Background
The risk of late recurrence has been well established in hormone receptor–positive (HR+) breast cancer, demonstrating a significantly higher annualized risk of recurrence after 5 years compared with patients with HR-negative breast cancer.1,2 Adjuvant endocrine therapy with tamoxifen and aromatase inhibitors is a mainstay of practice to reduce the risk of recurrence in patients with HR+ breast cancer.3 Several clinical trials have demonstrated the benefit of extended adjuvant endocrine therapy after the initial 5 years in some subsets of patients with HR+ breast cancer.4–6 However, multiple studies have shown that only 50% of patients adhere to adjuvant endocrine therapy and complete 5 years of treatment.7,8
Multiple prognostic models and biomarkers to predict the risk of late recurrence in HR+ breast cancer have been validated. One such model is the Clinical Treatment Score post-5 years (CTS5), which was developed to estimate late recurrence risk in patients with HR+ breast cancer after 5 years of adjuvant endocrine therapy.9,10 CTS5 utilizes tumor size, tumor grade, patient age, and number of involved nodes to generate a continuous score, a corresponding 3-risk group classification (low,- intermediate-, and high-risk groups), and a 5- to 10-year recurrence risk prediction in percentage format.9 This prognostic model was validated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and the Breast International Group (BIG) 1-98 trials, which primarily included patients with HR+, HER2-negative breast cancer.10,11
Overexpression of HER2 occurs in approximately 15% to 20% of all breast cancers. Without anti-HER2 therapy, HER2-positive (HER2+) breast cancer is associated with poor survival and resistance to chemotherapy and endocrine therapy.12 Trastuzumab, a recombinant humanized monoclonal antibody targeting HER2, has revolutionized the treatment of HER2+ breast cancer and substantially improved patients’ outcomes with early-stage and advanced HER2+ breast cancer. We previously demonstrated that late recurrence incidence in patients with HR+, HER2+ was low, particularly in patients without lymph node involvement.13 Currently, limited data exist with prognostic modeling of late recurrence risk in patients with HR+, HER2+ breast cancer, particularly in those treated with adjuvant trastuzumab. In this study, we evaluated the prognostic value of CTS5 in patients with HR+, HER2+ breast cancer treated with adjuvant trastuzumab in the North Central Cancer Treatment Group (NCCTG; now a part of the Alliance for Clinical Trials in Oncology) N9831 and the National Surgical Adjuvant Breast and Bowel Project (NSABP; now NRG Oncology) B-31 trials (ClinicalTrials.gov identifiers: NCT00005970 and NCT00004067, respectively).
Patients and Methods
Patient Population
Patients with stage I–III HR+, HER2+ breast cancer treated in the NCCTG N9831 and NSABP B-31 trials, who were free of recurrence 5 years after the enrollment, were included in this analysis. NCCTG N9831 is a randomized phase III trial that enrolled patients with operable node-positive or high-risk node-negative HER2+ breast cancer. There were 3 treatment arms in this trial: arm A received chemotherapy only with doxorubicin in combination with cyclophosphamide, followed by weekly paclitaxel (AC-T); arm B received AC-T followed by trastuzumab; and arm C received AC-T with concurrent trastuzumab and paclitaxel.
NSABP B-31 is a randomized phase III trial that enrolled patients with operable node-positive HER2+ breast cancer. There were 2 treatment arms in this trial: arm 1 received AC-T, and arm 2 received AC-T with concurrent trastuzumab, similar to arm C of the NCCTG N9831 trial, although the schedule of paclitaxel was different—weekly for NCCTG N9831 and every 3 weeks for NSABP B-31. Given the similar treatments in arm A and arm C in the NCCTG N9831 trial when compared with arm 1 and arm 2 in the NSABP B-31, respectively, only arm A and arm C in the NCCTG N9831 trial were included in this analysis.
Patients who participated in these trials signed protocol-specific informed consents approved by local Institutional Review Boards in accordance with federal and institutional guidelines. The primary results of NCCTG N9831 and NSABP B-31 were published by Romond et al14 and Perez et al.15–17 The current study was conducted in compliance with the Declaration of Helsinki, the International Conference on Harmonization, and Good Clinical Practice.
CTS5 Model
The CTS5 online model9 was used to generate the CTS5 score, risk of recurrence in years 5 to 10, and CTS5 risk group. This online model is available at www.cts5-calculator.com. Included in the online model are tumor size in millimeters (mm), tumor grade from 1 to 3, patient age, and number of involved nodes. Risk of recurrence in years 5 to 10 is reported as percentages. CTS5 risk groups are classified as low, intermediate, and high risk based on data obtained mainly from patients with HR+, HER2-negative breast cancer. Patient risk is considered low if their risk in years 5 to 10 is <5%, intermediate if their risk is between 5% and 10%, and high if their risk is >10%.
