Agreement between molecular subtyping and surrogate subtype classification: a contemporary population-based study of ER-positive/HER2-negative primary breast cancer

Christine Lundgren, Pär-Ola Bendahl, Åke Borg, Anna Ehinger, Cecilia Hegardt, Christer Larsson, Niklas Loman, Martin Malmberg, Helena Olofsson, Lao H Saal, Tobias Sjöblom, Henrik Lindman, Marie Klintman, Jari Häkkinen, Johan Vallon-Christersson, Mårten Fernö, Lisa Rydén, Maria Ekholm, Christine Lundgren, Pär-Ola Bendahl, Åke Borg, Anna Ehinger, Cecilia Hegardt, Christer Larsson, Niklas Loman, Martin Malmberg, Helena Olofsson, Lao H Saal, Tobias Sjöblom, Henrik Lindman, Marie Klintman, Jari Häkkinen, Johan Vallon-Christersson, Mårten Fernö, Lisa Rydén, Maria Ekholm

Abstract

Purpose: Oestrogen receptor-positive (ER+) and human epidermal receptor 2-negative (HER2-) breast cancers are classified as Luminal A or B based on gene expression, but immunohistochemical markers are used for surrogate subtyping. The aims of this study were to examine the agreement between molecular subtyping (MS) and surrogate subtyping and to identify subgroups consisting mainly of Luminal A or B tumours.

Methods: The cohort consisted of 2063 patients diagnosed between 2013-2017, with primary ER+/HER2- breast cancer, analysed by RNA sequencing. Surrogate subtyping was performed according to three algorithms (St. Gallen 2013, Maisonneuve and our proposed Grade-based classification). Agreement (%) and kappa statistics (κ) were used as concordance measures and ROC analysis for luminal distinction. Ki67, progesterone receptor (PR) and histological grade (HG) were further investigated as surrogate markers.

Results: The agreement rates between the MS and St. Gallen 2013, Maisonneuve and Grade-based classifications were 62% (κ = 0.30), 66% (κ = 0.35) and 70% (κ = 0.41), respectively. PR did not contribute to distinguishing Luminal A from B tumours (auROC = 0.56). By classifying HG1-2 tumours as Luminal A-like and HG3 as Luminal B-like, agreement with MS was 80% (κ = 0.46). Moreover, by combining HG and Ki67 status, a large subgroup of patients (51% of the cohort) having > 90% Luminal A tumours could be identified.

Conclusions: Agreement between MS and surrogate classifications was generally poor. However, a post hoc analysis showed that a combination of HG and Ki67 could identify patients very likely to have Luminal A tumours according to MS.

Keywords: Breast cancer; Gene expression; Intrinsic subtype; Molecular subtyping; Surrogate marker.

Conflict of interest statement

Author Anna Ehinger has received remuneration from Roche, Amgen and Novartis. Author Lao H. Saal has received remuneration and has stock ownership in SAGA Diagnostics AB. Author Maria Ekholm has had a consultant/advisory role in Pfizer and Novartis. The other authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Flow chart of the study cohort

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Source: PubMed

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