21-gene Recurrence Score Assay Research Articles

Tumor grade and progesterone receptor status in predicting benefit of chemotherapy in high genomic risk breast cancer

ABSTRACT Background Not all eligible breast cancer (BC) patients could afford the expensive test of 21-gene recurrence score (RS) assay. This study aimed to identify clinicopathological factors associated with high-risk RS and examine whether these factors correlate with the benefit of chemotherapy. Research design and methods Patients diagnosed with early-stage BC, node-negative, and estrogen receptor-positive disease were identified from the Surveillance, Epidemiology, and End Results Oncotype DX database. Result We included 74,605 patients. Those with higher grade (p < 0.001) and progesterone receptor-negative (PR Neg) (p < 0.001) had the highest odds of a high-risk RS. Among them, 3.2%, 10.1%, 39.1%, 18.6%, 41.6%, and 80.1% had high-risk RS tumors in PR-positive (PR Pos)/well-differentiated (G1), PR Pos/moderately differentiated (G2), PR Pos/poorly and/or undifferentiated (G3), PR Neg/G1, PR Neg/G2, and PR Neg/G3 groups, respectively. Receipt of chemotherapy was associated with improved breast cancer-specific survival (p = 0.010) and overall survival (p < 0.001) in high-risk RS cohort. However, there were no survival benefits from chemotherapy in patients with PR Neg/G3 disease and other groups after stratification by grade and PR status (all p ≥ 0.05). Conclusion Our study aids in refining patient selection for the RS testing, which is crucial given its economic implications. However, 21-gene RS remains pivotal for treatment decision-making.

Clinical and Genomic Risk for Late Breast Cancer Recurrence and Survival

BackgroundThe 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor–positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown.MethodsA patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry.ResultsRSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92).ConclusionsThe 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.)

Updated SEER database study of 21-gene assay to assess breast cancer–specific mortality and benefit of chemotherapy by race and ethnicity.

533 Background: In randomized studies (NSABP B-20, SWOG 8814, TAILORx, RxPONDER), the predictive effect of the 21-gene Breast Recurrence Score assay (RS) on chemotherapy (CT) benefit has been evaluated in patients with node-negative (N0) and node-positive (N+) breast cancer. Retrospective analyses of TAILORx and RxPONDER demonstrated differences in outcome by racial/ethnic groups (RG); however, there were no differences in CT benefit for any of the clinical outcome measures. In this study we characterized the association between the RS result and breast cancer-specific mortality (BCSM) and chemotherapy benefit in BCSM in RG in the recently updated, population-based SEER registries. Methods: Eligible patients were from the SEER 17 registries, November 2022 submission, and had non-metastatic, hormone receptor-positive, HER2-negative, node negative (N0) breast cancer diagnosed between 2006 and 2019 with a RS result. Analyses were weighted using the inverse of estimated propensity of using CT (yes vs. none/unknown). Prognosis was ascertained by estimating breast cancer specific survival (BCSS) at 9 years among patients with CT recorded as none/unknown by RG. The log-rank test was used to compare BCSM by RG. Multivariable Cox models, including RS result (26-100 vs. 0-25) x CT interaction, were used to assess whether RS result was predictive of CT benefit. Analyses were performed in the overall cohort and in Hispanic (H), non-Hispanic Asian and Pacific Islander (NHAPI), non-Hispanic Black (NHB), and non-Hispanic White (NHW) RGs. Results: There were 145,642 eligible patients and 3,212 breast cancer deaths. Median follow-up was 68 months. NHB patients had higher median RS result and CT usage than other groups (p &lt; .001). In N0 patients, higher RS result was associated with lower 9-year BCSS, both overall and by race/ethnicity (p &lt; .001). In Cox multivariable models (Table), the interaction between RS result by CT was significant among all N0 patients (p &lt; .001) and in NHB patients (p = 0.005), NHW patients (p = 0.002), and H patients (p = 0.019), but not in NHAPI patients (p = 0.766). Analyses of patients with N+ disease and more detailed analysis of CT benefit according to RS results by RG are underway and will also be presented. Conclusions: Real-world evidence from the SEER registries in over 145,000 patients confirms the 21-gene assay is prognostic for BCSS in all groups by race and ethnicity. The RS result was predictive of CT benefit in N0 patients overall and in Hispanic, NHB, and NHW patients, but not in NHAPI patients in this analysis. [Table: see text]

