Prediction Of Late Distant Recurrence Research Articles

The clinical usefulness of the CTS5 in the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer

BackgroundClinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late distant recurrence (DR) risk for breast cancer after 5-year adjuvant endocrine therapy.Patients and methodsAmong 560 postmenopausal women with pathological stage I–III estrogen receptor-positive (ER+) primary breast cancer, 383 women who had received 5-year adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study. The CTS5 was calculated for each patient using a previously published formula, and the patients were stratified by their CTS5 values into the low-, intermediate- and high-CTS5 risk groups.ResultsAccording to the CTS5, 205 (53.5%), 106 (27.7%) and 72 (18.8%) patients were classified into the low-, intermediate-, and high-CTS5 risk groups, respectively. A higher ER expression level was significantly associated with the low CTS5. The increased administration of adjuvant chemotherapy was significantly associated with a high CTS5. The occurrence of DR was higher in the intermediate and high CTS5 groups than in the low CTS5 group. The DRFS in the low CTS5 risk group was significantly better than that in the intermediate- or high-risk groups. In the ER-high or HER2-negative (HER2−) group, the DRFS in the low-risk group was significantly better than that of the intermediate- or high-risk groups. However, in the low-ER or HER2-positive group, there was no significant difference in DRFS among the three risk groups.ConclusionsIn postmenopausal women with ER+ breast cancer, low CTS5 was considered to be associated with a very low risk of late DR. Thus, extended endocrine therapy may be unnecessary for patients with low CTS5 scores. Extended endocrine therapy should be offered for patients with intermediate or high CTS5 scores, especially those with high-ER and HER2− breast cancer.

Abstract P5-06-20: Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer

Abstract <Background> The Clinical Treatment Score post-5 years (CTS5) is a prognostic tool to estimate the residual risk of distant recurrence (DR) after 5 years of endocrine therapy in postmenopausal women with estrogen receptor (ER)-positive breast cancer. (J Clin Oncol, 2018; 19: 1941-1947). CTS5 might be useful to decide the indication of extended adjuvant endocrine therapy after 5years. <Purpose> This study was conducted to elucidate the usefulness of CTS5 for the prediction of late DR in postmenopausal women with ER-positive early breast cancer treated in our department. <Patients and Methods> CTS5 was calculated in 377 postmenopausal patients with ER-positive breast cancer who underwent surgery between 2003 and 2009. They had received 5-year adjuvant endocrine therapy without DR. CTS5 is stratified into three groups; low, intermediate and high risk of DR. The relationships between CTS5 and the clinicopathological characteristics and prognosis were evaluated. <Results> According to CTS5, 202 (53.6%), 104 (27.6%) and 71 (18.8%) patients were divided into low, intermediate and high-risk of late DR groups. In the CTS5-high risk group, significantly more positive lymph nodes (p<0.0001), larger tumor size (p<0.0001), higher histological grade (p<0.0001), more administration of adjuvant chemotherapy (p<0.0001), more administration of adjuvant endocrine therapy of Aromatase inhibitor (AI) (p=0.0029), more visceral distant metastasis (p=0.0029), lower ER expression (p=0.0064) were observed. Significantly lower incidence of DR was observed in CTS5-low risk group. Thus, CTS5 was significantly prognostic for late DR. Intriguingly, in the CTS5-low risk group, administration of endocrine therapy of AI (p=0.0023), lower histological grade (HG1, 2; p=0.0011), ER high expression (TS; 6-8 p=0.0002), and positive PgR (p=0.0007) were significantly better DR-free survival (DRFS). <Conclusion> CTS5 demonstrated clinical validity for predicting late DR in this study cohort. IN the CTS5-low risk group, the incidence of late DR was significantly lower than that of in CTS5-intermediate or high risk group. The low CTS5 might be useful to decide the indication of 5-year adjuvant endocrine therapy in the postmenopausal patients with ER-positive early breast cancer. Citation Format: Wakako Tajiri, Azusa Sugii, Hideki Ijichi, Hiroki Ueo, Chinami Koga, Yoshiaki Nakamura, Masahiro Okamoto, Kennichi Taguchi, Eriko Tokunaga. Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-20.

