill M, Hasmueller S, Griesinger F, Koehler A, Otremba B, Schindlbeck C, Reimer T, Krauter J, Tome O, Otto F, Friedrichs K, Albert U-S, Gebauer G, Nitz U, Harbeck N. Results of multigene assay (MammaPrint®) and molecular subtyping (BluePrint®) substantially impact treatment decision making in early breast cancer: Final analysis of the WSG PRIME decision impact study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-10.

Background: The use of molecular tools for prognosis and prediction of CT benefit in EBC has increased the complexity of decision making. The 21-gene RS (Oncotype DX) is included in the ASCO (2007) and NCCN guidelines (2006) for prognosis (risk of distant recurrence [DR]) and prediction of CT benefit in N0, ER+ EBC. In 2015, the NCCN added that the RS assay could be considered for select patients with 1-3 N+, ER+ EBC. Recently the ASCO BC biomarker/guideline group (J Clin Oncol 2016) advised that the “clinician should not use the 21-gene RS to guide decisions” and called the evidence quality “intermediate” and the recommendation “moderate” based on review of 2 N+ studies. It also advised no change in N+ clinical practice until the prospective SWOG S1007 study (RxPONDER) matures in several years. These discordant recommendations have led to major confusion among physicians, pts and payers. To address this controversy we herein report a comprehensive analysis of the body of evidence regarding the clinical utility of the RS in N+, ER+ EBC. Methods: All published studies involving N+, ER+ EBC with RS data were analyzed by type of study design and category of trial (validation, supportive, decision impact, cost-effectiveness, and prospective outcomes). Results: 30 studies provided clinical evidence supporting the value and utility of the RS in N+, ER+ pts. 7 studies employed a prospective-retrospective design or were prospective outcomes with clinical utility in >8000 N+ pts (Table). 23 additional studies assessed the impact of RS on CT decisions or cost-effectiveness. Study in N+/ER+Type of studyNEndpoints/resultsSWOG S8814 (Lancet Oncol 2010)Pro-retro36710-year DFS and BCSS: RS predicts risk of DFS event, BC death, and CT benefit (none to slightly worse if very low risk RS and 1-3 N+)TransATAC (JCO 2010)Pro-retro3069-year DR: RS predicts risk of DR in pts treated with ET without CTECOG E2197 (JCO 2008)Pro-retro2325-year DR: RS predicts DR risk in CT+ET treated ptsNSABP B-28 (ASCO-BCS 2012)Pro-retro106510-year DRFI: RS predicts DR risk in CT+ET treated ptsPACS-01 (ASCO 2014)Pro-retro5305-year DRFI/DFS: RS predicts DR risk in CT+ET treated ptsSEER (npj BC 2016)Prospective outcomes46915-year BCSM: RS predicts BCSM; pts with RS Conclusions: The 21-gene RS has now been studied in >10,000 N+, ER+ EBC pts across 30 studies worldwide, including 2 prospective outcomes studies in >5000 pts, confirming that the RS consistently identifies low risk 1-3 N+ pts in whom CT can effectively and safely be avoided. This evidence suggests that ER+ pts with few N+ and low RS should have a discussion of the pros and cons of adjuvant CT until the results of RxPONDER provide a definitive answer in several years. Citation Format: Mamounas E, Goldstein L, Penault-Llorca F, Roche H, Gluz O, Harbeck N, Nitz U, O'Shaughnessy J, Albain K. Chemotherapy (CT) decision in patients (pts) with node-positive (N+), ER+, early breast cancer (EBC) in the wake of new ASCO guideline – A different take on the evidence for the 21-gene recurrence score (RS) assay [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-02.

Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Use of weekly nab- paclitaxel (Nab-Pac) vs. conventional paclitaxel and also addition of carboplatinum(Carbo) to anthracycline-taxane(A/T) containing chemotherapy results in significantly higher pCR rates in TNBC with unclear impact on survival and increased toxicity. The ADAPT study seeks to compare Carbo vs. gemcitabine(Gem) added to nab- paclitaxel as a short 12-week A-free regimen. It also assesses efficacy in early responders vs. non-responders by 3-week proliferation and/or imaging response. Methods: ADAPT TN compares 12-week neoadjuvant regimens: Carbo vs. Gem combined with Nab-Pac and aims to identify early-response markers for pCR (yPN0 and ypT0/is). TNBC patients (centrally confirmed ER/PR Results: 336 patients were enrolled from 47 centers between 06/13-02/15 (n=182 ArmA: Nab-Pac/Gem and n=154 ArmB: Nab-Pac/Carbo). 90% and 95% completed therapy according to protocol respectively (n.s.). Median age was 50y. At baseline: A/B: 73% and 74%% had G3 tumors, median Ki-67 of 70% and 75%; 62.6% and 62.9%% had cT2-4c tumors, pN0 status prior to chemotherapy was confirmed in 50.5% and 50%, respectively. pCR (ypT0/is/ypN0) was A: 28.7% and B: 45.9% (p Nab/Gem arm was associated with significantly higher frequency of dose reductions (20.6% vs. 11.9% (p=0.03), treatment related SAE's (13% vs. 5%, p=0.02), grade 3-4 infections (6.1% vs. 1.3%, p=0.04) and ALAT elevations (11.7 vs. 3.3%, p=0.01) compared to the Nab-Carbo arm. Within the planned interim analysis (n=130: A/B: 69/61), baseline Ki-67 (Nab- Pac/Carbo arm), age>50 years, and low cellularity ( Validation of responder definitions for the whole study will be presented at the meeting. Conclusions: This is the first large randomized study comparing two short 12-week anthracycline- free regimens in unselected TNBC. Our results suggest superior efficacy and excellent toxicity of Nab-Pac/Carbo vs. Gem. Longer A/T-Carbo containing regimens render quite comparable pCR rates, thus overtreatment by 4xEC in unselected TNBC may be present in some patients. Early response criteria seem to differ according to regimen; their assessment may be impaired by substantial tumor necrosis already after the first therapy cycle. Citation Format: Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, Pelz E, Kates RE, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial. [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 P1-13-01.

Introduction: Tumor-infiltrating lymphocytes (TILs) have been associated with prognosis and with chemotherapy response among patients with BC, particularly in presence of high-risk features. The WSG planB trial randomized 2448 patients with HER2- N0/1 BC for comparison of anthracycline-free (6xTC) vs. standard anthracycline-taxane chemotherapy (4xEC-4xDoc). Recurrence Score® (RS) was incorporated for risk stratification in hormone receptor positive (HR+) BC. The present analysis focuses on the correlation of TILs with clinical/pathological parameters and their prognostic impact among planB patients. Methods: Stromal TILs were evaluated using a pathologist and two-observer approach. Three independent observers evaluated digital sections on H&E staining as previously suggested (Salgado et al., Ann Oncol. 2014); the median of the three values (TILmed) was used for statistical analysis. Spearman correlations of TILmed with clinical/pathological parameters (including central KI67 expression, quantitative ER measurements, nodal involvement, and RS) and univariate impact on event-free survival (EFS) were analyzed. Results: Our analysis included 300 patients with HR- and 1124 patients with HR+ HER2- BC. Both in HR- and HR+ BC, a significant association between TILmed and (i) central grading (correlation coefficient r=0.147, p=0.012 and r=0.195, p Conclusion: In this dataset, presence of stromal TILs was moderately associated with clinical features of high-risk breast cancer (including RS) and decreased EFS. TILs will be evaluated as a prognostic or predictive factor (in multivariate and subgroup analyses) when the outcome results are evaluated after prolonged follow up. Furthermore, an updated analysis including the complete planB dataset will be presented. Citation Format: Liedtke C, Gluz O, Heinisch F, Feuerhake F, Kreipe HH, Clemens M, Nuding B, Kraemer S, Reimer T, Svedman C, Shak S, Nitz U, Kates RE, Harbeck N, Christgen M. Association of TILs with clinical parameters, recurrence score, and prognosis in patients with early HER2-negative breast cancer (BC) – A translational analysis of the prospective WSG planB trial. [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 P2-07-01.

Background Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1–3 positive lymph nodes (LNs) only. Patients and methods A total of 2011 BC patients (18–65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. Results Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18–0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). Conclusion EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1–3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. Clinical Trial number ClinicalTrials.gov, NCT02115204.