Abstract PO2-02-03: Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country

Abstract INTRODUCTION: Oncotype DX® recurrence score (ODX RS) is a 21-gene assay warranted to determine the the prognosis in patients with hormone receptor positive, HER-2 negative early stage breast cancer. In this context, the test is also predictive of benefit of adjuvant chemotherapy.1,2,3 OBJECTIVES: We aimed to correlate the clinical and pathological factors associated with Oncotype DX® 21-Gene in patients diagnosed with early stage Breast Cancer. Additionally, description of adjuvant treatment patterns and survival outcomes were described according to the Oncotype DX® 21-Gene result. METHODS: Data from medical records from a single center in Brazil were collected retrospectively from women over 18 years diagnosed with early breast cancer between 2012 and 2022. Included patients were diagnosed with stage T1-T2 breast cancer, hormone receptor positive, HER-2 negative, with up to three positive lymph nodes. All included patients had an Oncotype DX® test performed after definitive breast surgery. The ODX RS has been categorized into two levels according to menopausal status. Correlation between breast cancer recurrence and clinicopathological characteristics was done. The software SPSS was used for statistical analyzes with the significance of 0.05. RESULTS: From 197 patients, 20 have had breast cancer recurrence (10.15%) whom 10 were premenopausal and 10 were postmenopausal. The median ODX RS in these 20 patients was 15 (ranged from 9 to 31). The most common site of recurrence was breast and regional recurrence in 18 patients (90%). Adjuvant chemotherapy was omitted in 16 patients (80%) who have had breast cancer recurrence. Among premenopausal patients whose ODX RS was &amp;gt;20, 33 patients (91.66%) received adjuvant chemotherapy. Among postmenopausal patients whose ODX RS was &amp;gt;25, 19 (86.36%) received adjuvant chemotherapy. The probability of recurrence free survival was worse in premenopausal patients &amp;gt; 44-years-old compared to those with &amp;lt; =44 years-old (p = 0.036) and also worse in histological grade 3 tumors compared to grade 1 (p=0.0048). Tumor size &amp;gt;14 millimeters (mm) was correlated to worse recurrence free survival in premenopausal patients (p=0.017). Low estrogen and progesterone receptor was associated with a higher ODX RS (p=0.0035 and p&amp;lt; 0.0001, respectively) in premenopausal patients, but not associated with recurrence free survival. Clinicopathological characteristics and recurrence free survival correlation in postmenopausal patients were not significant. CONCLUSION: This retrospective analysis suggests that factors other than the Oncotype DX® score, such as age and grade contributed to worse survival outcomes among our patients population. Of note, age older than 44 years-old, histological grade 3 and tumor size &amp;gt;14 mm were associated with a higher probability of recurrence in premenopausal patients, despite the Oncotype DX® score. REFERENCES: 1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med [Internet]. 2004;351(27):2817–26. Available from: http://dx.doi.org/10.1056/NEJMoa041588. 2. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med [Internet]. 2018;379(2):111–21. Available from: http://dx.doi.org/10.1056/NEJMoa1804710. 3. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med [Internet]. 2021;385(25):2336–47. Available from: http://dx.doi.org/10.1056/NEJMoa2108873. Table 1 – Clinical and pathological characteristics of 197 hormone receptor positive, HER-2 negative early breast cancer patients who did the Oncotype DX® 21-Gene Recurrence Score assay. Data from medical records collected retrospectively of women diagnosed with early breast cancer between 2012 and 2022 from a single center in Brazil. Figure 1 – Probability of recurrence free survival in premenopausal patients according to age &amp;lt;=44 (blue line) or &amp;gt; 44-years-old (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Figure 2 – Probability of recurrence free survival in premenopausal patients according to histological grade. Tumor with histological grade 1 (blue line) or histological grade 3 (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Citation Format: Carolina Cavalcanti Gonçalves Ferreira, Julio Araujo, Shermann Brandão Rodrigues Moreira, Antônio Buzaid, Débora Gagliato. Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country [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 PO2-02-03.