Abstract P5-06-04: Prognostic value of EndoPredict and Oncotype Recurrence Score according to patient's age

Abstract Background: EndoPredict (EPclin) and Oncotype Recurrence Score (RS) have both shown their prognostic ability for women with estrogen receptor positive (ER), HER2-negative breast cancer, with EPclin outperforming RS specifically in node-positive population and for the prediction of late distant recurrence (DR). Age is an important risk factor for breast cancer but no data is available on the performance of genomic assays according to patient’s age. Here, we investigate whether EPclin and RS provide differential prognostic value in different age groups. Methods: 928 postmenopausal women with ER-positive, HER2-negative breast cancer were included in this analysis for whom information on EPclin and RS were available. None of the patients included in this analysis received chemotherapy. Age at diagnosis was treated as a categorical variable (≤60 years, 60-70 years, >70 years). Primary endpoint was DR and we used Cox regression models to assess the prediction of DR by EPclin and RS according to age. Results: 300 (32.3%) women were aged 60 years or younger, 377 (40.6%) between 60 and 70 years, and 251 (27.1%) were older than 70 years. Women aged 60 years or older had significantly more node-positive disease, higher grade tumors, and more DR than those aged 60 or younger. RS scores were similar between age groups whereas EPclin scores were significantly higher in older women compared to younger women, reflecting the combined molecular plus clinical nature of the EPclin. Overall, both RS and EPclin were prognostic but with decreasing prognostic value with increasing age (Table). We observed a significant interaction between continuous age and both tests (RS: P=0.004; EPclin: P=0.026). In women aged 70 years and older, RS did not provide any prognostic information (HR=1.22 (0.96-1.55); LR-χ2=2.5) whereas EPclin showed significant prognostic ability in this age group (HR=2.02 (1.59-2.57); LR-χ2=30.4) (Table). Kaplan-Meier estimates were significantly different between low and high risk groups for both tests in women aged less than 70 years. No significant risk stratification was achieved by RS in women aged 70 years or older whereas EPclin distinctively stratified older patients into low and high risk groups with significant different 10-year DR risks. Conclusion: Genomic assays are increasingly used in the clinic to determine prognosis for women with ER-positive, HER2-negative breast cancer. Here, we show that the effect sizes and prognostic value of EPclin and RS are different across age groups, and only the EPclin was prognostic in elderly patients. Our results indicate that tests that incorporate clinical parameters in their score are likely to be more prognostic in elderly patients and should be used in the decision-making process when using genomic assays. Hazard Ratios (HRs (95% CI)) for continuous EPclin/RS scores and risk groups according to age groups≤60 years60-70 years>70 years(N=300)(N=377)(N=251)RS2.23 (1.57-3.15)1.59 (1.32-1.91)1.22 (0.96-1.55)LowReferenceReferenceReferenceIntermediate3.79 (1.40-10.24)2.74 (1.44-5.23)1.75 (0.97-3.15)High8.86 (3.07-25.57)6.55 (3.25-13.19)1.63 (0.67-3.96)EPclin3.47 (2.28-5.27)2.74 (2.17-3.45)2.02 (1.59-2.57)LowReferenceReferenceReferenceHigh9.60 (3.60-25.57)5.55 (2.91-10.61)3.68 (1.89-7.17) Citation Format: Ivana Sestak, Ralf Kronenwett, Richard Buus, Jack Cuzick, Mitchell Dowsett. Prognostic value of EndoPredict and Oncotype Recurrence Score according to patient's age [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-04.

Abstract P5-06-08: Predicting distant recurrence of ER+ HER2- breast cancer after 5 years of endocrine therapy: The CTS5-tool validation in real life

