10-year Risk Of Distant Recurrence Research Articles

Abstract PO1-02-02: Update of RSClin with extended TAILORx follow-up and development and validation of a new tool for risk of late distant recurrence

Abstract Background: RSClin® (Sparano et al J Clin Oncol 2020, PMID 33306425) is an educational tool that estimates the 10-year risk of distant recurrence (DR) and the absolute benefit of chemotherapy in HR-positive, HER2-negative, node-negative early breast cancer. The RSClin tool integrates the Recurrence Score® (RS) result with the clinical-pathological features tumor grade, tumor size and patient age using patient-specific meta-analysis (PSMA) applied to the NSABP B-14, TAILORx and NSABP B-20 studies. Approximately 3 years of additional follow-up data have accumulated in the TAILORx study since the RSClin tool was developed, including 50% more DR events in the RS 11-25 group (375 vs. 250), and 46% more DR events in the overall population (561 vs. 384). Methods: The RSClin tool estimates were updated to include the extended follow-up data from TAILORx. As before, the PSMA included 10,004 women with hormone-receptor positive, HER2-negative, node-negative breast cancer from the NSABP B-14 (n=577) trial receiving endocrine therapy (ET) alone and the TAILORx trial receiving ET alone (n=4854) or chemotherapy (CT) plus ET (n=4573). The baseline risk estimate used TAILORx event rates with ET alone. Since there was evidence of differing hazard ratios in years 0-5 versus 5+, models using time-varying effects were used. A patient-specific estimator of absolute CT benefit was computed by combining a PSMA estimate of the individualized relative CT effect from the TAILORx and NSABP B-20 (n=550 HER2-negative) trials with risk estimates for ET alone. Similar methods were used to develop and validate a new tool for assessing the risk of late DR (from year 5 to 10) in patients who survive DR-free for 5 years on ET alone after surgery. External validation of DR risk estimation was performed in an independent cohort of 1098 women enrolled in the Clalit Health Service registry. Results: With the updated data, the model integrating RS result with clinical-pathological features was more informative for DR risk than either RS result alone or the clinical-pathological features alone, both for 10-year DR risk and for late DR risk (likelihood ratio tests, each p≤.001). The updated 10-year RSClin risk estimates are similar to the existing RSClin tool risk estimates with slightly lower risk estimates for very high RS results and more precise estimates for mid-range RS results. The updated chemotherapy effect estimates are slightly lower than for the existing RSClin. The updated RSClin tool 10-year risk estimates were strongly associated with DR risk in the independent Clalit registry (Cox regression p< .001) and closely approximated the observed DR risk (Lin concordance 0.87). The new tool’s late DR risk estimates beyond 5 years were strongly associated with late DR risk in the Clalit registry (Cox regression p=.002) and closely approximated the observed late DR risk (Lin concordance 0.92). Conclusions: The RSClin tool 10-year DR risk estimates have been updated to incorporate extended follow-up data from the TAILORx study. A new tool for assessing late DR risk has been developed and validated that provides more prognostic information than either clinical-pathological features or genomic risk used individually. Citation Format: Joseph Sparano, Michael Crager, Robert Gray, Gong Tang, Jess Hoag, Frederick Baehner, Charles Geyer, Steven Shak, Norman Wolmark, Salomon Stemmer. Update of RSClin with extended TAILORx follow-up and development and validation of a new tool for risk of late distant recurrence [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-02.

Long-term outcomes and effects of hypofractionated radiotherapy in microinvasive breast cancer: Analysis from a randomized trial

PurposeThe natural history of microinvasive (T1mi) breast cancer is uncertain. The objective was to evaluate long-term local and distant recurrence rates following breast conserving surgery (BCS) in a prospective cohort of patients with T1mi compared to T1a-2 disease who received whole breast irradiation (WBI) in the context of a randomized trial of hypofractionation. Methods1234 patients with T1-2 N0 breast cancer were randomized to receive adjuvant WBI of 42.5Gy in 16 daily fractions, or 50Gy in 25 daily fractions after BCS. An analysis of patients with T1mi tumors compared with T1a-2 disease was performed. Kaplan-Meier estimates of local recurrence (LR), distant recurrence, and overall survival (OS) were compared using the log-rank test. ResultsMedian follow-up was 12 years. T1mi was found in 3% (n = 38) of patients. The 10-year LR rate was 22.6% in T1mi vs. 6.9% in T1a-2 breast cancer [hazard ratio (HR) = 3.73; 95% confidence interval (CI): 1.93, 7.19; p < 0.001]. The 10-year risk of distant recurrence was 5.1% for T1mi, and 12.1% for T1a-2 disease (HR = 0.56; 95% CI: 0.19, 1.84; p = 0.36). Ten-year OS was 91.5% in T1mi and 84.4% in T1a-2 disease, (HR = 0.48; 95% CI: 0.18, 1.30; p = 0.14). Rates of LR did not differ whether treated by hypofractionation or conventional fractionation (HR = 1.21; 95% CI: 0.35, 4.18; p = 0.77). ConclusionsThe risk of LR was considerably higher in patients with T1mi compared to T1a-2 tumors, but OS remained very good. Future research should evaluate the utility of wider local excision and boost radiation to optimize local control for microinvasive breast cancer.

