PURPOSE:The West German Study Group PlanB trial evaluated an anthracycline-free chemotherapy standard (six cycles of docetaxel and cyclophosphamide [TC]) in the routine treatment of human epidermal growth factor receptor 2-negative early breast cancer (EBC).PATIENTS AND METHODS:Patients with pT1 to pT4c, all pN+, and pN0/high-risk EBC were eligible. High-risk pN0 was defined by one or more of the following: pT greater than 2, grade 2 to 3, high urokinase-type plasminogen activator/plasminogen activator inhibitor-1, hormone receptor (HR) negativity, and less than 35 years of age. After an early amendment, all HR-positive tumors underwent recurrence score (RS) testing, with chemotherapy omission recommended in RS less than or equal to 11 pN0 to pN1 disease. Patients were randomly assigned to four cycles of epirubicin (E)90/cyclophoshamide (C)600 followed by four cycles of docetaxel (T)100 or six cycles of T75C600 (administered once every 3 weeks). The primary end point was disease-free survival (DFS); secondary end points were overall survival (OS) and safety. The protocol specified P = .05 for a noninferiority margin of 4.4% for all patients combined.RESULTS:Of the 3,198 registered patients, 348 (RS ≤ 11) omitted chemotherapy, and 401 were not randomly assigned. The intention-to-treat population included 2,449 patients (1,227 EC-T v 1,222 TC: postmenopausal, 62.2% v 60.8%; pN0, 58.2% v 59.5%; pT1, 57.6% v 52.3%; HR positive, 81.4% v 82.2%; RS greater than 25 [in HR-positive patients], 26.2% v 27.5%). Within the safety population (1,167 v 1,178 patients), 87.5% v 93.0% completed therapy. After a 60-month median follow-up, 5-year outcomes were similar in the EC-T and TC arms (DFS, 89.6% [95% CI, 87.9% to 91.5%] v 89.9% [95% CI, 88.1% to 91.8%]; OS, 94.5% [95% CI, 93.1% to 95.9%] v 94.7% [95% CI, 93.3% to 96.1%]). The DFS difference was within the noninferiority margin of the original trial design. Five treatment-related deaths were reported for TC (one for EC-T), despite a trend toward more-severe adverse events in the latter. Interaction analysis revealed no predictive trends with respect to key factors, including triple-negative, luminal A/B-like, pN, age, and RS status.CONCLUSION:In the West German Study Group PlanB trial, 5-year outcomes for TC and EC-T were equally excellent. Six cycles of TC is an effective/safe option in human epidermal growth factor receptor 2-negative EBC with pN0 high genomic risk or pN1 EBC with genomically intermediate- to high-risk disease.

Hintergrund: FN und Infektionen sind Hauptursache höhergradiger Morbidität/Mortalität in der adjuvanten Therapie des Mammakarzinoms. Für TC liegen heterogene Daten zur Inzidenz der FN vor: in 3,3 – 6,6% mit G-CSF und bis zu 50% ohne G-CSF Prophylaxe. Der Stellenwert der G-CSF-Primärprophylaxe (PP) ist daher unsicher.

Abstract 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<14%). Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and the first prospective comparison of central and local pathology IHC/FISH assessment, RT-PCR for single markers, impact of central/local grade regarding allocation of patients to luminal A/B subtypes. 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<11 in pN0/pN1). Risk assessment by grade, HR, HER2 (IHC/FISH), Ki-67 was evaluated locally and centrally by an independent trial pathologist in all tumors. Clinical risk was estimated using AdjuvantOnline 8.0 (cut-off of 88% of breast cancer specific survival after 10 years without therapy in HR+ disease). 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 <14%/<20%: 50.4%/68.8%. If PR>20% was included in the luminal A/Ki-67<14% definition: 37.6%. 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 <26. Correlations between groups were: RS12 and luminal A/B Ki-6714 (rs = 0.26; p < 0.001). 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.

ABSTRACT Background St. Gallen Consensus recommends use of Ki-67 and/or grade for definition of luminal A/B for indication of adj. chemotherapy (cht) in HR-pos. disease. Multi-gene based assays e.g. Recurrence Score® (RS) are used for decision support regarding adjuvant cht. Final WSG-PlanB trial correlation analysis of risk assessment tools focussing on correlation between central and local pathology assessment and RS is presented. Methods PlanB trial: 6xTC vs. 4xEC-4xDOC, locally HER2-negative BC; n = 2,448 for cht. RS was used as selection criterion for cht vs. endocrine therapy alone in HR + BC (if RS Results 3196 patients recruited, 2448 randomized. RS available in 2551 patients with HR+ tumors. RS distributed: 0-11 (18%), 12-25 (60%), >25 (22%). In 354 patients, cht was omitted based on low RS. Central grade was available for 3038 samples, IHC results are currently available in 1476 cases. Moderate significant correlations were found between RS and both central grade (Spearman’s coefficient rs = .313; p Discussion First prospective data show that high-risk status according to RS is predictive of high risk by uPA/PAI-1, high grade by central pathology, and luminal B subtype by Ki-67. There is substantial heterogeneity in risk assessment in the low and intermediate risk RS groups, where there are still patients considered high-risk according to uPA/PAI-1, Ki-67 or central grade. Follow-up of the WSG-Plan B trial will clarify the significance of these findings regarding patient outcomes. Disclosure S. Shak and C. Svedman: Employee of Genomic Health, Inc. All other authors have declared no conflicts of interest.