Abstract Purpose: Extended adjuvant hormone therapy improves estrogen receptor (ER)-positive breast cancer outcome. The total duration of endocrine therapy is still a subject for debate. The CTS5 score, developed by Dowsett et al1., predicts late distant recurrence (LDR) between years 5 and 10 after diagnosis in ER-positive invasive breast cancers in postmenopausal women. This LDR risk might be used to select patients for extended endocrine therapy. The CTS5 score is calculated using age at the start of endocrine therapy, tumor size, grade, and lymph node status. The aim of this study is the validation of this tool in a series of women from the UZ Leuven. Methods: This retrospective cohort study included 1125 postmenopausal women consecutively diagnosed with invasive estrogen receptor (ER) positive breast cancer who stopped endocrine therapy after 4.5 to 5.5 years. Tissue was tested for ER positivity and considered positive if >1% of tumor nuclei were stained. HER2 status was defined according to ASCO guidelines. Statistical analysis was performed by Cox proportional hazards models which determined the prognostic performance of the CTS5 score for LDR. Results: A total of 1125 patients were included in this analysis, of which 1097 had a known HER2 status and 1023 were negative. 62 of 1125 (5.5%) developed an LDR between years 5 and 10. The continuous CTS5 was a significant predictor for LDR (HR =2.69 (1.99-3.60), p<0.001). The tool was not significant in the HER2 positive population (n=74), but numbers were small with only 5 LDR recorded (HR=0.92 (0.32-2.66), p=0.88). Further analysis was performed in a strictly HER2-negative cohort. In this cohort, 8 of the 401 patients (2.0%) with a CTS5 predicted low risk (<5% LDR risk) developed LDR, in the intermediate risk group (5-10% LDR risk) 16 out of 336 (4.8%) and in the high risk group (≥10% LDR risk) 32 out of 286 (11.2%) developed LDR. Conclusion: In our series of postmenopausal women, CTS5 accurately predicts late distant recurrence in ER-positive, HER2-negative early invasive breast cancers. The CTS5-score, identifying a patient group with LDR risk of ≥5%, might be used to discuss the benefits of extended endocrine therapy for individual patients. However, the exact predictive value for the benefit of prolonged therapy can only be based on a randomized controlled trial (RCT) using the LDR risk as a stratification factor. It would be of great value to expand the study population, especially HER2-positive tumors, and define the prognostic performance of the CTS5 score in premenopausal women. Further research is needed. 1. Dowsett, M. et al. Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor-Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5. J. Clin. Oncol. 36, 1941-1948 (2018). Citation Format: Josephine Van Cauwenberge, Ivana Sestak, Kevin Punie, Hans Wildiers, Giuseppe Floris, Ignace Vergote, Patrick Berteloot, Toon Van Gorp, Ann Smeets, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Caroline Weltens, Hilde Janssen, Patrick Neven. Predicting distant recurrence of ER+ HER2- breast cancer after 5 years of endocrine therapy: The CTS5-tool validation in real life [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-08.

P009 - Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer

P009 - Usefulness of CTS5 for the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer

Residual risk assessment with the Breast Cancer Index (BCI) for prediction of late distant recurrence (DR) in patients from the TransATAC study.

529Background: The Breast Cancer Index (BCI) is a gene-expression based signature comprised of two complementary functional domains: the molecular grade index (MGI) for tumor proliferation, and the...

Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor-Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5.

PurposeEstimating risk of late distant recurrence (DR) is an important goal for managing women with hormone receptor–positive breast cancer after 5 years of endocrine treatment without recurrence. We developed and validated a simple clinicopathologic tool (Clinical Treatment Score post–5 years [CTS5]) to estimate residual risk of DR after 5 years of endocrine treatment.Patients and MethodsThe ATAC (Arimidex, Tamoxifen, Alone or in Combination) data set (N = 4,735) was used to create a prognostic score for post–5-year risk of DR. Validity of CTS5 (ATAC) was tested in the BIG 1-98 data set (N = 6,711). Time to late DR, 5 years after finishing scheduled endocrine therapy, was the primary end point. Cox regression models estimated the prognostic performance of CTS5 (ATAC).ResultsCTS5 (ATAC) was significantly prognostic for late DR in the ATAC cohort (hazard ratio, 2.47; 95% CI, 2.24 to 2.73; P < .001) and BIG 1-98 validation cohort (hazard ratio, 2.07; 95% CI, 1.88 to 2.28; P < .001). CTS5 (ATAC) risk stratification defined in the training cohort as low (< 5% DR risk, years 5 to 10), intermediate (5% to 10%), or high (> 10%) identified 43% of the validation cohort as low risk, with an observed DR rate of 3.6% (95% CI, 2.7% to 4.9%) during years 5 to 10. From years 5 to 10, 63% of node-negative patients were low risk, with a DR rate of 3.9% (95% CI, 2.9% to 5.3%), and 24% with one to three positive nodes were low risk, with a DR rate of 1.5% (95% CI, 0.5% to 3.8%). A final CTS5 for future use was derived from pooled data from ATAC and BIG 1-98.ConclusionCTS5 is a simple tool based on information that is readily available to all clinicians. CTS5 was validated as highly prognostic for late DR in the independent BIG 1-98 study. The final CTS5 algorithm identified 42% of women with < 1% per-year risk of DR who could be advised of the limited potential value of extended endocrine therapy.