Clinical Treatment Score post-5 years as a predictor of late distant recurrence in hormone receptor-positive breast cancer: systematic review and meta-analysis.

The Clinical Treatment Score post-5 years (CTS5) integrates four clinicopathological variables to estimate the residual disease recurrence risk in hormone receptor-positive breast cancer patients who have been treated with five years of adjuvant endocrine therapy. This study aimed to determine the accuracy of the CTS5. A systematic review was performed in accordance with the PRISMA statement. Studies relevant for inclusion in the current review were identified from The Cochrane Library, EBSCO, Ovid, PubMed, and Embase. Six papers reported on 30 354 postmenopausal patients (age range 42 to 91 years). The pooled hazard ratio (HR) of distant recurrence relative to the low-risk CTS5 category was 5.41 (95% c.i. 4.50 to 6.51; P < 0.05) for the high-risk CTS5 category and 2.32 (95% c.i. 1.90-2.84; P < 0.05) for the intermediate CTS5 category. Three papers reported on 10 425 premenopausal patients (age range 18 to 54 years). The pooled HR of distant recurrence relative to the low-risk CTS5 category was 5.42 (95% c.i. 2.26 to 13.01; P < 0.05) for the high-risk CTS5 category and 2.82 (95% c.i. 1.35 to 5.88; P < 0.05) for the intermediate CTS5 category. Relative to high-risk postmenopausal patients, the mean observed 10-year distant recurrence risk for the high CTS5 category was 13.83 per cent, which differs significantly from the CTS5 estimation of 10-year distant recurrence risk (20.3 per cent, 95% c.i. 17.2 to 24; P = 0.000). The CTS5 can predict late distant recurrence risk in pre- and postmenopausal hormone receptor-positive breast cancer patients. CTS5 overestimates the risk for high-risk patients and thus, its use in these patients warrants caution.

Abstract P1-13-06: The influence of the oncotype DX breast recurrence score on persistence to endocrine therapy in patients with low-risk ER/PR+ invasive breast cancer

Abstract Intro: The Oncotype DX breast recurrence score provides newly diagnosed patients with low-risk ER/PR+ invasive breast cancer with an estimation of their 10-year risk of distant recurrence if compliant with five years of endocrine therapy. Despite the well-established benefits of endocrine therapy, to include a decrease in local and distant disease recurrence, many patients will discontinue endocrine therapy prior to five years, defined as non-persistence. We hypothesized that the individual perception of risk of recurrence conveyed by the Oncotype DX breast recurrence score directly influences persistence with endocrine therapy and patients with higher Oncotype DX breast recurrence scores may have higher rates of persistence when compared to a similar cohort with lower recurrence scores. Further, we hypothesized that disease recurrence in women with low-risk (defined as less than 26) ER/PR+ breast cancer is due primarily to non-persistence with endocrine therapy. Methods: Our study included 198 patients with low-risk ER/PR+ breast cancer treated at a comprehensive cancer center between April 2011 and April 2014 with sufficient-follow-up data of at least 5 years. Persistence was determined by chart review and defined as a minimum duration of 55 months on endocrine therapy. Multivariable ANOVA and Fisher Chi Square Exact test were used to compare the recurrence score, 10-year risk of distant recurrence, and rates of recurrence between persistent vs non-persistent patients. Results: The average recurrence score of our cohort was 14.74 with an average 10-year risk of distant recurrence of 9.8 percent with five years of endocrine therapy. The average recurrence score was 15.24 in the persistent group vs. 13.18 for the non-persistent group (p=0.029). The average 10-year risk of distance recurrence was 10.1% in persistent patients vs 9% in non-persistent patients (p=0.019). The recurrence rate (both local and distant) was 4% in persistent patients vs 16% in non-persistent patients at 5- year follow (P=&amp;lt;0.01). Discussion: Non-persistence to endocrine therapy represents a major unmet need in breast cancer care. The Oncotype DX breast recurrence score significantly influences persistence to endocrine therapy as our retrospective review demonstrated that patients with low-risk ER/PR+ locally invasive breast cancer with higher Oncotype DX scores are more likely to complete the recommended 5-years of endocrine therapy. Further, despite having a lower average Oncotype DX score overall, the non-persistent group had a higher rate of recurrence when compared to the persistent group. This finding further substantiates the overall effectiveness of endocrine therapy in reducing the risk of future recurrence in patients with low-risk ER/PR+ breast cancer. Mindful framing of Oncotype DX test results by providers represents a potential avenue to increase persistence through the modulation of individual risk perception and may ultimately lead to decreased rates of disease recurrence in patients with low-risk ER/PR+ invasive breast cancer. Citation Format: Jonathan Pirruccello, Elaine Kuhn, Mary Chamberlin. The influence of the oncotype DX breast recurrence score on persistence to endocrine therapy in patients with low-risk ER/PR+ invasive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-13-06.

