ESR1, PGR, ERBB2, and MKi67 mRNA expression in postmenopausal women with hormone receptor-positive early breast cancer: results from ABCSG Trial 6.

Background: The purpose of this study was to assess the concordance of real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) detection of ESR1, PGR, ERBB2, and MKi67 messenger RNA (mRNA) in breast cancer tissues with central immunohistochemistry (IHC) in women treated within the prospective, randomized Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6.
Patients and Methods: We evaluated ESR1, PGR, ERBB2, and MKi67 mRNA expression by Xpert® Breast Cancer STRAT4 (enables cartridge-based RT-qPCR detection of mRNA in formalin-fixed paraffin-embedded tissues) and estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 protein expression by IHC [in situ hybridization (ISH) for HER2 IHC 2+] in 1115 surgical formalin-fixed paraffin-embedded specimens from patients of ABCSG Trial 6. Overall percent agreement (concordance), positive percent agreement (sensitivity), and negative percent agreement (specificity) between STRAT4 and IHC were determined for each marker. The primary objective of the study was concordance between STRAT4 mRNA measurements of ESR1, PGR, ERBB2, and MKi67 with central reference laboratory IHC (and ISH for HER2 IHC 2+ cases). Time to distant recurrence was analyzed by Cox models.
Results: All performance targets for ER, PR, and Ki67 were met. For HER2, the negative percent agreement target but not the positive percent agreement target was met. Concordance between STRAT4 and IHC was 98.9% for ER, 89.9% for PR, 98.2% for HER2, and 84.8% for Ki67 (excluding intermediate IHC 10%-20% staining). In univariable and multivariable Cox regression analyses, all four biomarkers tested by either STRAT4 RT-qPCR or by central IHC (ISH) had a comparable time to distant recurrence indicating similar prognostic value.
Conclusions: With the exception of HER2, we demonstrate high concordance between centrally assessed IHC and mRNA measurements of ER, PR, and Ki67 as well as a high correlation of the two methods with clinical outcome. Thus, mRNA-based assessment by STRAT4 is a promising new tool for diagnostic and therapeutic decisions in breast cancer.
Competing Interests: Disclosure MF has received honoraria from AstraZeneca, Bayer, Biomedica, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Myriad Genetics Inc., Pfizer, and Roche. FF reports travel grant and personal fee from AstraZeneca, Novartis, Roche, Eli Lilly, and Springer outside the submitted work. CFS has received grants, personal fees, and non-financial support from Amgen, AstraZeneca, Novartis, Pfizer, Tesaro, and Roche. ZB-H has received travel funding from Roche. RG received honoraria, travel funding, and research funding from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Merck, Merck Sharp & Dohme, Novartis, Takeda, Sandoz, and Roche. SFL has received personal fees from Roche, AstraZeneca, Novartis, and Biogena outside the submitted work. SH has received travel funding and honoraria from Accord Healthcare GmbH, AstraZeneca, Celgene, Eli Lilly, Myriad, Novartis, Pfizer, and Roche outside the submitted work. WH has received honoraria from Roche outside the submitted work. NCW, XL, JW, and MB are employed by Cepheid, an operating company of Danaher, and have stock in Danaher. DH is employed at ABCSG and ABCSG has received funding for the study from Cepheid. MG reports personal fees/travel support from Amgen, Daiichi Sankyo, AstraZeneca, Eli Lilly, LifeBrain, Nanostring, Novartis, TLC Biopharmaceuticals, all outside the submitted work; an immediate family member is employed by Sandoz. No other disclosures are reported. PD has received funding from Amgen, AstraZeneca, Pfizer, Roche and Merck via Hirslanden Klinik St. Anna and grants form Cepheid/Danaher, Agendia, and Myriad via ABCSG. The remaining authors have declared no conflicts of interest.
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