Abstract GS6-01: Integration of clinical variables for the prediction of late distant recurrence in patients with oestrogen receptor positive breast cancer treated with 5 years of endocrine therapy

Abstract Background: The prediction of late distant recurrence (DR) is an important clinical goal for managing women with hormone receptor positive disease who have reached the end of 5 years' endocrine treatment without recurrence. Molecular profiles have produced conflicting results for the prediction of late DR. Here, we develop and validate a simple clinicopathological tool (Clinical Treatment Score post-5 years (CTS5)) to estimate the residual risk of DR after 5 years' endocrine treatment, which should help in discussions with patients about the potential benefits or not of continued endocrine therapy. Patients and Methods: The ATAC dataset (N=4735) of postmenopausal women with oestrogen receptor (ER) positive breast cancer treated with 5 years' tamoxifen or anastrozole was used as a training cohort to establish a prognostic score for post-5-year risk of DR. CTS5 was based on five categories for nodal status, linear and quadratic terms for tumour size (capped at 30mm), three categories for grade, and continuous age. The validity of the CTS5 was tested in the BIG1-98 dataset (N=6711), which included postmenopausal women with ER-positive breast cancer treated with tamoxifen or letrozole (either monotherapy or sequential). Both cohorts included women who were alive and DR-free 5 years after randomization. Time to late DR, defined beginning at 5 years after ATAC or BIG 1-98 randomization, was the primary endpoint. Cox regression models estimated the prognostic performance of the CTS5. Hazard Ratios (HRs) are for a change of one Standard Deviation. Results: The CTS5 model was a significant predictor for late DR in ATAC (HR=2.47 (95% CI, 2.24-2.73), P&amp;lt;0.001) and performed better than the established 0-10 year CTS model (Cuzick et al., JCO, 2011). CTS5 was confirmed as highly predictive for late DR in the BIG1-98 validation cohort (HR=2.07 (1.88-2.28), P&amp;lt;0.001). Of greatest importance was that CTS5 risk stratification defined in the training cohort as low (&amp;lt;5% risk of DR during years 5-10), intermediate (5-10% risk), high (&amp;gt;10% risk), identified 43% of the validation cohort as low risk, with an observed DR rate of 3.6% (95% CI 2.7-4.9) during years 5-10. Within nodal subgroups, 63% of node-negative were low risk with 3.9% (2.9-5.3) DR rate between years 5-10, and 24% having 1-3 nodes positive were low risk with 1.5% (0.5-3.8) DR rate between years 5-10. Separation of intermediate-risk from high-risk categories was also shown in the training set but improvements in calibration seem necessary for clinical utility for that assessment. Conclusion: The CTS5 is a simple tool based on information that is readily available to all clinicians. It was more accurate in its prediction of DR risk in years 5-10 than the published CTS model. CTS5 was validated as highly prognostic for late DR in the independent BIG 1-98 study. The algorithm identified a subgroup of women with either node-negative disease or 1-3 positive nodes as having less than 1% per year risk of DR who could be advised of the limited value of extended endocrine therapy. Citation Format: Sestak I, Regan M, Dodson A, Viale G, Thürlimann B, Colleoni M, Cuzick J, Dowsett M. Integration of clinical variables for the prediction of late distant recurrence in patients with oestrogen receptor positive breast cancer treated with 5 years of endocrine therapy [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 GS6-01.