Comparison of risk assessment in 1652 early ER positive, HER2 negative breast cancer in a real-world data set: classical pathological parameters vs. 12-gene molecular assay (EndoPredict)

BackgroundRisk assessment on the molecular level is important in predictive pathology to determine the risk of metastatic disease for ERpos, HER2neg breast cancer. The gene expression test EndoPredict (EP) was trained and validated for prediction of a 10-year risk of distant recurrence to support therapy decisions regarding endocrine therapy alone or in combination with chemotherapy. The EP test provides the 12-gene Molecular Score (MS) and the EPclin-Score (EPclin), which combines the molecular score with tumor size and nodal status. In this project we investigated the correlation of 12-gene MS and EPclin scores with classical pathological markers.MethodsEndoPredict-based gene expression profiling was performed prospectively in a total of 1652 patients between 2017 and 2020. We investigated tumor grading and Ki67 cut-offs of 20% for binary classification as well as 10% and 30% for three classes (low, intermediate, high), based on national and international guidelines.Results410 (24.8%) of 1652 patients were classified as 12-gene MS low risk and 626 (37.9%) as EPclin low risk. We found significant positive associations between 12-gene MS and grading (p < 0.001), EPclin and grading (p = 0.001), 12-gene MS and Ki67 (p < 0.001), and EPclin and Ki67 (p < 0.001). However, clinically relevant differences between EP test results, Ki67 and tumor grading were observed. For example, 118 (26.3%) of 449 patients with Ki67 > 20% were classified as low risk by EPclin. Same differences were seen comparing EP test results and tumor grading.ConclusionIn this study we could show that EP risk scores are distributed differentially among Ki67 expression groups, especially in Ki67 low and high tumors with a substantial proportion of patients with EPclin high risk results in Ki67 low tumors and vice versa. This suggests that classical pathological parameters and gene expression parameters are not interchangeable, but should be used in combination for risk assessment.

Development and Validation of a Simulation Model-Based Clinical Decision Tool: Identifying Patients Where 21-Gene Recurrence Score Testing May Change Decisions.

PURPOSEThere is a need for industry-independent decision tools that integrate clinicopathologic features, comorbidities, and genomic information for women with node-negative, invasive, hormone receptor–positive, human epidermal growth factor receptor-2–negative (early-stage) breast cancer.METHODSWe adapted an extant Cancer Intervention and Surveillance Modeling Network simulation model to estimate the 10-year risk of distant recurrence, breast cancer–specific mortality, other-cause mortality, and life-years gained with chemoendocrine versus endocrine therapy. We simulated outcomes for 1,512 unique patient subgroups based on all possible combinations of age, tumor size, grade, and comorbidity level; simulations were performed with and without 21-gene recurrence scores (RSs). Model inputs were derived from clinical trials, large US cohort studies, registry, and claims data. External validation was performed by comparing results to observed rates in two independent sources. We highlight results for one scenario where treatment choice may be uncertain.RESULTSChemoendocrine versus endocrine therapy in a 65-69-year-old woman with a small (≤ 2 cm), intermediate-grade tumor, and mild comorbidities provides a 1.3% absolute reduction in 10-year distant recurrence risk, with 0.23 life-years gained. With these tumor features, a woman like this will have a 28% probability of having an RS 16-20, 18% RS 21-25, and 11% RS 26+. If testing is done, and her RS is 16-20, chemoendocrine therapy reduces 10-year distant recurrence risk to 1%, with 0.20 life-years gained, a similar result as without testing. The absolute benefits would increase to 4.8%-5.5% if the RS was 26+. The model closely reproduced observed rates in both independent data sets.CONCLUSIONOur validated clinical decision tool is flexible, readily adaptable to include new therapies, and can support discussions about genomic testing and early breast cancer treatment.

PCN23 The Development and Validation of a Simulation Model-based Clinical Decision Tool to Support Oncology Practice

There are several challenges in treating women diagnosed with node-negative, hormone receptor positive, HER2 negative (“early-stage”) breast cancer. The goal of this study is to demonstrate the application of a novel simulation model-based calculation engine for a clinical decision tool that reflects current clinical needs and facilitates modern personalized treatment decisions for women diagnosed with early-stage breast cancer. We developed a novel breast cancer simulation model within the Cancer Intervention and Surveillance Modeling Network (CISNET) to derive estimates for the risk of distant recurrence, breast cancer specific mortality, other cause mortality and life-years gained with endocrine vs. chemo-endocrine therapy for individual women based on their age, tumor size, grade, 21-gene recurrence score and comorbidity level. The model uses an empiric Bayesian analytical approach to combine information from several data sources to provide individual estimates which capture uncertainty in all predictors’ effects on outcomes and sampling variation. External validation of the model was performed by comparing model-based breast cancer mortality rates and observed rates in the Surveillance Epidemiology and End Results (SEER) registry. The model estimates varied based on a woman’s age, tumor size, grade, comorbidity-level and 21-gene recurrence assay score. For example, in a 65–69-year-old woman diagnosed with a small (≤2cm), intermediate grade tumor and mild comorbidities, the absolute benefit of chemotherapy on the 10-year risk of distant recurrence ranged from 2%-5.5% , and the life-years gained with chemotherapy ranged from 0.34 to 0.93 life-years as the recurrence score ranged from 0 to 40+. In external validation, the model estimated breast cancer-specific mortality rates by recurrence score category was similar to the observed distributions in SEER data. The model can be used to synthesize existing evidence and develop a calculation-engine for a web-based clinical decision tool that could help facilitate shared decision-making between clinicians and patients in early-stage breast cancer settings.

