Validation of the RSClin risk calculator in the National Cancer Data Base

Abstract

Background: Guidelines recommend the use of genomic assays such as OncotypeDx to aid in decisions regarding the use of chemotherapy for hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. The RSClin prognostic tool integrates OncotypeDx and clinicopathologic features to predict distant recurrence and chemotherapy benefit, but further validation is needed before broad clinical adoption.

Methods: This study included patients from the National Cancer Data Base (NCDB) who were diagnosed with stage I-III HR+/HER2- breast cancer from 2010 to 2020 and received adjuvant endocrine therapy with or without chemotherapy. RSClin-predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3%-5%), and high (>5%). Cox models were used to model mortality adjusted for age, comorbidity index, insurance, and race/ethnicity.

Results: A total of 285,441 patients were identified for inclusion from the NCDB, with an average age of 60 years and a median follow-up of 58 months. Chemotherapy was associated with improved overall survival only for those predicted to have intermediate (adjusted hazard ratio [aHR], 0.68; 95% confidence interval [CI], 0.60-0.79) and high benefit per RSClin (aHR, 0.66; 95% CI, 0.61-0.72). Consistent benefit was seen in the subset with a low OncotypeDx score (<26) and intermediate (aHR, 0.66; 95% CI, 0.53-0.82) or high (aHR, 0.71; 95% CI, 0.58-0.86) RSClin-predicted benefit. No survival benefit with chemotherapy was seen in patients with a high OncotypeDx score (≥26) and low benefit per RSClin (aHR, 1.70; 95% CI, 0.41-6.99).

Conclusions: RSClin may identify high-risk patients who benefit from treatment intensification more accurately than OncotypeDx, and further prospective study is needed.

Keywords: aromatase inhibitors; breast neoplasms; chemotherapy; clinical decision-making; gene expression profiling; hormone antagonists; precision medicine.

Figure 1:. Histogram for Distributions of RSClin Predictions.

Predictions of risk of distant recurrence on aromatase inhibitor (left) and absolute chemotherapy benefit as percentage reduction in distant recurrence (right) are illustrated for the overall study population. For this study, RSClin predicted chemotherapy benefit was stratified into low (<3% reduction in distant recurrence), intermediate (3–5%), and high (>5%) – these divisions are illustrated above.

Figure 2:. Correlation of RSClin Predictions and Mortality Rate in Patients Treated with or without Chemotherapy.

Mortality rate is compared between patients treated with and without chemotherapy within three subgroups of RSClin predicted chemotherapy benefit (reported as absolute reduction in 10-year distant recurrence rate with chemotherapy). A significant survival benefit is seen starting at the 3 – 5% subgroup. Inverse probability of treatment weighting is applied to mitigate effect of patient fitness on treatment decisions, and hazard ratios are listed for chemotherapy benefit in a multivariable Cox model that also incorporates age and comorbidity index.

Figure 3:. Continuous Prediction of Survival Benefit with Chemotherapy as a Function of RSClin Predicted Benefit.

Relationship was modeled with a cubic spline regression with four knots, with inverse probability of treatment weighting and covariates of age and comorbidity index included in the model. A significant overall survival benefit with chemotherapy was seen when RSClin predicted chemotherapy benefit was at least 3%.

Figure 4:. Survival Benefit of Chemotherapy, Stratified by RSClin Predicted Benefit and Clinical / Demographic Factors.

Analysis is pictured with inverse probability of treatment weighting and models also incorporated age and comorbidity index as variables. No clear subgroup clearly benefits from chemotherapy when RSClin predicted benefit was < 3%, although there was a trend towards benefit in patients with grade 3 tumors. Conversely, nearly all subgroups demonstrated a clear survival advantage with chemotherapy when RSClin predicted benefit was > 5%. Notable exceptions include lobular tumors and Hispanic patients.

Figure 5:. Mortality Rate in Patients in Discordant RSClin and OncotypeDx Risk Groups.

High RSClin is defined as predicted absolute chemotherapy benefit of > 5%, intermediate as between 3% and 5%, and a low risk as less than 3% benefit. High OncotypeDx risk is defined as score of 26 or higher. Inverse probability of treatment weighting is applied to survival curves.