Background: Routine use of multigene RT-PCR based assays as Recurrence Score (RS) vs. single markers (grade, uPA/PAI-1, HR, HER2, Ki-67) is controversially discussed in early BC. Several definitions of luminal A/B subtypes have been proposed by St. Gallen guidelines and individual researchers (grade 1/2 vs. 3, Ki-67 cut-offs 14 or 20%). Recently, integration of PR>20% was proposed as an immunhistochemical luminal A subtype definition (Ki-67 Methods: planB trial (04/09 to 11/11: n=2,449 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2− BC; n=3197 registered; n=3072 available for central tumor bank). RS was used as selection criterion for chemotherapy (CTx) omission in HR+ BC (if RS Results: RS distribution in 2569 HR+ tumors: 0–11 (18%), 12–25 (60%), >25 (22%) (RS1853%/34%/13%). Luminal A subtype based on Ki-67 cut-off of 20% was included in the luminal A/Ki-67 Luminal A/B based on local/central grade: 79%/21%; 67.9%/32.1%. In 354 pN0-1 patients, CTx was omitted based on low RS (88% compliance). In this group, 62% were high-risk by clinical-pathological criteria. Allocation to luminal A/B subtypes based on local/central grade varied substantially: overall concordance was 72%, but 40% of locally luminal B (HR+/G3) were luminal A (HR+/G1/2) by central and 60% of centrally luminal B were luminal A locally. Moderate correlations were found between RS and central grade (Spearman correlation rs=0.317; p < 0.001), local grade (0.321; p < 0.001) and Ki-67 (rs = 0.374; p < 0.001), particularly due to poor correlations in the RS group Inclusion of PR>20% moderately improved the correlation between luminal subtypes and RS to rs=0.34; p < 0.001. Data on allocation to luminal subtypes by local/central Ki-67 will be presented at the meeting. Conclusions: Our results represent the first prospective correlation of different luminal A/B definitions vs. a guideline mentioned gene signature (RS). High RS usually implies high grade and luminal B classification, the converse is not true. There is substantial heterogeneity in risk assessment by luminal A/B classification and grade in low/intermediate RS groups. Concordance for central/local assessment of grade and luminal A/B status was limited. There is strong need for standardization of molecular subtype's immunhistochemical/clinical definition prior to implementation into daily routine. Clinical significance of these findings will be addressed by further follow up of the WSG-planB trial. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-08.

Background: Despite extensive research, there is still no consensus on optimal predictors for use of taxane-based chemotherapy (cht) in early breast cancer. Some studies have revealed HER2 as a significant predictive marker for efficacy of taxanes and anthracyclines. TIMP-1 and Topo-II are reported to be predictive for anthracycline efficacy. In our previous reports, both Ki-67≥20% and central G3 status emerged as significant predictors for taxane benefit. We have now compared HER2 and Topo-II (as protein expression and gene amplification) and TIMP-1 immunoreactivity as well as factor combinations (HT (HER2/TIMP-1) and 2T (Topo-II/TIMP-1) regarding their predictive value for benefit from taxane-based cht. Methods: The EC-Doc trial randomized 1950 patients with 1–3 positive LN to 6x CEF/CMF vs. 4xEC-4xDoc. Significantly better DFS and OS favoring EC-Doc have been previously reported (Nitz et al., SABCS 2008). Protein expression and gene amplification data as well central histology/grade were available for 772 patients. Survival analysis was performed using Cox proportional hazards and Kaplan-Meier statistics. Analysis of HER2 survival impact status was prospectively planned. Results: The entire and the investigated study populations did not differ regarding baseline characteristics. After median follow up of 64 months, both DFS (5y 90% vs. 80%, p=0.006) and OS (5y 95% vs. 92%, p=0.022) rates significantly favored EC-Doc vs. CEF in this cohort as well. HER2 over-expression (3+ and/or FISH≥2.0) was reported in 158 tumors (20%), Topo-II aberration (deletion or amplification) was reported in 78 (49.4%) HER2+ and in 83 (13.6%) HER2−negative tumors; 496 tumors were classified as TIMP-1 immunoreactive (65.2%). None of these factors were significantly prognostic for EFS in this collective. Regarding DFS, EC-Doc was strongly superior to FEC in HER2+ tumors (HR=0.29, 95%CI: 0.12−0.7, p=0.006) but not in HER2− tumors (p=0.18). In Topo-II aberrated tumors, the benefit of EC-Doc was remarkably strong (HR=0.28, 95% CI: 0.11−0.69, p=0.006), whereas the benefit was not significant in Topo-II normal tumors (p=0.16), which comprise more than ¾ of the total. In contrast, Topo-II protein overexpression (>10%) was not associated with a stronger benefit in either subgroup. The superiority of EC-Doc to FEC was significant in the larger group of TIMP-1 immunoreactive tumors (HR=0.57, p=0.025) but not in TIMP-1 negative tumors (p=0.14), similar behavior was seen in “HT” and “2T” subgroups (significance with HR about 0.5 in the “+” subgroups). In a multivariate model for DFS including age, tumor size, Ki-67, central grade, HR, HER2, TOPO_II aberration, TIMP-1 status, therapy and interactions of all these factors with therapy arm, the only significant therapy interaction was that of (high) Ki-67 (HR=0.76, 95% CI: 0.59−0.98, p=0.03); significant main effects in this model were age, central grade, and Ki-67. Conclusions: These data suggest predictive significance for Topo-II aberration, TIMP immunoreactivity and HER2 over-expression as well as a multivariate predictive significance of high Ki-67 for enhanced benefit of taxane-based cht. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-03.