Application of RSClin to guide treatment recommendations for premenopausal patients with early-stage hormone-positive breast cancer and intermediate risk oncotype recurrence scores.

e12511 Background: The RSClin model, which incorporates the Oncotype Recurrence Score (RS) and clinicopathologic features, was recently developed to further tailor prognosis and prediction of chemotherapy benefit for patients with early-stage hormone positive (HR+) breast cancer (BC) (Sparano et al, 2020). The RSClin calculator is available online to assist treatment planning for situations where chemotherapy benefit is uncertain. Covariates include Oncotype RS, tumor grade, tumor size and patient age. The risk calculator generates a 10-year distant recurrence risk and absolute chemotherapy benefit. This tool may be especially helpful to determine treatment management for premenopausal patients with early-stage HR+ BC with intermediate risk (IR) Oncotype RS (16-25). We retrospectively applied RSClin to this patient population to determine if it would have changed treatment recommendations. Methods: We identified premenopausal women with node-negative early-stage BC with IR RS (16-25) within our large Oncotype database. Using the RSClin model, we selected &gt;5% absolute chemotherapy benefit as a reasonable cutoff to recommend chemotherapy. We compared the treatment recommendation based on RSClin with the treatment previously recommended by breast oncologists at our large academic medical center in New York City. Results: There were 86 patients who met criteria with a median age of 46 years. Of these, 26 patients (30%) were recommended chemotherapy plus endocrine therapy (ET) and 60 (70%) were recommended ET alone. After applying the RSClin model (data available for 83/86 patients), 19 (23%) would have resulted in a change in treatment recommendation and 64 (77%) would have remained unchanged. Overall, 8 (10%) would have withheld chemotherapy when it was previously offered and 11 (13%) would have recommended chemotherapy when it was previously excluded. There were 8 (9%) secondary invasive breast events in this population, with 2 (2%) being ipsilateral, 3 (3%) being contralateral and 3 (3%) metastatic at a median follow up of 46.9 months. Conclusions: The RSClin model would have changed management of premenopausal patients with IR RS in 23% of patients. This model, although not yet prospectively validated, may help individualize therapy for patients with less definitive treatment plans. Using RSClin, we can aim to minimize recurrence rates and avoid unnecessary chemotherapy in selected patients. This model is easy to apply and will have important clinical utility moving forward.

A simulation model-based clinical decision tool to guide personalized treatment based on individual characteristics: Does 21-gene recurrence score assay testing change decisions?

e12507 Background: There is a need for web-based decision tools that integrate clinicopathologic features and genomic information to guide breast cancer therapy for women with node-negative, hormone receptor positive, HER2 negative (“early-stage”) breast cancer. We developed a novel simulation model-based clinical decision tool that provides prognostic estimates of treatment outcomes based on age, tumor size, grade, and comorbidities with and without 21-gene recurrence scores (RS). Methods: We adapted an extant breast cancer simulation model developed within the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) to derive estimates for the 10-year risks of distant recurrence, breast cancer-specific mortality, other cause mortality and life-years gained with endocrine vs. chemo-endocrine therapy for individual women based on their age, tumor size, grade, and comorbidity-level with and without RS test results. The model used an empiric Bayesian analytical approach to combine information from clinical trials, registry and claims data to provide individual estimates. External validation of the model was performed by comparing model-based breast cancer mortality rates and observed rates in the Surveillance Epidemiology and End Results (SEER) registry. Results: Several exemplar profiles were selected to illustrate the clinical utility of the decision tool. For example, the absolute chemotherapy benefit for 10-year distant recurrence risk and life-years gained, without RS testing, and the outcomes if a woman got tested and had a RS 16-20 are provided below for a 40-44-year-old woman and a 65–69-year-old woman diagnosed with a small (≤2cm), intermediate grade tumor and mild comorbidities. Conclusions: Simulation modeling is useful for creating clinical decision tools to support shared decision making for early-stage breast cancer treatment.[Table: see text]

Exploring the effects of genomic testing on fear of cancer recurrence among breast cancer survivors.

Fear of cancer recurrence (FCR) is the greatest unmet psychosocial need among breast cancer survivors (BCS). The Oncotype Dx® test predicts the 10-year risk of distant recurrence and benefit of adjuvant chemotherapy among women with early stage hormone receptor-positive breast cancer. Despite the test's clinical utility, psychosocial responses are poorly understood. A descriptive cross-sectional study was conducted to explore associations between Oncotype Dx® test results (Recurrence Score [RS]) and FCR, health-related quality of life (HRQOL), distress, anxiety, depression, illness representation and perceived risk. Bivariate analyses were used to examine the associations between variables followed by multiple linear regression to examine predictors of FCR. Greater FCR was associated with higher distress, anxiety, depression, illness representation and poorer HRQOL. BCS's with a high Oncotype Dx® RS reported higher overall fear (p=0.013) and greater perceived consequences of their cancer (p=0.034) compared to BCS's with a low RS. Using multiple linear regression, anxiety ( =0.21, p=0.016), greater emotional response =0.45, p<0.001) and perceived consequences ( =0.18, p=0.039) of illness explained 58% of the variance (p<0.001) in FCR. BCS's with higher risk of recurrence may experience higher FCR. However, for FCR, modifiable factors such as anxiety and illness representation (greater emotional response and perceived consequences of illness) may be more important than non-modifiable factors such as Oncotype Dx® test results and age. Further research is needed to develop personalized interventions to improve BCS's outcomes.

