Abstract P5-02-02: Central testing of ER, PR, HER2, and Ki67, routinely analyzed at 27 pathology departments in Sweden – Potential consequences for the choice of adjuvant therapy
Authors: Ekholm Maria , Grabau Dorthe , Bendahl Per-Ola , Elmberger Göran , Olsson Hans , Russo Leila , Viale Guiseppe , Fernö Mårten 
Published: May 2015

Abstract
Background
Immunohistochemical (IHC) techniques are still gold standard for measurement of estrogen receptors (ER), progesterone receptors (PR), the proliferation marker Ki67, and human epidermal growth factor receptor 2 (HER2) (confirmation with in situ hybridization for 2+) in routine breast cancer pathology. These biomarkers are also included in the St Gallen 2013 four-marker panel, as a surrogate for the intrinsic subtype classification; Luminal A-like, Luminal B-like (HER2-), Luminal B-like (HER2+), HER2+ (non-luminal), and Triple negative. Correct analyses are of outmost importance since these biomarkers are underlying treatment decisions in breast cancer. It is mandatory for departments performing breast cancer pathology to participate in quality assurance programs.
Aims
In 2013, SweQA-breast cancer (Swedish Quality Assurance) performed a study to investigate the agreement of ER-, PR-, Ki67-, and HER2-scoring between pathology departments in Sweden and a central reference laboratory (European Institute of Oncology (EIO), Milan, Italy). To explore the clinical consequences, the aim was also to investigate to what extent the central testing would potentially have altered the adjuvant medical therapy.
Methods
Twenty-seven of the 31 pathology departments in Sweden participated by collecting the first breast carcinoma diagnosed after the 15th each month during 2012, except for July and December (n=270). Paraffin embedded tumor tissue were collected and sent to EIO, where new sections, stainings, and evaluations were performed. These results were compared with the results from the routine analyzes performed in Sweden. Expression scores of ER, PR, Ki67, and HER2 were dichotomized according to predefined thresholds from the St Gallen consensus statement of 2013 (Goldhirsch et al. Ann Oncol 24(9);2206-13;2013).
Results
The pairwise agreement figures for ER, PR, and Ki67 were; 99% (kappa-value (κ)=0.95), 95% (κ=0.84), and 85% (κ=0.70) respectively. Eight of the PR discrepant cases were locally positive but centrally negative, whereas six showed the opposite pattern. In 34 of the 39 discrepant cases for Ki67, one or both assessments were located near cut-off (15-25%). When categorizing HER2 as 0/1+ vs. 2+/3+, agreement was 86% (κ=0.65). The HER2-IHC 2+/3+ cases in Sweden were further analyzed with in situ hybridization as part of clinical routine, and when these results were used to obtain the final HER2 status, only 1 discrepant case of 265 evaluable cases was observed. When using the St Gallen 2013 surrogate definition for the five intrinsic subtypes, the overall pairwise agreement between Sweden and Italy, for all tumors with complete data (n=256), was 86% (κ=0.78).
Conclusions
The agreement was very good (κ&gt;0.80) or good (κ 0.61-0.80) for all four biomarkers (ER, PR, Ki67, and HER2). Almost 90% of the discrepant cases for Ki67 were explained by values near cut-off. When strictly applying the St Gallen 2013 surrogate definition of the five intrinsic subtypes, without regard to TNM stage, the results of the central testing would potentially have altered the medical adjuvant treatment for 37 of the 256 patients (14%). For 28 of these 37 patients, the discordance was explained by Ki67.
Citation Format: Maria Ekholm, Dorthe Grabau, Per-Ola Bendahl, Göran Elmberger, Hans Olsson, Leila Russo, Guiseppe Viale, Mårten Fernö. Central testing of ER, PR, HER2, and Ki67, routinely analyzed at 27 pathology departments in Sweden – Potential consequences for the choice of adjuvant therapy [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 P5-02-02.