Background: Anthracycline-taxane based adjuvant chemotherapy (cht) is considered standard in node-positive and high-risk node-negative BC. However, retrospective analyses suggest that in HER2−BC, benefit from anthracyclines may not outweigh acute and long term toxicities. Recurrence Score (RS) identifies patients who are not candidates for cht based on their low relapse risk, as well as minimal, if any, benefit of cht. The WSG Plan B trial investigates anthracycline-free cht in HER2− BC and is the first trial in Europe prospectively incorporating RS for decision making regarding adjuvant cht in both N0 and N+ BC. Methods: Plan B trial randomizes HER2− BC patients with high-risk N0 (at least one risk factor: ≥pT2; negative HR status; G2-3; age ≤35 years old; high uPA/PAI-1) or N+ disease to 6xTC (Docetaxel 75Cyclophosphomide600) vs. 4xEC (Epirubicin90Cyclophosphomide600)-4xDocetaxel100 G-CSF prophylaxis is recommended according to current ASCO guidelines. The statistical design previews n=2.448 randomized to cht; patients with HR+ BC, N0-3 and a RS ≤11 receive endocrine therapy only. Results: From April 2009 to June 2011, 3037 patients have been recruited and 2296 randomized (TC/EC-Doc: 1146/1150; age The most frequent SAEs were: leucopenia, febrile neutropenia (TC/EC-Doc:37 (3.3%)/31 (2.7%), n.s.), infections and heart/vascular events (TC/EC-Doc 29/40, n.s.). In patients ≥65 years old, there is a trend towards more febrile neutropenia (13 vs. 5; p=0.06) in the TC, and more severe mucositis/diarrhea/nausea (3 vs. 15; p=0.007) and heart/vascular events (5 vs. 14; p=0.06) in the EC-Doc arm. There were 5 therapy related deaths (TC 5 (0.4%)/EC-Doc 0, p=0.03); 3 in patients Detailed data on relationship between the protocol specified, RS-guided treatment assignment and toxicity, and use of G-CSF support will be updated for the meeting. Conclusions: The Plan-B trial is one of the largest randomized phase III trials currently evaluating anthracycline-free adjuvant cht in HER2− BC. The cht administered within the study was generally well tolerated, but higher number of treatment-related deaths has been observed within the TC arm. The short term toxicity profile seems be different between both study arms, particularly in patients >65 years old. On the basis of prognosis as determined by RS, cht has been spared after a shared decision process in a substantial group of patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-18-03.