Statistical Analysis
Patient demographics, including age, follow-up time, and tumor size, were summarized using median and range, whereas the remaining categorical variables were summarized with frequency and percent. CTS5 score was summarized as median (range) and mean [SD] for each risk group. Cox proportional regression model calculated the hazard ratio (HR) and 95% confidence intervals. The proportional hazard assumption was checked using the Schoenfeld residual test. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS) at 6, 8, and 10 years for each risk group and to draw corresponding curves. RFS was defined as the time from randomization to breast cancer recurrence, which included local, regional, or distant recurrence of breast cancer or breast cancer–related death. Follow-up rates were estimated using the reversed Kaplan-Meier estimator. All tests were 2-sided, with the alpha level set at 0.05 for statistical significance. The analysis was completed with RStudio version 3.6.2 (R Foundation for Statistical Computing).
Results
Patients Characteristics
From a total of 5,026 patients (1,895 patients from the NCCTG N9831 trial and 3,131 patients from the NSABP B-31 trial), 1,058 (55.8%) in NSABP B-31 and 1,687 (53.9%) in NCCTG N9831 had HR+, HER+ breast cancer. Of those, 1,862 patients with HR+, HER2+ disease who were free of recurrence 5 years after diagnosis were included in this analysis. There were 1,204 patients in the NCCTG N9831 trial and 658 patients in the NSABP B-31 trial. Patient baseline characteristics were summarized in Table 1. Using the reversed Kaplan-Meier estimator, the 10-year follow-up rate was 90.5% overall (87.1% in the NSABP B-31 trial and 93.7% in the NCCTG N9831 trial; Figure S1 in the supplementary materials, available online with this article). Median ages were similar in both trials, with 48.5 years (range, 28–77 years) in the NSABP B-31 and 49 years (range, 22–79 years) in the NCCTG N9831 trial. Other clinicopathologic characteristics were similar between the 2 trials. Median tumor size was 2.3 cm (range, 0.1–17 cm) in the NSABP B-31 and 2.4 cm (range, 0.1–12 cm) in the NCCTG N9831. Distribution of tumor grade and lymph node status were also similar in both trials, with the majority of patients having N1 disease: 63.1% in NSABP B-31 and 53.5% in NCCTG N9831. Among 369 patients in the NCCTG N9831 trial with available data regarding extended adjuvant endocrine therapy, 56 (16%) patients took adjuvant endocrine therapy for >5 years. However, the data regarding extended adjuvant endocrine therapy were not available for the NSABP B-31 trial.
Patient Clinicopathologic Characteristics and CTS5 Risk Groups
CTS5 Risk Stratification and Distribution
Of 1,862 patients, the median CTS5 score was 4.2 (range, 1.8–6.0). In NSABP B-31, 53 (8.1%) patients were classified as low-risk, 144 (21.9%) as intermediate-risk, and 461 (70.1%) as high-risk per the CTS5 model. In NCCTG N9831, 94 (7.8%) patients were classified as low-risk, 289 (24%) as intermediate-risk, and 821 (68.2%) as high-risk. There was no statistically significant difference between the CTS5 distributions in the 2 trials (Table 1).
CTS5 Score and Outcome
Given that there was no significant difference in clinicopathologic characteristics and CTS5 distribution between the 2 clinical trials, patients treated in arm 1 and arm 2 of the NSABP B-31 were combined with those treated in arm A and arm C of the NCCTG N9831, respectively. In all treatment arms combined (n=1,862), the CTS5 score as a continuous variable was significantly associated with RFS in the univariate Cox regression analysis (Table 2). Each 1-point increment in the CTS5 score corresponds to a 35% worsening in RFS (HR, 1.35; 95% CI, 1.12–1.63; P=.002). However, the C index was 0.556. Besides the CTS5 score, N3 disease was significantly associated with worsening RFS (HR, 1.71; 95% CI, 1.17–2.49; P=.005). However, there was no significant difference in RFS with age and tumor size. Therefore, we performed further multivariate Cox analysis adjusting for age, tumor grade, tumor size, and number of lymph nodes. In this model, the CTS5 score as a continuous variable was not significantly associated with RFS (HR, 1.25; 95% CI, 0.96–1.62; P=.097). In addition, higher tumor grade was paradoxically associated with less recurrence and death after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.56–0.91; P=.006).