Abstract PS4-21: Comparison of risk assessment in primary ER+, HER2- Breast Cancer in a real-world data set: Classical pathological parameters vs. 12-gene molecular assay (EndoPredict)

Abstract Background: Risk assessment on molecular level is becoming more common in modern pathology to determine the recurrence risk for patients diagnosed with estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer (BC). The gene expression test EndoPredict (EP) was trained and validated to predict a 10-year risk of distant recurrence to support therapy decision regarding endocrine therapy alone or in combination with chemotherapy. The EP test provides the 12-gene molecular score (12-gene MS) and the EPclin-Score (EPclin) combining the molecular score with tumor size and nodal status. In this project we investigated the correlation of 12-gene MS and EPclin scores with classical pathological markers like tumor grading and proliferation. Methods: Retrospectively, we investigated EP test results in a total of 1652 patients tested in clinical routine from 2017 to 2020 at the Institute of Pathology, Charité University Hospital, Berlin. Consecutive cases with valid EP test result and available tumor grading and proliferation (Ki67) status were included in the dataset. 12-gene MS and EPclin were classified as low or high risk based on validated cutoff values at 5 and 3.32867, respectively. Ki67 cut-offs were set according to St. Gallen guidelines at 20% for binary classification (Bustreo et al., 2016) and Federal Joint Committee (G-BA) guidelines, using 10% and 30% for three classes (low, intermediate, high). Results: In our dataset with 1652 cases, 1242 (75.2%) cases were detected as 12-gene MS high risk and 1026 (62.1%) as EPclin high risk score. Mean Ki67 expression was 17.5% (95%CI 16.9 - 17.9). As expected we found a strong association between risk scores and clinical parameter with p-values ≤ 0.001: In the Ki67 binary low group (N=1203, Ki67≤20%) 695 (57.8%) patients had a EPclin high risk score while in the Ki67 binary high expression group (&amp;gt;20%) still 118 (26.3%) patients had a EPclin low risk score. Similar results were found using three Ki67 classes: In the Ki67 low (N=557, &amp;lt;10%) group 299 (53.7%) patients had EPclin high results and in the Ki67 high (N=101, &amp;gt;30%) group, 28 (27.7%) patients were classified as EPclin low (p&amp;lt;0.001). Regarding tumor grading we observed a correlation between poorly differentiated breast cancer (G3) and a higher EPclin risk score. Nevertheless, in Grade 1 tumors (N=140) 57.9% of patients had a EPclin high risk score (p=0.001). In comparison, in 25% (N=46) of G3 cases EPclin risk score was low. Similar results were seen using 12-gene-MS, not shown here. Conclusions: In this study we could show that EP risk scores are distributed differently among Ki67 expression groups, especially in Ki67 low (&amp;lt;10%) and high (&amp;gt;30%) tumors with a substantial proportion of patients with EPclin high risk results in Ki67 low tumors and vice versa. Our research group is currently collecting a long time follow up of all patients. Citation Format: Paul Jank, Carsten Denkert, Judith L Lindner, Annika Lehmann, Berit M Pfitzner, Jens-Uwe Blohmer, David Horst, Ralf Kronenwett, Wolfgang D Schmitt. Comparison of risk assessment in primary ER+, HER2- Breast Cancer in a real-world data set: Classical pathological parameters vs. 12-gene molecular assay (EndoPredict) [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 PS4-21.

Abstract GS4-10: Development and validation of a tool integrating the 21-gene recurrence score and clinicopathlogic features to individualize prognosis for distant recurrence and prediction of absolute chemotherapy benefit in early breast cancer

