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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.

Purpose: The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal early breast cancer. Methods: 452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires. Results: Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in “discordant” groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients’ State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients. Conclusions: MammaPrint and BluePrint test results strongly impacted physicians’ therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.

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 Prosigna's 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 oncologists' 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) physicians' 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) patients' decisional conflict status, anxiety levels, and functional status before/after Prosigna's 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.

Purpose: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Purpose: To evaluate the efficacy and safety of epirubicin/cyclophosphamide followed by paclitaxel/trastuzumab as neoadjuvant treatment in patients with HER2-overexpressing primary breast cancer (BC). Patients and Methods: Patients with HER2-overexpressing primary BC (≥2cm or inflammatory BC) received preoperative 4 cycles epirubicin/cyclophosphamide (90/600 mg/m2), q3w) followed by 4 cycles paclitaxel 175 mg/m2 q3w with trastuzumab 6 mg/kg body weight q3w (8 mg/kg as loading dose) followed by surgery. Trastuzumab was continued after surgery until completion of 12 months treatment. The primary endpoint was pathological complete response (pCR) defined as no invasive tumor in the breast and axillary lymph nodes. Results: Two hundred seventeen patients were enrolled. 39% achieved a pCR. Breast conserving surgery was possible in 138/217 (64%) of the patients. Median follow-up was 41 months and 3-year disease-free survival (DFS) was 88% in patients with pCR compared to 73% in patients without pCR (p=0.01). Three year overall survival (OS) was 96% in patients with pCR compared to 86% without pCR (p=0.025). In multivariate analysis pCR remained a significant prognostic factor for DFS and OS (DFS hazard ratio (HR) 2.5 [95% CI 1.2-5.1] p=0.013; OS HR 4.9 [95% CI 1.4-17.4] p=0.012). A cardiac event was reported in 8/217 (3.7%) patients; 6 had an LVEF decrease and two developed 2 (0.9%) clinical congestive heart failure. Conclusion: The neoadjuvant combination of trastuzumab and chemotherapy results in a high chance for a pCR. However, those patients without a pCR have an increased risk for relapse and death and are therefore candidates for further improvement of anti-HER2 directed therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-03.

Purpose: The WSG BCIST study was designed to assess the influence of Prosigna results, on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with ER-positive, HER2-negative, lymph-node negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in the WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay results concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N=198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.