Abstract PO2-09-03: Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants

Abstract Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 (BRCA1/2) pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline PALB2 PV have not previously been described. This is of particular relevance as PALB2 BC has demonstrated biologic features similar to BRCA1/2 BC such as poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) sensitivity. Methods: Patients with early-stage, HR+, HER2-, invasive breast cancer and a germline PALB2 PV were ascertained from academic cancer center databases and the Prospective Registry of MultiPlex Testing (PROMPT), an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. Study participants (pts) were categorized by age &amp;lt; 50 and ≥50. Oncotype DX RS were retrospectively reviewed and categorized as those that would and would not warrant consideration of chemotherapy (≥16 and &amp;lt; 16, respectively, for pts &amp;lt; 50; ≥26 and &amp;lt; 26, respectively, for pts ≥50). Yates corrected Chi-square tests were used to compare RS distributions between carriers and a previously published genetically unselected reference population. Results: Oncotype DX reports were reviewed for 20 pts with BC and germline PALB2 PV. Median RS was 19 (range 6-41) overall. Four patients were diagnosed under the age of 50 (range 33-48); median RS for these individuals was 19 (range 12-41). Sixteen patients were diagnosed at age 50 or greater (median 59, range 50-70); median RS for these individuals was also 19 (range 6-31). Compared to the genetically unselected reference population, Oncotype DX RS in pts with PALB2-associated BC demonstrated a numerical but not statistically significant shift in distribution towards categories in which chemotherapy would be considered. Among pts under the age of 50, 75% had Oncotype DX RS for which chemotherapy would be considered and 25% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.726 compared to reference). Among pts aged 50 and older, 25% had Oncotype DX RS for which chemotherapy would be considered and 75% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.579 compared to reference). Conclusions: Compared to data from the published genetically unselected commercial database, BC associated with PALB2 PV may have higher Oncotype DX RS reflective of intrinsically less favorable biology and greater therapeutic sensitivity. Larger datasets are forthcoming to confirm presence of significant differences in Oncotype DX RS distributions between BC with and without PALB2 PV. Table 1. Oncotype DX RS distribution by age among pts with gPALB2 PV and genetically unselected reference *Jakubowski et al., J Surg Oncol 2020. PMID 3249731 Citation Format: Payal Shah, Siddhartha Yadav, Jamie Brower, Jada Hamilton, Erica Simmons, Judy Garber, Kenneth Offit, Mark Robson, Fergus Couch, Susan Domchek. Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants [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 PO2-09-03.

Use of axillary ultrasound to guide breast cancer management in the genomic assay era.

Chemotherapy is conventionally offered to non-stage IV breast cancer patients with metastatic nodes. However, the RxPONDER trial showed that chemotherapy can be omitted in selected patients with 1-3 metastatic nodes if the 21-gene assay recurrence score is ≤25. We aimed to investigate if axillary ultrasound can identify this group of patients with limited nodal burden so that they can undergo upfront surgery followed by gene assay testing, to potentially avoid chemotherapy. T1-3, node positive, hormone receptor-positive and HER2-negative breast cancer patients ≥50 years old with axillary lymph node dissection (ALND) were reviewed from 2 centres. Patients with neoadjuvant chemotherapy and bilateral cancers were excluded. Number of ultrasound-detected abnormal axillary nodes, demographic and histological parameters were correlated with the number of metastatic nodes found on ALND. 138 patients were included, 59 (42.8%) and 79 (57.2%) patients had 1-3 and >3 metastatic nodes on ALND respectively. On logistic regression and ROC analysis, the number of ultrasound-detected abnormal nodes was significant (p <0.001) for predicting limited nodal burden (ROC AUC = 0.7135). Probabilities of <4 metastatic nodes with ultrasound cut-offs of 5, 6 and 8 abnormal nodes were 0.057, 0.026 and 0.005 respectively, with 100% specificity. A cut-off of ≤5 ultrasound-detected abnormal nodes can distinguish between patients with limited versus high nodal burden, with high specificity. Hence, incorporating the number of abnormal ultrasound-detected nodes into clinical practice may prove useful in guiding between upfront surgery and gene assay testing or neoadjuvant chemotherapy in this group of patients.

