Use of proteomic strategies to identify a risk classifier that estimates probability of distant recurrence in early-stage hormone receptor (HR)-positive breast cancer is relevant to physiological cellular function and therefore to intrinsic tumor biology. We used a 298-sample retrospective training set to develop an immunohistochemistry-based novel risk classifier called CanAssist-Breast (CAB) which combines 5 prognostically relevant biomarkers and 3 clinico-pathological parameters to arrive at probability of distant recurrence within 5 years from diagnosis. Five selected biomarkers, namely, CD44, ABCC4, ABCC11, N-cadherin, and pan-cadherin, were chosen based on their role in tumor metastasis. The chosen biomarkers represent the hallmarks of cancer and are distinct from other proliferation and gene expression–based prognostic signatures. The 3 clinico-pathological parameters integrated into the machine learning–based CAB algorithm are tumor size, tumor grade, and node status. These features are used to calculate a “CAB risk score” that classifies patients into low- or high-risk groups and predicts probability of distant recurrence in 5 years. Independent clinical validation of CAB in a retrospective study comprising 196 patients indicated that distant metastasis-free survival (DMFS) was significantly different in the 2 risk groups. The difference in DMFS between the low- and high-risk categories was 19% in the validation cohort (P = .0002). In multivariate analysis, CAB risk score was the most significant independent predictor of distant recurrence with a hazard ratio of 4.3 (P = .0003). CanAssist-Breast is a precise and unique machine learning–based proteomic risk-classifier that can assist in risk stratification of patients with early-stage HR+ breast cancer.
CanAssist‐Breast (CAB) is an immunohistochemistry (IHC)‐based prognostic test for early‐stage Hormone Receptor (HR+)‐positive breast cancer patients. CAB uses a Support Vector Machine (SVM) trained algorithm which utilizes expression levels of five biomarkers (CD44, ABCC4, ABCC11, N‐Cadherin, and Pan‐Cadherin) and three clinical parameters such as tumor size, grade, and node status as inputs to generate a risk score and categorizes patients as low‐ or high‐risk for distant recurrence within 5 years of diagnosis. In this study, we present clinical validation of CAB. CAB was validated using a retrospective cohort of 857 patients. All patients were treated either with endocrine therapy or chemoendocrine therapy. Risk categorization by CAB was analyzed by calculating Distant Metastasis‐Free Survival (DMFS) and recurrence rates using Kaplan‐Meier survival curves. Multivariate analysis was performed to calculate Hazard ratios (HR) for CAB high‐risk vs low‐risk patients. The results showed that Distant Metastasis‐Free Survival (DMFS) was significantly different (P‐0.002) between low‐ (DMFS: 95%) and high‐risk (DMFS: 80%) categories in the endocrine therapy treated alone subgroup (n = 195) as well as in the total cohort (n = 857, low‐risk DMFS: 95%, high‐risk DMFS: 84%, P < 0.0001). In addition, the segregation of the risk categories was significant (P = 0.0005) in node‐positive patients, with a difference in DMFS of 12%. In multivariate analysis, CAB risk score was the most significant predictor of distant recurrence with hazard ratio of 3.2048 (P < 0.0001). CAB stratified patients into discrete risk categories with high statistical significance compared to Ki‐67 and IHC4 score‐based stratification. CAB stratified a higher percentage of the cohort (82%) as low‐risk than IHC4 score (41.6%) and could re‐stratify >74% of high Ki‐67 and IHC4 score intermediate‐risk zone patients into low‐risk category. Overall the data suggest that CAB can effectively predict risk of distant recurrence with clear dichotomous high‐ or low‐risk categorization.