Background: Despite progress in adjuvant breast cancer (BC) treatment, overtreatment due to decisions based on conventional prognostic factors (lymph nodes (LN), grade, tumor size) alone remains an important clinical problem. Recurrence Score®, RS is validated using pre-specified analyses, genes, cutt-offs in several randomized patient collectives as a potent prognostic and predictive marker in HR positive BC. Here, we present the first WSG-Plan B trial preplanned correlation analysis of central grade, nodal status, RS, and luminal A/B subtypes. Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is a randomized Phase-III-trial evaluating anthracyline-free adjuvant chemotherapy (Cht) (6x TC) vs. standard 4xEC-4xDOC in high-risk N0 and N+ HER2-negative BC. In HR+ BC with 0-3 LN, RS is the decision criterion for (>11) or against (≥11) Cht randomization. Tumor blocks are prospectively evaluated by a central pathologist for grade, histology and Ki-67. In HR+ disease, molecular subtypes (luminal A vs. B) are grouped using a Ki-67 cut-off of 13.25% (Cheang et al, JNCI 2009) and 20% (Penault-Llorca et al JCO 2009). Exploratory analysis with Elston-Ellis central grade and Ki-67 based (mitosis measured by Ki-67) grade will be performed. Results: As of June 2010, 1375 patients in 96 centers have been registered and 1067 randomized into Plan B. In 298 patients, RS results and clinical-pathological characteristics were available. In 266 patients complete information on all factors was available (132 N0, 134 N+). RS groups using the pre-specified trial cut-offs of 0-11, 12-25 and 30) were 48%, 38%, 14%. Central grade 1, 2, or 3 was observed in 4%, 50%, and 46% of cases. We observed a modest (Spearman) correlation between central grade and RS (e.g 83.8% of G3 tumors with RS >25, rs=0.331, P25), and guideline-recommended 30 (see table 1).Discussion: For the first time, we demonstrate a modest but significant correlation between centrally assed tumor grade, molecular classes by IHC Ki-67 cutt offs, and RS, particularly in the high RS group. However, our data also indicate that there is substantial discordance between the methods and thus an urgent need for optimzing risk-stratification classifiers. Table 1. Association of RS and molecular subtypes Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-12.

Background: Both the Oncotype DX multi-gene assay and invasion factors uPA/PAI-1 are guideline-recommended (ASCO, AGO) biomarkers for decision support regarding adjuvant chemotherapy in primary breast cancer (BC). Material and Methods: The West German Study Group (WSG) Plan B trial (planned n=2,448) is evaluating anthracyline-free adjuvant chemotherapy (6x TC) vs. standard 4xEC-4xDOC in HER2- negative BC with 0-3 positive lymph nodes, Oncotype DX is used as selection criterion where pts with RS> 11 are randomized to one of the two chemotherapy arms and pts with RS ≥11 treated with hormonal therapy alone. uPA/PAI-1 (both low vs. either/both high), measured by ELISA, is obtained as an optional risk factor. Results: By June 2010, 1064 patients had been randomized in Plan B (96 recruiting centers). In 153 patients (27 centers), uPA and PAI-1 had been measured; for 131 (84 N0, 47 N+) of these, Oncotype DX Recurrence Score® (RS) results were also available. When considered as continuous variables, RS was weakly positively correlated (Spearman's coefficient) with uPA (rs=0.18, p=0.04) and with PAI-1 (rs=0.23, p=0.01). When considered as risk categories/(Table 1), there was a weak concordance between RS and uPA/PAI-1, using either the standard RS cutoff points (18 and 30) or the TAILORx trial cutoff points (11 and 25). Table T: Association between RS and uPA/PAI-1 categories Assignment of high risk was most strongly concordant between uPA/PAI-1 and RS (RS > 25: 22/25 patients had high uPA/PAI-1; RS >30: 14/15 patients had high uPA/PAI-1). This high-risk concordance extends to N0 patients (RS>25: 17/19 N0 pts had high uPA/PAI-1; RS>30: 11/12 pts had high uPA/PAI-1). Discussion: For the first time, risk groups in primary breast cancer according to both Oncotype DX and uPA/PAI-1 have been compared. These preliminary data show that the high RS group seems highly concordant with the prospectively assessed invasion markers uPA/PAI-1. However, within low and intermediate RS, uPA/PAI-1 could still identify a substantial collective at risk; low uPA/PAI-1 could define a clinically relevant low-risk collective within risk groups that would be classified as “intermediate” according to the multigene assay Oncotype DX. Additional recruitment and outcome assessment of the ongoing multicenter WSG Plan B trial will address the clinical significance of these findings. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-05.