Abstract B082: Early risk stratification of ER+/HER2– breast cancer patients using digital pathology and multi-task, weakly-supervised deep learning

Abstract Breast cancer prognostication guides treatment decisions, with transcriptomic assays like Prosigna and Oncotype DX providing valuable risk of recurrence (ROR) scores in ER+/HER2– patients. However, these tests are costly and require sufficient biopsy tissue for accuracy. Pathology images are routinely available and could expedite rapid risk stratification at lower cost. We propose a multi-modal, multi-task deep neural network that learns transcriptomic ROR using digital pathology images and hormone receptor expression status. Because the incorporation of both pathology images and clinical data has proven beneficial in other deep learning models, we hypothesized that incorporation of this complementary information would improve ROR predictions compared to using pathology images alone. We modified the “clustering-constrained-attention multiple-instance learning” (CLAM) deep learning method to perform multi-task regression and infer continuous risk scores (instead of discrete risk categories). We evaluated (1) PAM50 ROR-P, calculated using a multivariate model based on intrinsic subtype centroids and a proliferation score, and (2) a 21-gene assay recurrence score (RS) (research version of Oncotype DX), calculated from component scores relating to proliferation, ER, HER2, and invasion. Using data from 899 patients in the Carolina Breast Cancer Study, a population-based study of diverse patients including 50% Black women and 50% women under age 50, we constructed training (n=714), validation (n=93), and test (n=92) sets. Genomic data were assayed by Nanostring, and digital pathology was based on H&amp;E-stained whole slide images (WSIs). Models were assessed using Pearson correlation between measured and predicted ROR-P or RS. The model with the highest correlations on the test set used H&amp;E WSIs and ER/PR/HER2 expression status as inputs and generated 10 independent outputs: ROR-P, four PAM50 centroid correlations (i.e., Basal, HER2-enriched, Luminal A, and Luminal B), RS, and four RS component scores. Prediction was strong when considering all participants in the test set (ROR-P, 0.78; RS, 0.83, N, 92) but was reduced among more clinically homogeneous ER+/HER2– patients (ROR-P, 0.55; RS, 0.49; N, 49). For RS, correlations were higher in models that included ER/PR/HER2 (Overall, 0.83; ER+/HER2–, 0.50) than in those that relied on pathology alone (Overall, 0.60, ER+/HER2–, 0.34). Future models will consider strategies to enhance performance in ER+/HER2– patients, such as oversampling of ER+/HER2– patients and use of loss functions designed to focus learning on mis-predicted examples. In summary, multi-task, tissue-based regression deep learning models recapitulate transcription-based risk assays with high correlations and, with optimization (especially integration of additional clinicopathologic data), hold promise for personalized treatment decisions from early, routinely-collected biopsy images. Citation Format: Jakub R Kaczmarzyk, Luke A Torre-Healy, Richard A Moffitt, Rajarsi Gupta, Alina M Hamilton, Tahsin M Kurc, Katherine A Hoadley, Melissa A Troester, Joel H Saltz. Early risk stratification of ER+/HER2– breast cancer patients using digital pathology and multi-task, weakly-supervised deep learning [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B082.

Utilization and outcomes of the 21-gene recurrence score in de novo metastatic breast cancer

ABSTRACT Background Limited data exist regarding the utility and validity of the 21-gene recurrence score (RS) in patients with de novo metastatic breast cancer (dnMBC). This study aimed to investigate the practice patterns as well as associated survival outcomes based on 21-gene RS in dnMBC. Research design and methods The Surveillance, Epidemiology, and End Results Oncotype database was queried for women with hormone receptor-positive and Her2-negative dnMBC. Results A total of 153 patients were identified, including 62.7% and 37.3% of patients who had RS < 26 and ≥ 26, respectively. Patients with RS ≥ 26 were more likely to receive chemotherapy compared to those with RS < 26 (61.4% vs. 28.1%, p < 0.001). Patients with RS ≥ 26 had an inferior breast cancer-specific survival (BCSS) (2-year BCSS: 84.3% vs. 89.5, p = 0.067) and overall survival (OS) compared to those with RS < 26 (2-year OS: 76.9% vs. 87.4%, p = 0.018). The multivariate Cox proportional hazard models showed that those with RS ≥ 26 had a significantly inferior BCSS (hazard ratio [HR] 2.251, 95% confidence interval [CI] 1.056–4.799, p = 0.036) and OS (HR 2.151, 95%CI 1.123–4.120, p = 0.021) compared to those with RS < 26. Conclusions The 21-gene RS assay is an important prognostic factor in patients with dnMBC.