Univariate and Multivariate Cox Regression Model Predicting Recurrence or Mortality (RFS) in the Overall Group (N=1,862)a
Among patients who received concurrent trastuzumab in arm C of the NCCTG N9831 and arm 2 of the NSABP B-31 (n=829; Table 3), the CTS5 score as a continuous variable did not reach statistical significance (HR, 1.29; 95% CI, 0.98–1.71; P=.069) with a C index of 0.539. When evaluating other variables used to calculate the CTS5 score, age and tumor size were not significantly associated with RFS. Only lymph node status with N3 disease was significantly associated with worsening outcomes (HR, 1.86; 95% CI, 1.09–3.17; P=.023) compared with patients with N0–N1 disease. As was observed in the analysis of all treatment groups, higher tumor grade among patients treated with trastuzumab was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50–1.00; P=.048).
Univariate Cox Regression Model Predicting Recurrence or Mortality in Patients Treated With Trastuzumab (N=829)a
CTS5 Risk Group and Outcome
As a categorical variable, CTS5 divided patients into low-, intermediate-, and high-risk groups. In all treatment arms combined from both NCCTG N9831 (arm A and arm C) and NSABP B-31 trials (arm 1 and arm 2), patients in the CTS5 intermediate-risk group had significantly better outcomes compared with the high-risk group (HR, 0.61; 95% CI, 0.43–0.87; P=.007) using univariate Cox regression analysis. However, RFS in the CTS5 low-risk group was not significantly different from the high-risk group (HR, 0.66; 95% CI, 0.37–1.15; P=.143). The C index for the CTS5 risk group was 0.553. In addition, in the trastuzumab-treated arm C of the NCCTG N9831 and arm 2 of the NSABP B-31, there was no significant difference in RFS between each CTS5 risk group (Table 2). A similar trend was observed with the Kaplan-Meier analysis. In all treatment arms combined (Figure 1), there was a statistically significant difference in RFS between each CTS5 risk category (P=.012). However, when directly comparing the CTS5 low-risk and high-risk groups, there was no significant difference between these groups (P=.100). Moreover, among patients who received trastuzumab (Figure 2), there was no statistically significant difference in RFS between all CTS5 risk groups (P=.309).
Kaplan-Meier curve for recurrence-free survival in all treatment arms combined from arm A and arm C of the NCCTG N9831 and arm 1 and arm 2 of the NSABP B-31 trials.
Abbreviation: CTS5, Clinical Treatment Score post-5 years.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.7015
Kaplan-Meier curve for recurrence-free survival in patients who received trastuzumab from arm C of the NCCTG N9831 and arm 2 of the NSABP B-31 trials.
Abbreviation: CTS5, Clinical Treatment Score post-5 years.
Citation: Journal of the National Comprehensive Cancer Network 22, 7; 10.6004/jnccn.2024.7015
Furthermore, unlike patients with HR+, HER2-negative breast cancer, in whom the 5- to 10-year risk of recurrence was <5% in the low-risk category, 5% to 10% in the intermediate-risk category, and >10% in the high-risk category, the incidence of recurrences or deaths in patients with HR+, HER2+ disease in all treatment arms combined was 7.5% in the low-risk category, 4.8% in the intermediate-risk category, and 10.4% in the high-risk category. Among patients who received adjuvant trastuzumab, the incidence of recurrences or deaths between years 5 and 10 was 10.6% in the low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category (Table 4).
Risk of Late Recurrence Between Years 5 and 10
Discussion
The CTS5 model is a prognostic tool designed to evaluate the risk of late recurrence to facilitate decision-making for extended adjuvant endocrine therapy after 5 years if a patient did not experience recurrence.9 The CTS5 online calculator is a commonly used tool, which has been accessed >88,000 times and is currently widely used in the clinic.18 However, this model was developed in the ATAC and BIG 1-98, mainly including patients with HER2-negative or unknown status. Furthermore, given that ATAC and BIG 1-98 trials completed their accrual in 2000 and 2003,18 and trastuzumab was approved in the adjuvant setting in 2005, it was not likely that patients participating in ATAC and BIG 1-98 trials received trastuzumab in the adjuvant setting.