Der Recurrence Score (Oncotype DX)® (RS) und die Invasionsfaktoren uPA und PAI-1 sind in den ASCO und AGO-Leitlinien Entscheidungskriterien für den Einsatz der adjuvanten Chemotherapie beim frühen Mammakarzinom. Vorgestellt werden prospektive Daten zur Korrelation von RS, uPA/PAI-1 und der molekularen Subtypen aus der Plan B Studie der WSG.

Die WSG Plan-B Studie vergleicht den Standard EC-Doc mit einem anthracyclinfreien taxanhaltigen Schema (TC) bei Patientinnen mit HER2 negativem Mammacarcinom (MC). Plan-B integriert erstmals den 21-Gen Recurrence Score (RS) Oncotype DX neben Grading, molekularem Subtyp, Ki-67 und uPA/PAI-1 zur entscheidenden Risikostratifizierung bei hormonrezeptorpositivem MC mit bis zu 3 positiven Lymphknoten. Plan-B untersucht die Anwendung des RS im klinischen Alltag und den Nutzen von Gen- bzw. proteinbasierter sowie histopathologischer Risikoevaluation zur Vermeidung von Übertherapien.

Recurrence Score (Oncotype DX®) (RS) und Invasionsfaktoren uPA und PAI-1 sind Entscheidungskriterien bei der adjuvanten Chemotherapie. Vorgestellt werden prospektive Daten zur Korrelation von RS, uPA/PAI-1 und den molekularen Subtypen im Rahmen einer Interimanalyse der laufenden Plan-B Studie.

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, r s =0.331, P s =0.34, P s =0.438, P 25), 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.

Einführung: Die Indikationsstellung zur adjuvanten Chemotherapie auf dem Boden der konventionellen Prognose- und Prädiktionsfaktoren ist suboptimal und führt regelhaft zu Über- und Unterbehandlung.

TPS106^ Background: Anthracycline- and taxane-based adjuvant chemotherapy (CHT) is standard of care in N+ breast cancer (BC) and shown to be the most effective regimen in N- BC, but overtreatment remains a major problem in both groups. Although a retrospective meta-analysis suggested highest benefit of anthracyclines (vs. CMF) in HER2+ BC, patient groups with HER2- BC deriving anthracycline benefit still need to be defined prospectively. Modern gene signatures identify a substantial number of patients at low risk of recurrence currently misclassified by conventional prognostic factors. The WSG Plan B trial compares an anthracycline-containing CHT regimen (ECx4-Docx4), with an anthracycline-free taxane-based regimen (TCx6) in patients with HER2- BC. In order to assess whether molecular-based risk assessment may prevent overtreatment, Plan B incorporates the 21-Gene Recurrence Score (RS) as mandatory risk stratification in hormone-receptor (HR)+ patients with 0-3 involved lymph nodes. Recent data suggest that patients with low RS do not derive significant benefit from adjuvant CHT regardless of nodal status. Methods: Patients aged 18 to 75 years with high-risk primary BC are eligible. High-risk criteria comprise N+ or tumor size >2 cm, grade 2-3, age <35 years, high uPA/PAI-1 or HR- in N0 patients. A total of 2,448 patients are planned to be randomized to receive either 4 × epirubicin90/cyclophosphamide600 q3w followed by 4 × docetaxel100 q3w or 6 × Docetaxel75cyclophosphamide600 q3w. Importantly, patients with 0-3 positive lymph nodes and low RS (<11) will be spared CHT but receive endocrine therapy alone. Central pathology and evaluation of histology, grade, expression of KI-67, HR, HER2 and 2T Score (Topo-IIa/TIMP-1) will be performed prospectively. Furthermore, blood samples for pharmacogenomic and circulating tumor cells analyses will be obtained prior to randomization. The primary study endpoint is event-free survival. Secondary endpoints comprise overall survival, toxicity, quality of life, and economical endpoints as well as translational research. Between 03/2009 and 01/2010, 730 patients have been registered. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.