The 21-Gene Recurrence Score Assay Improved Multidisciplinary Treatment Compliance in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Patients: An Analysis of 2,323 Patients.

The 21-gene recurrence score (RS) can guide adjuvant chemotherapy decisions in the multidisciplinary treatment (MDT) of patients with early breast cancer. This study aimed to evaluate the influence of the 21-gene RS assay on patient' compliance with MDT and its association with disease outcomes. Patients diagnosed with pN0-1, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer between January 2013 and June 2019 were enrolled. A logistic regression model was used to identify parameters associated with treatment adherence. Prognostic indicators were evaluated using the Cox proportional hazard models. After the assay, patients were less likely to violate the treatment plan (14.9% vs. 23.1%, p < 0.001), and higher compliance rates were observed for chemotherapy (p = 0.042), radiotherapy (p = 0.012), and endocrine therapy (p < 0.001). Multivariable analysis demonstrated that the 21-gene RS assay (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.09-1.88; p = 0.009) was independently associated with MDT compliance. Moreover, compliance with MDT was independently associated with better disease-free survival (hazard ratio, 0.43; 95% CI, 0.29-0.64; p < 0.001), regardless of the 21-gene RS assay (interaction p = 0.842). The 21-gene RS assay improved the MDT compliance rate in patients with early breast cancer. Adherence to MDT is associated with a better prognosis.

Impact of reactive changes on multigene testing: histopathologic analysis of low-grade breast cancers with high-risk 21-gene recurrence scores.

The 21-gene recurrence score (RS) assay predicts the recurrence risk and magnitude of chemotherapy benefit in patients with invasive breast cancer (BC). This study examined low-grade tumors yielding a high-risk RS and their outcomes.Kindly check the edit made in the article titleOk METHODS: We compared patients with grade 1 BC and a high-risk RS to those with low-risk RS. Histologic sections were reviewed and features reported to elevate the RS were noted, mainly biopsy cavity and reactive stromal changes (BXC). A total of 54 patients had high-risk RS (median RS of 28, range 26-36). On review, BXC were seen in all cases. Thirty BCs in this group also had low to negative PR. Treatment regimens included: chemoendocrine therapy (63%), endocrine therapy alone (31%) and no adjuvant therapy (6%). There were no additional breast cancer events over a median follow-up of 54.0 months (range 6.2 to 145.3). A total of 108 patients had low-risk RS (median RS of 7, range 0-9). BXC were seen in 47% of cases and none were PR negative. One patient had a recurrence at 64.8 months while the rest had no additional events over a median of 68.1 months (2.4 to 100). We provide further evidence that reactive stromal changes and/or low-PR scores enhance the elevation of the RS. A high-RS result in low grade, PR-positive BC may not reflect actual risk and any suspected discrepancies should be discussed with the management teams. Multigene testing results should be interpreted after correlation with pathologic findings to optimize patient care.

Concordance between 21-gene recurrence score assay and clinicopathological predictive models in early-breast cancer patients cared for at a cancer center in Colombia.