Abstract 4744: Clinical validation of a prognostic model integrating Breast Cancer Index (BCI) with tumor size and grade for prediction of late distant recurrence in hormone receptor-positive (HR+) breast cancer with 1-3 positive nodes

Abstract Background: The Breast Cancer Index (BCI) 11-gene expression signature has been previously demonstrated to significantly predict risk of overall (10y), early (0-5y), and late (≥5y) distant recurrence in patients with HR+, node negative breast cancer. A distinct BCI model that integrated tumor size and grade (BCIN+) was developed and validated for prediction of distant recurrence in HR+ women with 1-3 positive nodes (N1) (Sestak et al., SABCS 2015, P2-08-12; Zhang et al, ASCO 2016, abstract no. 541). The objective of this analysis was to evaluate BCIN+ performance in the subset of patients that were treated with no more than 5 years of adjuvant endocrine therapy. Methods: The validation study included 402 HR+ N1 patients diagnosed between 1993 to 2007 with ≥5y follow-up and available tumor blocks. Patients treated with ≤5y of endocrine therapy ± chemotherapy (n=276) were included in this analysis. BCIN+ risk scores and categories (low vs high, using a pre-defined cutpoint) were determined blinded to clinical outcome. Kaplan-Meier estimates of overall (0-15y) and late (≥5y) distant recurrence, hazard ratios and 95% CIs were estimated. Multivariate analysis adjusting for standard prognostic factors (age, tumor type, surgery type, PR and HER2 status) was performed using Cox proportional hazards model. Results: Mean age was 53y. 99% were ER+, 89% PR+, and 14% HER2+. The majority of tumors were T1 (61%) or T2 (34%), and 16%, 53%, and 31% were grade 1, 2, and 3, respectively. 79% of patients were treated with adjuvant chemotherapy. BCIN+ significantly separated patients into low and high risk groups for both overall (P&amp;lt;0.0001) and late (P=0.0067) distant recurrence. For overall distant recurrence, BCIN+ classified 18% of patients into the low risk group. The 15y risk of distant recurrence was 2.1% (95% CI: 0.0-6.0%) in the BCIN+ low risk group vs 36.8% (95% CI: 29.3-43.4%) in the high risk group (HR: 21.88; 95% CI: 3.04-157.32). Of patients that were distant recurrence-free for at least 5y, 22% were classified as BCIN+ low risk. The risk of distant recurrence at year 15 was 2.1% (95% CI: 0.0-6.0%) in the BCIN+ low risk group vs 19.0% (11.6-25.8%) in the high risk group (HR: 9.49; 95% CI: 1.29-69.7). Conclusions: In this subset analysis from an independent validation study, BCIN+ identified a significant proportion of N1 patients that were associated with a considerably low 15y risk of distant recurrence after ≤5 years of endocrine therapy ± chemotherapy. BCIN+ may provide additional prognostic information to facilitate selection of N+ patients for extended endocrine treatment wherein patients identified as BCIN+ low may be considered adequately treated with adjuvant therapy alone. Citation Format: Yi Zhang, Piiha-Lotta Jerevall, Brock E. Schroeder, Amy Ly, Hannah Nolan, Catherine A. Schnabel, Dennis C. Sgroi. Clinical validation of a prognostic model integrating Breast Cancer Index (BCI) with tumor size and grade for prediction of late distant recurrence in hormone receptor-positive (HR+) breast cancer with 1-3 positive nodes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4744. doi:10.1158/1538-7445.AM2017-4744

Prediction of late distant recurrence (DR) using the Prosigna (PAM50) test in a Danish Breast Cancer Cooperative Group (DBCG) cohort of postmenopausal women diagnosed with hormone receptor-positive (HR+) early breast cancer (EBC) allocated to 5yr of endocrine therapy (ET).

544 Background: Accurate assessment of the risk of late DR (5-10 yr after surgery) may be used to tailor the duration of ET for patients with HR+ EBC. The Prosigna (PAM50) risk of recurrence (ROR) ...

Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score.

