Pogue–Geile, Katherine L.

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.

Abstract Our objective was to validate the NSABP 8-gene trastuzumab-benefit signature, developed and initially validated in NRG Oncology/NSABP B-31 in Alliance/NCCTG N9831. The B-31 and N9831 trials demonstrated the benefit of adding trastuzumab to chemotherapy in the adjuvant setting for HER2+ breast cancer patients. NSABP investigators utilized gene expression profiles of N9831 patients (N = 892) to blindly assign patients to large-, moderate-, or no-trastuzumab benefit groups and then NCCTG investigators assessed the degree of trastuzumab benefit using Cox models adjusted for age, nodes, estrogen receptor/progesterone receptor status, tumor size, and grade. Hazard ratios and 2-sided P values for recurrence-free survival of the predicted large- (n = 387), moderate- (n = 401), and no-benefit (n = 104) groups, based on the 8-gene signature were 0.47 (95% CI = 0.31 to 0.73, P < .001), 0.60 (95% CI = 0.39 to 0.92, P = .02), and 1.54 (95% CI = 0.59 to 4.02, P = .38), respectively (Pinteraction = .02), providing validation of the 8-gene signature in an independent study.

PURPOSE Recent trials have shown potential benefit of extended adjuvant endocrine therapy and relatively high risk of recurrence (RoR) after 5 years in hormone receptor-positive (HR+) human epidermal growth factor receptor 2–negative (HER2−) breast cancer. Although risk of late relapse in HR+ HER2− breast cancer is fairly well defined, the risk in HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab-based chemotherapy remains largely unknown. METHODS We included 3,177 patients with HER2+ breast cancer treated with adjuvant chemotherapy alone or with trastuzumab from the North Central Cancer Treatment Group N9831 (ClinicalTrials.gov identifier: NCT00005970 ) and National Surgical Adjuvant Breast and Bowel Project B-31 (ClinicalTrials.gov identifier: NCT00004067 ) trials. RESULTS Overall, HR+ breast cancer was significantly associated with improved recurrence-free survival (RFS) during the first 5 years (hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P < .001). Among patients treated with trastuzumab, cumulative hazard for RFS was lower in patients with HR+ HER2+ breast cancer during the first 5 years (10.96% v 17.48%; hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P < .001). However, there was no significant difference in RFS based on HR status during years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88; P = .12). A comparable degree of trastuzumab benefit was observed in HR+ and HR− breast cancers ( P for interaction = .87). Furthermore, we observed low RoR in years 5 to 10 among patients with HR+ HER2+ breast cancer: 3.23% in patients without lymph node involvement (N0) and 6.39% in patients with involvement of one to three lymph nodes (N1). CONCLUSION The benefit of adjuvant trastuzumab persists for a long time. A distinct pattern of recurrence was observed between HR+ and HR− HER2+ disease but with similar degree of benefit from adjuvant trastuzumab. RoR in years 5 to 10 in HR+ HER2+ breast cancer is low, particularly in patients with N0 or N1 disease.

Abstract Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. Experimental Design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28–0.66; P &lt; 0.001; and age &gt; 40; HR, 0.56; 95% CI, 0.45–0.69; P &lt; 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29–0.68; P &lt; 0.001; and age &gt; 40; HR, 0.42; 95% CI, 0.33–0.54; P &lt; 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor–positive subset, but not the hormone receptor–negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.