Abstract 2971: Digital image analysis based IHC4+C assay and prognosis in hormone receptor-positive breast cancer
Authors: Abubakar Mustapha , Pharoah Paul D. , Sherman Mark E. , Garcia-Closas Montserrat , Dowsett Mitch 
Published: August 2018

Abstract
Background
The immunohistochemical (IHC) 4 + clinical treatment score (C) i.e. IHC4+C assay combines IHC assessment of four routinely measured markers in the clinical setting, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and KI67, with other clinical parameters for aiding decision-making on adjuvant chemotherapy in hormone positive (HR+) breast cancer. It is low cost, widely available and has been shown to provide similar prognostic information to the 21-gene (Oncotype DX) test. Clinical use of IHC4+C is limited by the need for standardized scoring of the IHC markers. Here, we examine the prognostic value of a digital image analysis (DIA) based IHC4+C assay in two study populations and compare this with pathologists' visual assay in a subset of patients. We also evaluated its potential clinical relevance in relation to the Nottingham prognostic index [NPI; i.e. low (&lt;3.4), intermediate (3.4-5.4) and high (&gt;5.4)] and IHC defined breast cancer subtypes (i.e. luminal A-like and B-like).
Methods
Using DIA data on ER, PR, HER2 and KI67, in addition to clinicopathological characteristics of tumors, we computed DIA based IHC4+C (i.e. DIAIHC4+C) assay for 2,034 women from study populations in Poland (PBCS) and the United Kingdom (SEARCH). A total of 246 deaths occurred over a median follow-up period of 6.7 years. A relevant threshold was determined using quartile analysis and the relationship between dichotomous categories (&gt;75th vs ≤ 75th percentile) of DIAIHC4+C and 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and in Cox proportional hazard regression models, overall and stratified by study, NPI and subtype.
Results
DIAIHC4+C score was associated with worse 10-year BCSS overall [HR (95% CI) &gt;75th vs ≤ 75th percentile = 2.92 (1.77, 4.82); p-value &lt;0.0001] and in both the PBCS [3.48 (1.40, 8.65); p-value = 0.007] and SEARCH [3.87 (2.24, 6.68); p-value &lt;0.0001] study populations. DIAIHC4+C was associated with significantly worse survival outcomes in women with intermediate NPI [1.94 (1.31, 2.88); p-value = 0.001] and luminal A-like subtype of HR+ tumors [5.37 (3.50, 8.26); p-value &lt;0.0001]. DIA and visual IHC4+C results were highly correlated (r = 0.95) and survival associations and model fit parameters were similar for DIA [3.82 (2.08, 7.00); p-value &lt; 0.0001; AIC = 472.3] and visual [4.73 (2.55, 8.76); p-value &lt; 0.0001; AIC = 466.1] IHC4+C scores amongst 444 patients with data from both sources.
Conclusion
These findings are in support of the prognostic value of DIAIHC4+C assay in HR+ breast cancer and demonstrate its potential clinical relevance as an adjunct to the NPI. Given the advantages of being high-throughput and highly reproducible, DIA based methods could find use in the standardization of the analytical processes for the IHC4+C assay.
Citation Format: Mustapha Abubakar, Paul D. Pharoah, Mark E. Sherman, Montserrat Garcia-Closas, Mitch Dowsett. Digital image analysis based IHC4+C assay and prognosis in hormone receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2971.