BackgroundCanAssist-Breast is an immunohistochemistry based test that predicts risk of distant recurrence in early-stage hormone receptor positive breast cancer patients within first five years of diagnosis. Immunohistochemistry gradings for 5 biomarkers (CD44, ABCC4, ABCC11, N-Cadherin and pan-Cadherins) and 3 clinical parameters (tumor size, tumor grade and node status) of 298 patient cohort were used to develop a machine learning based statistical algorithm. The algorithm generates a risk score based on which patients are stratified into two groups, low- or high-risk for recurrence. The aim of the current study is to demonstrate the analytical performance with respect to repeatability and reproducibility of CanAssist-Breast.MethodsAll potential sources of variation in CanAssist-Breast testing involving operator, run and observer that could affect the immunohistochemistry performance were tested using appropriate statistical analysis methods for each of the CanAssist-Breast biomarkers using a total 309 samples. The cumulative effect of these variations in the immunohistochemistry gradings on the generation of CanAssist-Breast risk score and risk category were also evaluated. Intra-class Correlation Coefficient, Bland Altman plots and pair-wise agreement were performed to establish concordance on IHC gradings, risk score and risk categorization respectively.ResultsCanAssist-Breast test exhibited high levels of concordance on immunohistochemistry gradings for all biomarkers with Intra-class Correlation Coefficient of ≥0.75 across all reproducibility and repeatability experiments. Bland-Altman plots demonstrated that agreement on risk scores between the comparators was within acceptable limits. We also observed > 90% agreement on risk categorization (low- or high-risk) across all variables tested.ConclusionsThe extensive analytical validation data for the CanAssist-Breast test, evaluating immunohistochemistry performance, risk score generation and risk categorization showed excellent agreement across variables, demonstrating that the test is robust.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5443-5) contains supplementary material, which is available to authorized users.
Aims: Assessment of 'risk of recurrence' in ER+ breast cancer patients based on clinical parameters and existing hormone receptor signaling pathway and/or proliferation based biomarkers is insufficient, leading to treatment of majority of patients with chemotherapy. First generation risk identification tests like OncotypeDx and Mammaprint are not impactful in India and SE Asia as are largely prognostic with limited chemotherapy-predictivity and are prohibitively expensive. A cost-effective 'predictive' test which will accurately estimate the 'risk of recurrence' for a 'broader' (node - & +) set of breast cancer patients in low resource settings is urgently required. Materials and Methods: Using a retrospective training cohort of 300 node– and node+ patients, we developed 'CanAssist-Breast'- a Morphometric Immunohistochemistry based test comprising 5 biomarkers plus three clinical parameters (Tumor size, grade and node status) to arrive at 'CanAssist-Breast Score'. The risk stratification model was developed using cutting edge support vector based machine learning technology. CanAssist-Breast Score stratifies patients into an all actionable 'low or high' risk for recurrence, with no intermediate zone. CanAssist-Breast biomarkers include cancer stem cell markers, Cadherins, and ATP transporter proteins - all critical players in the various steps of chemotherapy resistance leading to metastasis. Results: We validated CanAssist-Breast in accordance with EGAPP recommendations which require that prognostic tests be validated both analytically and clinically prior to being utilized in patients. Analytical validation experiments were performed to assess 'variation' in the outcome prediction due to critical IHC variables. We tested inter-pathologists, sample, operator and laboratory site variation and found high concordance in the outcome predictions across all variables, confirming the robustness and reproducibility of the test. Extended clinical validation on 1000+ pre and post-menopausal cases shows NPV of 95%. The majority of patients in 'low risk' had Stage 2, Grade 2/3 disease over Stage 1, Grade 1 disease, demonstrating that CanAssist-Breast reclassifies patients who would be considered high risk clinically. In a head-to-head pilot study of 100 patients with Oncotype Dx, CanAssist-Breast test had about 80% concordance with Oncotype in the 'low risk' category. Importantly, CanAssist-Breast correctly stratified few recurred cases as 'high risk' which were called 'low risk' by Oncotype Dx and thus were not treated with chemotherapy. Conclusion: In conclusion, we have developed a robust, accurate and low-cost prognostic test to predict risk of recurrence and enable optimal treatment planning in patients with early stage Breast Cancer. Citation Format: SP S, Bakre MM, Ramkumar C, Basavaraj C, Attuluri A, Madhav L, Prakash C, Naidu N, Malpani S. Development and validation of a broad-based second generation multi marker “Morphometric IHC” test for optimal treatment planning of stage 1 and 2 breast cancer patients in low resource settings [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-08-10.
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