Gil, Angelica

Background: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor–positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. Patients and Methods: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. Results: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12–1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98–1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09–3.17; P=.02) compared with N0–N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50–1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. Conclusions: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. ClinicalTrials.gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).

Abstract Background: Although risk of late relapse in hormone receptor-positive (HR+) breast cancer is well established, most existing data pertain to the HR+ HER2-negative (HER2-) subgroup. CTS5 is one of the models for predicting risk of late relapse in HR+ HER2- breast cancer. However, the value of this model in HR+ HER2+ disease is less known, particularly in the context of adjuvant trastuzumab. Here, we evaluated CTS5 in patients with early stage HR+ HER2+ breast cancer treated in the NCCTG N9831 (Alliance for Clinical Trials in Oncology) and NSABP B-31 (NRG) trials. Methods: Stage I-III HR+ (ER+ and/or PR+) HER2+ breast cancer patients who were free of recurrence after 5 years in N9831 and B-31 trials were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. N9831 and B-31 trials were analyzed separately. Results: 1,204 patients in N9831 and 658 patients in B-31 met the entry criteria. Baseline characteristics were similar between both trials, including median age, tumor size, and follow up. Similar distribution within CTS5 risk group was observed in both trials; 68.2% and 70.1% patients were high risk, 24% and 21.9% as intermediate risk, as well as 7.8% and 8.1% as low risk classified in N9831 and B-31, respectively. Using univariate Cox regression analysis, CTS5 score as a continuous variable was associated with recurrence-free survival (RFS) in the entire study cohort, including patients who received chemotherapy alone or in combination with trastuzumab, (HR 1.37, 95%CI 1.03-1.81, p=0.03, C index 0.57 in N9831 and HR 1.36, 95%CI 1.06-1.76, p=0.02, C index 0.54 in B-31), but not in patients who received concurrent trastuzumab (HR 1.19, 95%CI 0.73-1.2, p=0.49, C index 0.54 in N9831 and HR 1.35, 95%CI 0.96-1.9, p=0.08, C index 0.54 in B-31). As categorical variable in the entire study cohort, CTS5 risk group was not significantly associated with RFS among patients with intermediate vs. low (HR 0.47, 95%CI 0.18-1.22, p=0.12 and HR 1.61, 95%CI 0.66-3.92, p=0.29) and high vs. low (HR 1.23, 95%CI 0.57-2.67, p=0.6 and HR 1.93, 95%CI 0.85-4.41, p=0.12) with the C index of 0.58 and 0.53 in N9831 and B-31 respectively. There was also no significant difference in RFS among 3 CTS5 risk groups with Kaplan-Meier estimates. Among patients who received concurrent trastuzumab, similar trends were observed with no statistical difference in RFS between high vs. low (HR 0.68, 95%CI 0.24-1.97, p=0.48 and HR 1.44, 95%CI 0.52-3.96, 0.49) with the C index of 0.55 and 0.51 in N9831 and B-31, respectively. Paradoxically, patients with intermediate risk had better RFS than low risk (HR 0.18, 95%CI 0.03-0.97, p=0.05) in N9831 but no significant difference in B-31 (HR 1.31, 95%CI 0.44-3.95, p=0.63). Conclusions: While CTS5 score as a continuous variable was associated with outcome in overall HR+ HER2+ population, this model was not prognostic in patients receiving adjuvant trastuzumab in both N9831 and B-31 trials. Furthermore, the correlation (C index) was modest and CTS5 risk group as a categorical variable could not stratify outcome in this group of patients. This study underlines the need to develop a new prognostic model to better delineate the risk of late relapse in HR+ HER2+ breast cancer patients receiving trastuzumab as this model can facilitate clinical decision for extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, U10CA180868 and U10CA180822 (NRG), Genentech. https://acknowledgments.alliancefound.org Citation Format: Tanyami Pai, Angelica Gil, Yaohua Ma, Zhuo Li, Pooja Advani, Moreno Moreno-Aspitia, Gerardo Colon-Otero, Edith A. Perez, Yan Asmann, Katherine Pogue-Geile, E. A. Thompson, Saranya Chumsri. Prognostic value of clinical treatment score post-5 years (CTS5) and late relapse risk in hormone receptor-positive HER2-positive breast cancer in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-03.

529 Background: Multiple prognostic models exist to predict late relapse risk in early stage hormone receptor-positive (HR+) breast cancer (BC). The CTS5 is one such model that has been validated in HR+ HER2-negative BC. The value of this model in HR+ HER2+ has not been established. Here, we assessed CTS5 in patients (pts) with early stage HER2+ BC treated in the NCCTG N9831 (Alliance) trial. Methods: Pts with stage I-III HER2+ HR+ BC who survived ≥ 5 years were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. Results: From 3,130 pts, 1,204 pts met the criteria and were included. Median age was 49 (22-79) years and median tumor size was 2.4 (0.1-12) cm. 63.6% had grade 3 tumors, 33.6% grade 2, and 2.8% grade 1. Median follow up was 10.89 (5.01-15.32) years. Based on CTS5, 821 (68.2%) pts were classified as high risk, 289 (24%) as intermediate risk, and 94 (7.8%) as low risk. Overall, using univariate Cox regression analysis, there was no statistically significant difference in recurrence free survival (RFS) among pts with intermediate vs. low (HR 0.47 95%CI 0.18-1.22, p = 0.12) and high vs. low (HR1.23 95%CI0.57-2.67, p = 0.6) with the C index of 0.58. Among pts who received concurrent trastuzumab (H) with HR+ BC, there was also no statistical difference in RFS between high vs. low (HR 0.68 95%CI0.24-1.97, p = 0.48) with the C index of 0.55. Paradoxically, pts with intermediate risk had better RFS than low risk (HR 0.18 95%CI0.03-0.97, p = 0.05). As a continuous variable, there is also no significant improvement in RFS per 1 unit increase in CTS5 score (HR 1.19 95%CI 0.73-1.96, p = 0.49) with the C index of 0.54. After 5 years, 7.06% (n = 30/425) of HR+ pts treated with concurrent H recurred. Conclusions: The CTS5 model is not prognostic in pts with early stage HR+ HER2+ BC receiving adjuvant H. While most HR+ HER2+ pts are classified as high risk by CTS5, the recurrence between years 5-10 was low in pts who received adjuvant H. This study highlights the need to develop a new predictive model for risk of late relapse in this specific group of pts to enable clinicians to determine which pts would benefit from extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00005970 .