Abstract P4-11-08: Pathological assessment of discordant cases for molecular (BluePrint and MammaPrint) vs clinical subtypes for breast cancer, among 6,694 patients from the EORTC 10041/BIG 3-04 (MINDACT) trial
Authors: Viale Giuseppe , Slaets Leen , de Snoo Femke A , Bogaerts Jan , van 't Veer Laura J , Rutgers Emiel J , Piccart-Gebhart Martine J , van den Akker Jeroen , Stork-Sloots Lisette , Russo Leila , Dell'Orto Patrizia , Cardoso Fatima 
Published: May 2015

Abstract
Background
Biology has become the main driver of breast cancer (BC) therapy. Biological subtypes have been recommended as a guide for treatment selection. Molecularly identified subtypes can be determined by gene expression profiling. Alternatively, pathology can be used to define surrogates of these subtypes. These methodologies are not always concordant, which can lead to different systemic therapies. The purpose of this preplanned translational research is to investigate the concordance between molecular based BluePrint and MammaPrint breast cancer subtypes and pathological surrogates (based on ER, PgR, HER2 & Ki67) and to characterize the discordant cases.
Methods
MINDACT is an international, prospective, randomized, phase III trial investigating the clinical utility of MammaPrint in selecting patients with early BC for adjuvant chemotherapy (CT), which enrolled 6,694 patients. Molecular subtyping data were obtained by MammaPrint and BluePrint (Agendia, Amsterdam, the Netherlands) on frozen samples (n=6,694) classifying patients in the following subtypes: Luminal A (Luminal-type/MammaPrint Low Risk); Luminal B (Luminal-type/MammaPrint High Risk); HER2-type; and Basal-type. ER, PgR, HER2 and Ki67 protein status were centrally assessed on FFPE blocks by IHC and/or FISH in the European Institute of Oncology, Milan, Italy (n=5,740; 86%). Patients were also classified according to the St. 2013 Gallen recommendations [Goldhirsch et al. 2013], which recognizes an additional category (Luminal B-like HER2+).
Results
Ki67 is often used as biomarker to distinguish Luminal A from Luminal B subgroups. The concordance between MammaPrint and centrally assessed Ki67 in Luminal-type patients is 60%, with a κ score of 0.26 (95% CI 0.24–0.28) indicating that Ki67 and MammaPrint cannot reliably substitute for each other. When using a cut-point of 20% instead of 14% the concordance increased to 78%, with a κ score of 0.44 (95% CI 0.41–0.47).
There is a relatively large group of clinical HER2+ cases that are BluePrint Luminal-type (208 out of 541; 38%) indicating that tumor expression of the Luminal profile is dominant compared with expression of the HER2 profile.
These patients have high IHC ER results and all except for 1 fall into the group that St Gallen separately defines as Luminal B-like HER2-positive.
These patients may have lower response to trastuzumab [von Minckwitz et al. JCO 2012].
98 out of 622 BluePrint Basal-type patients are clinical Luminal HER2-. 2/3 of these patients have low centrally assessed IHC PR expression and 1/3 have low centrally assessed ER expression (≥1% and &lt;10%).
Conclusions
Marked differences are observed between BluePrint and MammaPrint (microarray based) breast cancer subtypes and centrally re-assessed pathological surrogates (based on ER, PR, HER2 & Ki67). The greatest discordance is seen in the sub-stratification of Luminal patients, and in the HR+/HER2+ patients. The observed subtype discrepancies may have an important impact on treatment decision making.
Citation Format: Giuseppe Viale, Leen Slaets, Femke A de Snoo, Jan Bogaerts, Laura J van 't Veer, Emiel J Rutgers, Martine J Piccart-Gebhart, Jeroen van den Akker, Lisette Stork-Sloots, Leila Russo, Patrizia Dell'Orto, Fatima Cardoso, On Behalf of the TRANSBIG Consortium & the MINDACT Investigators. Pathological assessment of discordant cases for molecular (BluePrint and MammaPrint) vs clinical subtypes for breast cancer, among 6,694 patients from the EORTC 10041/BIG 3-04 (MINDACT) trial [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 P4-11-08.