Abstract Background: The 21-gene recurrence score (RS) provides prognostic information for distant recurrence (DR) and predictive information for chemotherapy (CT) benefit in early breast cancer, whereas clinicopathologic features provide only prognostic information. We used patient-specific meta-analysis (PSMA) methods (Crager et al, J Appl Stat 2014 [PMID: 26664111]; Tang et al. J Clin Oncol 2011 [PMID: 22010013]) to develop an online tool that assesses individualized estimates of DR risk and absolute CT benefit. We also externally validated this new tool for estimating DR risk in an independent cohort.Methods: The PSMA included 10,004 women with hormone-receptor positive, HER2-negative, node-negative breast cancer from the NSABP B-14 (n=577) trial receiving endocrine therapy (ET) alone and TAILORx trial receiving ET alone (n=4854) or CT plus ET (n=4573). The baseline risk used TAILORx event rates with ET alone. A patient-specific estimator of absolute CT benefit was computed by combining PSMA of the individualized relative CT effect from the TAILORx and NSABP B-20 (n=550 HER2-negative) trials and risk estimates with ET alone. External validation of DR risk estimation was performed in an independent cohort of 1098 women enrolled in the Clalit Health Service registry who had a 21-gene RS performed, of whom 222 (20%) received CT in addition to ET as per the recommendation of their treating physician guided by the RS. Results: The new tool is more informative for DR risk than RS or clinicopathologic factors alone (p&amp;lt;0.001, likelihood ratio test). The risk estimate was significantly associated with DR risk in the independent Clalit cohort (p&amp;lt;0.001), and closely approximated the observed 10-year DR risk (Lin concordance 0.962). Since the RS strongly influenced CT use, propensity score matching could not appropriately be used for evaluation of CT benefit in Clalit. Using this tool for a 55-year-old woman with a low clinical risk 1.5 cm intermediate grade tumor, the absolute CT benefit estimate ranges from 0% to 15% as RS ranges from 11 to 50; this compares to a range of 2% to 8% if the relative CT benefit were held constant. Over the same RS range for a 55-year-old woman with high clinical risk 2.5 cm poor grade tumor, the tool’s absolute CT benefit estimate ranges from 1% to 33% compared to 4% to 17% if the relative CT benefit were held constant. This indicates that incremental CT benefit observed with higher RS is driven not only by a higher underlying recurrence risk, but also by prediction of relative CT benefit.Conclusions: We describe a validated clinical tool integrating clinicopathologic and genomic features to guide adjuvant chemotherapy of hormone-receptor positive, HER2-negative, axillary node-negative breast cancer with greater precision than using clinicopathologic or genomic data alone. The individualized CT effect prediction provided by the RS, based on contemporary treatments, contributes substantially to the estimate of absolute CT benefit. Support: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180822, U10CA180868, and UG1CA189859. The content is solely the responsibility of the authors. Mention of commercial products does not imply endorsement by the U.S. government. Additional support was provided by the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp (BCRS) issued by the United States Postal Service. Citation Format: Joseph A Sparano, Michael R Crager, Gong Tang, Robert J Gray, Salomon M Stemmer, Steve Shak. Development and validation of a tool integrating the 21-gene recurrence score and clinicopathlogic features to individualize prognosis for distant recurrence and prediction of absolute chemotherapy benefit in early breast cancer [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 GS4-10.

Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer

PurposeClinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer.MethodsThe validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5–10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan–Meier curves were used with associated 10-year DR risks (%).Results2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78–2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32–2.56)). The 10-year DR risks were 2.9% (1.9–4.5), 7.2% (5.3–9.9), and 12.9% (10.0–16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2–6.7), 6.9% (4.4–10.8), and 11.1% (7.4–16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded.ConclusionsThe CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy.

367 Poster - The REMAR (Rhein-Main-Registry)-Study: Prospective evaluation of oncotype DX® Assay in Addition to Ki-67 for adjuvant treatment decisions in early breast cancer

Background: The 21-gene Recurrence Score® (RS) assay predicts the likelihood of chemotherapy benefit and 10-year risk of distant recurrence. Thus, this test might be useful to guide adjuvant treatment decisions in HR+/HER2− early breast cancer (EBC). The Oncotype DXÒ Test clinical utility was validated worldwide in major trials including more than 63,000 patients. There are only few studies that investigate the correlation of Ki67 with tumor grade and RS result. The REMAR-Study was designed to assess this correlation as a prospective, non-interventional, multicenter and non-randomized study.

Prognostic Value of EndoPredict in Women with Hormone Receptor-Positive, HER2-Negative Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) accounts for approximately 5%-15% of all invasive breast cancer cases. Most of the correlations between multigene assays and patient outcome were derived from studies based on patients with invasive ductal carcinoma (IDC) or without distinction between the subtypes. Here, we investigate the prognostic value of EndoPredict (EPclin) in a large cohort of ILCs pooled from three phase III randomized trials (ABCSG-6, ABCSG-8, TransATAC). The primary objective of this analysis was to determine the prognostic value of EPclin for distant recurrence (DR) in years 0-10 in postmenopausal women with ILC. The primary outcome was DR. 470 women (17.9%) presented with ILC, 1,944 (73.9%) with IDC, and 216 (8.2%) with other histologic types. EPclin was highly prognostic in women with ILC [HR = 3.32 (2.54-4.34)] and provided more prognostic value than the Clinical Treatment Score [CTS; HR = 2.17 (1.73-2.72)]. 63.4% of women were categorized into the low EPclin risk group and they had a 10-year DR of 4.8% (2.7-8.4) compared with 36.6% of women in the high-risk group with a 10-year DR risk of 26.6% (20.0-35.0). EPclin also provided highly prognostic information in women with node-negative disease [HR = 2.56 (1.63-4.02)] and node-positive disease [HR = 3.70 (2.49-5.50)]. EPclin provided highly significant prognostic value and significant risk stratification for women with ILC. Ten-year DR risk in the EPclin low-risk groups were similar between ILC and IDC. Our results show that EPclin is informative in women with ILC and suggest that it is equally valid in both histologic subtypes.