We have previously shown that the PAM50-based risk of recurrence (ROR) score is significantly correlated with distant recurrence in both the translational research cohort within the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial (TransATAC) and Austrian Breast and Colorectal Cancer Study Group 8 (ABCSG 8) randomized trials. Here, we focus on the ROR score for predicting distant recurrence after 5 years of follow-up in a combined analysis of these two randomized trials. Long-term follow-up data and tissue samples were obtained from 2,137 postmenopausal women with hormone receptor-positive early-stage breast cancer from the ABCSG 8 and TransATAC trials. We used Cox proportional hazard regression models to determine the prognostic value of ROR for distant recurrence beyond 5 years in the combined data set. A total of 2,137 women who did not have a recurrence 5 years after diagnosis were included in the combined analyses. The Clinical Treatment Score (CTS) was the strongest prognostic factor 5 years after diagnosis (univariable: likelihood ratio [LR] χ(2) = 94.12, bivariable: LR χ(2) = 61.43). The ROR score was significantly prognostic by itself in years 5 to 10. In the node-negative/human epidermal growth factor receptor 2-negative subgroup, more prognostic value for late distant recurrence was added by the ROR score compared with the CTS. The ROR score added clinically meaningful prognostic information to the CTS in all patients and all subgroups in the late follow-up period. These results suggest that the ROR score may be helpful for separating patients into risk groups who could be spared or potentially benefit from extended hormonal therapy beyond 5 years of treatment.

Abstract S6-04: Prediction of late distant recurrence after 5 years of endocrine treatment: A combined analysis of 2485 patients from the ABCSG-8 and transATAC studies using the PAM50 risk of recurrence (ROR) score

Abstract Background: Extended adjuvant endocrine therapy beyond 5 years is known to be of benefit to some oestrogen receptor (ER+) patients. Given the significant burden extended endocrine therapy presents, individual prediction of late recurrence risk would be highly valuable. We have previously shown that the PAM50 based Risk of Recurrence (ROR) score is significantly correlated with late recurrence in both the transATAC and ABCSG8 cohorts. Here, we assess the value of the ROR score for predicting distant recurrence beyond 5 years in a combined analysis of these two cohorts. Methods: Long-term follow-up data and tissue samples were obtained from 2,485 postmenopausal women with hormone receptor positive (HR+) early breast cancer from the ABCSG-8 and transATAC trials. We used univariate and multivariate models to determine the prognostic value of ROR (with tumour size) for distant recurrence in years 5-10 in the combined dataset. Changes in likelihood ratio tests (DLR-χ2) are presented. Results: A total of 2137 women who did not have a recurrence in years 0-5 were included in the combined analyses of late recurrence risk. In the univariate and multivariate analyses, CTS was the strongest prognostic score in the late follow-up period (ΔLR-χ2 = 95.17, ΔLR-χ2 = 61.65, respectively) in all patients. The ROR score also added significant prognostic information in years 5-10 in the univariate and multivariate analyses, but somewhat less than the CTS (ΔLR-χ2 = 66.09, ΔLR-χ2 = 32.57, respectively) (Table 1). The risk of distant recurrence at 10 years for the low risk group was 5.7% (95% CI 4.5% to 7.2%), for intermediate risk 14.6% (12.0% to 17.6%), and for high risk 29.3% (25.5% to 33.6%). Patients with a luminal A subtype had a 70% lower risk of late distant recurrence than those with a luminal B subtype (HR = 0.30 (0.21-0.43), P&amp;lt;0.0001). Conclusions: The results of this combined analyses showed that the ROR score added prognostic information to CTS in all patients and in all patient subgroups in the late follow-up period. The risk of distant recurrence in years 5-10 was statistically significantly different for the low, intermediate risk and high risk groups. These results suggest that the ROR score may be used to separate patients into risk groups who could be spared or could benefit from extended hormonal therapy beyond 5 years of treatment. Hazard Ratio (HR) and changes in likelihood ratio test (DLR-χ2) for univariate and multivariate analyses according to all groups. Univariate Multivariate* HR (95% CI)ΔLR-χ2 (P-value)HR (95% CI)ΔLR-χ2 (P-value)All patients (N = 2137) CTS2.05 (1.80-2.34)95.17 (&amp;lt;0.0001)1.88 (1.63-2.17)61.65 (&amp;lt;0.0001)ROR2.88 (2.22-3.72)66.09 (&amp;lt;0.0001)2.14 (1.65-2.79)32.57 (&amp;lt;0.0001)Node-negative (N = 1580) CTS2.10 (1.57-2.81)22.17 (&amp;lt;0.0001)1.65 (1.19-2.30)8.28 (0.004)ROR2.67 (1.86-3.85)28.50 (&amp;lt;0.0001)2.13 (1.44-3.15)14.61 (0.0001)Node-positive (N = 557) CTS1.94 (1.58-2.37)37.48 (&amp;lt;0.0001)1.82 (1.47-2.25)26.90 (&amp;lt;0.0001)ROR2.72 (1.89-3.92)29.72 (&amp;lt;0.0001)2.28 (1.57-3.30)19.14 (&amp;lt;0.0001)HER2-negative (N = 1974) CTS2.02 (1.76-2.32)79.67 (&amp;lt;0.0001)1.84 (1.58-2.15)51.09 (&amp;lt;0.0001)ROR3.02 (2.29-4.00)62.06 (&amp;lt;0.0001)2.31 (1.73-3.07)33.48 (&amp;lt;0.0001)*Addition of either score to each other Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-04.

Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population

Biomarkers to improve the risk-benefit of extended adjuvant endocrine therapy for late recurrence in patients with oestrogen-receptor-positive breast cancer would be clinically valuable. We compared the prognostic ability of the breast-cancer index (BCI) assay, 21-gene recurrence score (Oncotype DX), and an immunohistochemical prognostic model (IHC4) for both early and late recurrence in patients with oestrogen-receptor-positive, node-negative (N0) disease who took part in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial. In this prospective comparison study, we obtained archival tumour blocks from the TransATAC tissue bank from all postmenopausal patients with oestrogen-receptor-positive breast cancer from whom the 21-gene recurrence score and IHC4 values had already been derived. We did BCI analysis in matched samples with sufficient residual RNA using two BCI models-cubic (BCI-C) and linear (BCI-L)-using previously validated cutoffs. We assessed prognostic ability of BCI for distant recurrence over 10 years (the primary endpoint) and compared it with that of the 21-gene recurrence score and IHC4. We also tested the ability of the assays to predict early (0-5 years) and late (5-10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathological variables, we calculated the change in the likelihood-ratio χ(2) (LR-Δχ(2)) from Cox proportional hazards models. Suitable tissue was available from 665 patients with oestrogen-receptor-positive, N0 breast cancer for BCI analysis. The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-C risk groups (p<0·0001) with 6·8% (95% CI 4·4-10·0) of patients in the low-risk group, 17·3% (12·0-24·7) in the intermediate group, and 22·2% (15·3-31·5) in the high-risk group having distant recurrence. The secondary analysis showed that BCI-L was a much stronger predictor for overall (0-10 year) distant recurrence compared with BCI-C (interquartile HR 2·30 [95% CI 1·62-3·27]; LR-Δχ(2)=22·69; p<0·0001). When compared with BCI-L, the 21-gene recurrence score was less predictive (HR 1·48 [95% CI 1·22-1·78]; LR-Δχ(2)=13·68; p=0·0002) and IHC4 was similar (HR 1·69 [95% CI 1·51-2·56]; LR-Δχ(2)=22·83; p<0·0001). All further analyses were done with the BCI-L model. In a multivariable analysis, all assays had significant prognostic ability for early distant recurrence (BCI-L HR 2·77 [95% CI 1·63-4·70], LR-Δχ(2)=15·42, p<0·0001; 21-gene recurrence score HR 1·80 [1·42-2·29], LR-Δχ(2)=18·48, p<0·0001; IHC4 HR 2·90 [2·01-4·18], LR-Δχ(2)=29·14, p<0·0001); however, only BCI-L was significant for late distant recurrence (BCI-L HR 1·95 [95% CI 1·22-3·14], LR-Δχ(2)=7·97, p=0·0048; 21-gene recurrence score HR 1·13 [0·82-1·56], LR-Δχ(2)=0·48, p=0·47; IHC4 HR 1·30 [0·88-1·94], LR-Δχ(2)=1·59, p=0·20). BCI-L was the only significant prognostic test for risk of both early and late distant recurrence and identified two risk populations for each timeframe. It could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy. Avon Foundation, National Institutes of Health, Breast Cancer Foundation, US Department of Defense Breast Cancer Research Program, Susan G Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, AstraZeneca, Cancer Research UK, and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden (London, UK).