Abstract P2-10-08: Prospective comparison of Recurrence Score and different definitions of luminal subtypes by central pathology assessment of single markers in early breast cancer: results from the phase III WSG-planB Trial
Authors: Gluz O , Kreipe HH , Kates RE , Christgen M , Liedtke C , Shak S , Clemens M , Salem M , Liedtke B , Aktas B , Markmann S , Uleer C , Augustin D , Thomssen C , Nitz U , Harbeck N 
Published: August 2014

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&gt;20% was proposed as an immunhistochemical luminal A subtype definition (Ki-67&lt;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&lt;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%), &gt;25 (22%) (RS1853%/34%/13%).

Luminal A subtype based on Ki-67 cut-off of &lt;14%/&lt;20%: 50.4%/68.8%. If PR&gt;20% was included in the luminal A/Ki-67&lt;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 &lt; 0.001), local grade (0.321; p &lt; 0.001) and Ki-67 (rs = 0.374; p &lt; 0.001), particularly due to poor correlations in the RS group &lt;26. Correlations between groups were: RS12 and luminal A/B Ki-6714 (rs = 0.26; p &lt; 0.001).

Inclusion of PR&gt;20% moderately improved the correlation between luminal subtypes and RS to rs=0.34; p &lt; 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.