12102Background: In triple-negative breast cancer (TNBC), pathological complete response (pCR, ypT0/is/ypN0) is associated with improved prognosis. The randomized prospective WSG-ADAPT TN phase II ...

Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied by massive T cell infiltration, TH1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1's therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.

Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Use of weekly nab- paclitaxel (Nab-Pac) vs. conventional paclitaxel and also addition of carboplatinum(Carbo) to anthracycline-taxane(A/T) containing chemotherapy results in significantly higher pCR rates in TNBC with unclear impact on survival and increased toxicity. The ADAPT study seeks to compare Carbo vs. gemcitabine(Gem) added to nab- paclitaxel as a short 12-week A-free regimen. It also assesses efficacy in early responders vs. non-responders by 3-week proliferation and/or imaging response. Methods: ADAPT TN compares 12-week neoadjuvant regimens: Carbo vs. Gem combined with Nab-Pac and aims to identify early-response markers for pCR (yPN0 and ypT0/is). TNBC patients (centrally confirmed ER/PR Results: 336 patients were enrolled from 47 centers between 06/13-02/15 (n=182 ArmA: Nab-Pac/Gem and n=154 ArmB: Nab-Pac/Carbo). 90% and 95% completed therapy according to protocol respectively (n.s.). Median age was 50y. At baseline: A/B: 73% and 74%% had G3 tumors, median Ki-67 of 70% and 75%; 62.6% and 62.9%% had cT2-4c tumors, pN0 status prior to chemotherapy was confirmed in 50.5% and 50%, respectively. pCR (ypT0/is/ypN0) was A: 28.7% and B: 45.9% (p Nab/Gem arm was associated with significantly higher frequency of dose reductions (20.6% vs. 11.9% (p=0.03), treatment related SAE's (13% vs. 5%, p=0.02), grade 3-4 infections (6.1% vs. 1.3%, p=0.04) and ALAT elevations (11.7 vs. 3.3%, p=0.01) compared to the Nab-Carbo arm. Within the planned interim analysis (n=130: A/B: 69/61), baseline Ki-67 (Nab- Pac/Carbo arm), age>50 years, and low cellularity ( Validation of responder definitions for the whole study will be presented at the meeting. Conclusions: This is the first large randomized study comparing two short 12-week anthracycline- free regimens in unselected TNBC. Our results suggest superior efficacy and excellent toxicity of Nab-Pac/Carbo vs. Gem. Longer A/T-Carbo containing regimens render quite comparable pCR rates, thus overtreatment by 4xEC in unselected TNBC may be present in some patients. Early response criteria seem to differ according to regimen; their assessment may be impaired by substantial tumor necrosis already after the first therapy cycle. Citation Format: Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, Pelz E, Kates RE, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II trial. [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 S6-07.

Das Sachverstandigengutachten, welches von der Bundesregierung zur Versorgung Brustkrebsbetroffener in Auftrag gegeben wurde, zeigt zahlreiche Bereiche der Unter-, Uber- und Fehlversorgung auf. Dies und die im Gesundheitswesen allgegenwartige Kostensteigerung waren die Haupttriebfedern, das Mammakarzinom in die Reihe der "disease-management-fahigen" Erkrankungen aufzunehmen. Um dabei fur die Kostentrager einen Anreiz zu schaffen, wurde eine Bindung an den Risikostrukturausgleich geschaffen. Eckpfeiler der strukturierten Behandlungsprogramme sollen Patientenorientierung, Interdisziplinaritat, leitlinienkonforme Behandlung und Qualitatssicherung sein. In NRW ist jetzt das erste Programm an den Start gegangen, welches als wichtigsten Partner in der Betreuung den DMP-Koordinator (spezifisch geschulter niedergelassener Frauenarzt) und den interdisziplinaren Brustkrebsschwerpunkt benannt hat. Weite Teile insbesondere der Qualitatssicherung und Leitlinienorientierung sind in dem gestartetem Programm noch nicht endgultig ausgestaltet. Eine erste Beurteilung kann fruhestens in 1–2 Jahren erfolgen.