Our group previously demonstrated that the risk of late recurrence in patients with HR+, HER2+ breast cancer receiving adjuvant trastuzumab in the NCCTG N9831 and NSABP B-31 trials was low, particularly in patients with limited lymph node involvement. In patients with no lymph node involvement (N0), the risk of recurrence in years 5 to 10 was 3.23%, and in patients with involvement of 1 to 3 lymph nodes (N1), the risk of recurrence was 6.39%.13 Because the CTS5 model is the most common clinicopathologic model used worldwide to evaluate the risk of late recurrence, our study further assessed whether the model also applied to patients with early-stage HR+, HER2+ breast cancer in the NCCTG N9831 and NSABP B-31 trials. Overall, among patients with HR+, HER2+ breast cancer treated with adjuvant chemotherapy alone or in combination with trastuzumab, the CTS5 score as a continuous variable was significantly associated with the risk of late recurrence, with a 35% worsening in RFS with each 1-point increment in CTS5 score (HR, 1.35; 95% CI, 1.12–1.63; P=.002). However, when adjusting for all other variables in the multivariate analysis, the CTS5 score was no longer significant (HR, 1.25; 95% CI, 0.96–1.62; P=.097). Furthermore, among patients who were treated with adjuvant trastuzumab, the CTS5 score as a continuous variable did not reach statistical significance for the risk of late recurrence (HR, 1.29; 95% CI, 0.98–1.71; P=.07). Nevertheless, the sample size in this group of patients was smaller than the overall population. Furthermore, CTS5 as a categorical variable was not significantly associated with RFS in overall patients and among patients treated with adjuvant trastuzumab. C indexes were also marginal at 0.553 and 0.532, respectively, which is not considerably more than random chance alone.
We further evaluated the possibility of discrepancy of CTS5 in HER2+ versus HER2-negative disease. When assessing each individual variable in CTS5, only tumor grade and lymph node status were significantly associated with RFS. For lymph node status, only N3 disease was significantly associated with worse RFS compared with N0–N1 disease. Other variables used in CTS5, including age and tumor size, were not significantly associated with worsening RFS. However, in contrast to patients with HR+, HER2-negative breast cancer, in whom a higher tumor grade confers worse outcome, a higher tumor grade in HR+, HER2+ breast cancer confers better RFS with less recurrence or death in years 5 to 10 in the overall group and in patients who were treated with trastuzumab. Corresponding to this observation, patients in the intermediate-risk category paradoxically appeared to have a lower risk of recurrence than those in the low-risk category. Moreover, there was no significant difference in RFS between patients in low versus high-risk categories. This is likely due to the fact that most patients in the low-risk category had low-grade tumors. These tumors may represent luminal tumors, which have a higher risk of late recurrence, rather than the HER2-enriched subtype.
In addition, when comparing the distribution between each risk category, more patients in the NSABP B-31 and NCCTG N9831 trials were categorized as higher-risk categories compared with the previous publication by Dowsett et al.9 In the ATAC and BIG 1-98 trials, 42% to 42.6% of patients were categorized as low risk, 31.3% to 31.8% as intermediate risk, and 20.7% to 25.5% and as high risk. In contrast, only 7.8% to 8.1% of patients were categorized as low risk in the NSABP B-31 and NCCTG N9831 trials, whereas 21.9% to 24% of patients were categorized as intermediate risk and 68.2% to 70.1% as high risk. This is likely due to the fact that the majority of HER2+ tumors are high-grade, and more patients in the NSABP B-31 (100%) and NCCTG N9831 (91.5%) trials had lymph node involvement compared with the ATAC (32%) and BIG 1-98 (39.1%) trials.
More importantly, patients with HR+, HER2+ breast cancer who were treated with adjuvant trastuzumab and categorized as the low-risk category based on the CTS5 model still had a substantial risk of late recurrence, similar to patients in the high-risk category. In the original CTS5 model publication,9 patients were considered low risk if their risk in years 5 to 10 was <5%, intermediate risk if their risk was between 5% and 10%, and high risk if their risk was >10%. In contrast, 10.6% of patients with HR+, HER2+ breast cancer categorized in the low-risk category who received adjuvant trastuzumab had recurrence or death between years 5 and 10 compared with 9.8% in the high-risk category and 5.6% in the intermediate-risk category.
Conclusions
The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ breast cancer, particularly in patients treated with adjuvant trastuzumab. Patients treated with adjuvant trastuzumab, categorized as the low-risk category by the CTS5 model, may still have a substantial risk of late recurrence. Therefore, using the CTS5 model in HR+, HER2+ breast cancer may mislead clinicians and patients to the wrong decision regarding extended adjuvant endocrine therapy. Future studies are needed to develop risk models and biomarkers to identify patients with a higher risk of late recurrence and determine which patients could benefit from extended adjuvant endocrine therapy in HR+, HER2+ breast cancer.
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