Abstract P5-06-05: Discordant classification and outcomes between Prosigna and Oncotype Dx Recurrence Score for ER-positive, HER2-negative, node-negative breast cancer

Abstract Background: Several multigene assays are available for managing ER-positive, HER2-negative early stage breast cancer but with little direct comparative information within this patient population. Existing evidence suggests that current multigene assays provide broadly equivalent risk information for the population of women with ER-positive, HER2-negative breast cancers. However, for the individual patient tests may provide differing risk categorization (Bartlett et al, JNCI 2016). We have previously demonstrated the prognostic value of different commercially available tests including Prosigna (ROR) and Oncotype Dx (RS) (Dowsett et al, JCO 2013; Sestak et al, JAMA Onc 2018). Here, we investigate risk classification and 10-year DR rates in patients that had discordant risk categorization between ROR and RS. Methods: A total of 663 postmenopausal women with ER-positive, HER2-negative, node-negative early stage breast cancer from the TransATAC study for whom both signatures were available were included in this analysis. The primary endpoint was distant recurrence (DR). Predefined ROR cut-off points for low/intermediate and intermediate/high of 40/60 were used. Comparisons were made using two sets of RS cut-off points 1) TailoRX cut-off points of 10/25 and 2) original cut-off points of 18/31. Kaplan-Meier curves were used to estimate the mean risk of DR after 10 years of follow-up in predefined risk groups. Results: Using original RS cut-off points, 25 patients (3.8%) had a high-low discordance compared to ROR, with a total of 295 (44.5%) discordant cases. Using the TailoRx cut-off points, 40 patients (6.0%) had a high-low discordance compared to ROR, with a total of 396 (59.7%) discordant cases. Applying original RS cut-off points, patients categorized into ROR low but into intermediate or high by RS (86/365 (23.6%)) had a 10-year DR rate of only 6.3% (2.7-14.6) (Table). In contrast, patients categorized into RS low but into intermediate or high by ROR (144/423 (48.6%)) had a 10-year DR rate of 13.4% (8.3-21.2). Using the TailoRx cut-off points, patients categorized into ROR low but into intermediate or high by RS (261/365 (71.5%)) had a 10-year DR rate of 2.9% (1.4-5.9), while patients with an RS low but intermediate or high by ROR (62/166 (37.3%)) had a 10-year DR rate of 18.2% (10.2-31.2) (Table). Conclusion: Discordance in risk categorization at the individual patient-level between commercially available multigene assays for early stage breast cancer is not uncommon. Our results show that node-negative patients that were classified by ROR as low risk, regardless of RS risk stratification, had an excellent 10-year DR risk with endocrine therapy alone. In contrast, patients that were classified as RS low risk by either cut-off points but were classified as intermediate or high risk by ROR had a significantly worse 10-year outcome. Our results indicate that ROR better categorized women with node negative disease into respective risk groups. Risk stratification and 10-year DR risk (%) according to ROR and RS cut-off points.ROR cut-offsLow (N=365)Intermediate/High(N=298)Original RS cut-offsNumber10-year risk (%)Number10-year risk (%)Low (N=423)2791.5%14413.4%Intermediate/High (N=240)866.3%15424.8%TailoRx cut-offsLow (N=166)1042.1%6218.2%Intermediate/High (N=497)2612.9%23619.5% Citation Format: Ivana Sestak, Sean Ferree, Itay Shemesh, Wesley Buckingham, Jack Cuzick, Mitchell Dowsett. Discordant classification and outcomes between Prosigna and Oncotype Dx Recurrence Score for ER-positive, HER2-negative, node-negative 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 P5-06-05.

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, &amp;gt;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&amp;gt;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 P6-10-14: A new model to predict 10-year distant recurrence risk for operable endocrine-responsive breast cancer population

Abstract Background Few currently available biomarker panels can predict the risk of long-term distant recurrence (DR) in endocrine-responsive breast cancer (ERBC) patients based on lymph-node (LN) status. A new model, DGM-CM6 (Distant Genetic Model-Clinical variable Model 6), has been developed for the prediction of DR risk in our previous studies. To interrogate the prognostic value of our DGM-CM6 model for ERBC patients stratified by LN status, we retrospectively studied 752 operable breast cancer patients treated in a cancer center from 2005 to 2014. Patients and Methods Of 752 tumors, a total of 499 ERBC patients was identified from both IHC method (n=490) and PAM50 method (n=404). ERBC patients were classified by high and low-risk groups using the cutoff (&amp;lt;33 or 33) of DGM-CM6 score. Wilcoxon rank sum test was used for the association study between DGM-CM6 score and ERBC subtype status. Kaplan-Meyer survival curves were used to compare the prognostic difference of DRFS and OS in different ERBC risk groups stratified by LN negative (LN-) and positive (LN+) status. Multivariate Cox proportional-hazards regression was used to determine the hazard ratio (HR) of risk groups adjusted by clinical confounders such as treatment and tumor stages. Results Significant differences were observed between DGM-CM6 low- and high-risk patients with 10-year DRFS in LN- (ERBC identified by IHC: P = 0.011; by PAM50: P&amp;lt; 0.0001) and LN+ (ERBC identified by IHC: P = 0.015; by PAM50: P = 0.019) by log-rank test. Compared to risk prediction by intrinsic subtype, DGM-CM6 performed better in LN- patients and equally good in LN+ patients. Further multivariate analysis confirmed the independent strength of DGM-CM6 model in the prediction of high- vs. low- risk groups in DRFS (P &amp;lt; 0.0001, HR: 6.76; 95% CI, 1.8-25.42) and OS (P = 0.01, HR: 6.06; 95% CI:1.55-23.47), respectively. Conclusion DGM-CM6 model can be used to predict low- and high-risk of 10-year distant recurrence in both LN- and LN+ ERBC patients. This model needs a large scale of clinical trials to validate its clinical utility. Table 1. Multivariate cox regression analyses for the prognosis of predicted risk groups after adjusted for other clinical variables in the distant recurrence (DR, p=0.005) and overall survival (OS, p=0.01) respectively. Results shows that there is no interaction between chemotherapy and risk groups (DR: p=0.163; OS: p=0.195). Abbreviations: DR, distant recurrence; OS: overall survival.GroupsDROSHR [95% CI]pvHR [95% CI]pvRisk: high vs.low6.76 [1.8;25.42]0.005 ***6.06 [1.55;23.74]0.01 ***Age: &amp;lt;50 vs. &amp;gt;50yrs0.86 [0.51;1.44]0.5630.68 [0.38;1.19]0.175LN: Pos. vs. Neg.1.64 [0.88;3.05]0.1161.6 [0.79;3.22]0.189Stage: II vs. I1.35 [0.76;2.4]0.31.45 [0.76;2.77]0.264Stage: III vs. I2.08 [0.59;7.3]0.2531.59 [0.34;7.46]0.557Grade: 2 vs. 12.14 [0.77;5.97]0.1461.81 [0.63;5.25]0.272Grade: 3 vs. 11.2 [0.4;3.62]0.7481.21 [0.38;3.86]0.752PAM50: Normal vs. LumA0.6 [0.13;2.64]0.4960.7 [0.16;3.16]0.645PAM50: LumB vs. LumA1.58 [0.84;2.98]0.1591.29 [0.65;2.59]0.469PAM50: Her2 vs. LumA0.81 [0.25;2.68]0.7311.01 [0.29;3.47]0.986RT: Yes vs. No0.88 [0.47;1.66]0.7010.71 [0.36;1.41]0.326CT: Yes vs.No0.36 [0.11;1.12]0.0770.3 [0.09;1]0.05 *Interaction: CT vs. Risk0.36 [0.09;1.51]0.1630.36 [0.08;1.68]0.195 Citation Format: Lei Lei, Skye Hung-Chun Cheng, Xiao-Jia Wang, Yin-Yuan Mo, Yun-Yun Zhou. A new model to predict 10-year distant recurrence risk for operable endocrine-responsive breast cancer population [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 P6-10-14.

Predicting Expected Absolute Chemotherapy Treatment Benefit in Women With Early-Stage Breast Cancer Using EndoPredict, an Integrated 12-Gene Clinicomolecular Assay.

PURPOSEPrevious studies have shown EndoPredict (EPclin), a test that integrates 12-gene expression data with nodal status and tumor size, to be predictive for risk of distant recurrence in women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative early-stage breast cancer. Here, we modeled expected absolute chemotherapy benefit on the basis of EPclin test results.METHODSThe effect of chemotherapy was modeled using previously validated 10-year risk of distant recurrence as a function of EPclin score for patients treated without chemotherapy. Average relative chemotherapy benefit to reduce breast cancer distant recurrence was evaluated using a published meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group. Absolute chemotherapy benefit differences were estimated across a range of interaction strengths between relative chemotherapy benefit and EPclin score. The average absolute benefit was calculated for patients with high and low EPclin scores using the distribution of scores in 2,185 samples tested by Myriad Genetics.RESULTSThe average expected absolute benefit of chemotherapy treatment for patients with a low EPclin score was 1.8% in the absence of interaction and 1.5% for maximal interaction. Conversely, the expected average absolute chemotherapy benefit for patients with a high EPclin score was 5.3% and 7.3% for no interaction and maximal interaction, respectively.CONCLUSIONFor women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative early-stage breast cancer, a high EPclin score identified which patients would benefit most from adjuvant chemotherapy in terms of absolute reduction of distant recurrence, regardless of the amount of interaction between EPclin and relative chemotherapy benefit. A high degree of prognostic discrimination for distant recurrence is more important for identifying patients likely to benefit most from chemotherapy than an interaction between EPclin and treatment-relative benefit.

Should a Multigene Signature be Used in all Luminal Early Breast Cancers.

Background: Multigene signatures refine the risk of recurrence and guide adjuvant chemotherapy decision in luminal breast cancers. The decision to perform the assay is highly variable among oncologists. In order to guide the appropriate clinical group in whom to perform a genomic signature, our study analyzed in a homogeneous cohort which clinical risk groups triggered the use of the PAM50-based signature and their concordance with the genomic risk.Methods: A real life cohort of 222 early breast cancer patients with hormone receptor positive and HER2 negative disease had a commercial PAM50-based assay (Prosigna®) performed at our institution. The assay provided the risk group, the 10-year risk of distant recurrence and the intrinsic molecular subtype of breast cancer.Results: Based on nodal involvement, Ki67, tumor grade, mitotic index, and tumor size, no clinical pattern could identify a specific genomic risk group. The discordance with the genomic risk was high in patients with clinical low risk tumors, both in node negative and node positive patients. Up to 60% of them had a 10% or more risk of distant recurrence. Moreover, we identified a subgroup of luminal A tumors with a high genomic risk of recurrence. Genomic risk and intrinsic subtype were strong determinants of chemotherapy decision.Conclusions: Clinical profiles could not reliably identify genomic risk groups and guide the decision to use a multigene signature. Significant discordance with the genomic risk was observed within low clinical risk and luminal A tumors.