The genomic-based 21-gene recurrence score assay (21-GRSA) allows to determine the usefulness of adjuvant chemotherapy in patients with luminal-type early breast cancer (LTEBC). Additional predictive models have also been developed, such as Magee equations (ME), the Predict model (PM), and the Tennessee nomogram score (TNS). To evaluate the concordance between 21-GRSA, ME, PM and TNS. Patients with unifocal LTEBC and 21-GRSA, ME, PM and TNS results were included. A subgroup analysis of women older than 50 years was carried out. Concordance between the models and 21-GRSA was evaluated using Cohen's kappa index (KI). One-hundred and twenty-two women were included. Concordance between 21-GRSA and ME (KI = 0.35) and PM (KI = 0.24) was fair (p < 0.001). Concordance between 21-GRSA and TNS was inferior (KI = 0.16, p = 0.04). Eighty patients older than 50 years with sufficient data to calculate all three predictive models were included. Concordance was found between the low-risk classification on 21-GRSA and all three combined models in 36/37 patients (negative predictive value of 97.3%). 21-GRSA can be omitted in women older than 50 years with LTEBC classified with low risk scores on all three predictive models.

Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer.

The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

Radiotherapy Use and Incidence of Locoregional Recurrence in Patients With Favorable-Risk, Node-Positive Breast Cancer Enrolled in the SWOG S1007 Trial

Little is known about regional nodal irradiation (RNI) practice patterns or rates of locoregional recurrence (LRR) with and without RNI in patients with limited nodal disease and favorable biology treated with modern surgical and systemic therapy, including approaches that de-escalate those latter treatments. To investigate how often patients with low-recurrence score breast cancer with 1 to 3 nodes involved receive RNI, incidence and predictors of LRR, and associations between locoregional therapy and disease-free survival. In this secondary analysis of the SWOG S1007 trial, patients with hormone receptor-positive, ERBB2-negative breast cancer, and a Oncotype DX 21-gene Breast Recurrence Score assay result of no more than 25, were randomized to endocrine therapy alone vs chemotherapy then endocrine therapy. Prospectively collected radiotherapy information was collected from 4871 patients treated in diverse settings. Data were analyzed June 2022 to April 2023. Receipt of RNI (targeting at least the supraclavicular region). Cumulative incidence of LRR was calculated by locoregional treatment received. Analyses were assessed for associations between invasive disease-free survival (IDFS) and locoregional therapy, adjusted for menopausal status, treatment group, recurrence score, tumor size, nodes involved, and axillary surgery. Radiotherapy information was recorded in the first year after randomization, so survival analyses were landmarked as starting at 1 year among those still at risk. Of 4871 female patients (median [range] age, 57 [18-87] years) with radiotherapy forms, 3947 (81.0%) reported radiotherapy receipt. Of 3852 patients who received radiotherapy and had complete information on targets, 2274 (59.0%) received RNI. With a median follow-up of 6.1 years, the cumulative incidence of LRR by 5 years was 0.85% among patients who received breast-conserving surgery and radiotherapy with RNI; 0.55% after breast-conserving surgery with radiotherapy without RNI; 0.11% after mastectomy with postmastectomy radiotherapy; and 1.7% after mastectomy without radiotherapy. Similarly low LRR was observed within the group assigned to endocrine therapy without chemotherapy. The rate of IDFS did not differ by RNI receipt (premenopausal: hazard ratio [HR], 1.03; 95% CI, 0.74-1.43; P = .87; postmenopausal: HR, 0.85; 95% CI, 0.68-1.07; P = .16). In this secondary analysis of a clinical trial, RNI use was divided in the setting of biologically favorable N1 disease, and rates of LRR were low even in patients who did not receive RNI. Disease-free survival was not associated with RNI receipt; omission of chemotherapy among patients similar to those enrolled in the S1007 trial is not an independent indication for use of RNI.

Twenty-one gene recurrence scores in individuals with breast cancer associated with CHEK2 and ATM germline pathogenic variants.

10585 Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2 or ATM PV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts &lt; age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( &lt; 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts &lt; age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( &lt; 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients &lt; 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS. [Table: see text]

SEER analysis of 9-year breast cancer specific mortality (BCSM) in patients (pts) with invasive lobular breast cancer (ILC) assessed by the 21-gene Breast Recurrence Score assay.

554 Background: Linking of the results of the 21-gene Breast Recurrence Score (RS) commercial assay to SEER registries provides opportunity to assess real world prognostic performance of the assay in important subgroups of early breast cancer (BC). ILC is less common than invasive ductal carcinoma (IDC) and the performance of the RS assay in ILC is of interest. The relationship between RS results and 5-year BCSM in patients with ILC was reported based on a linkage in 2015 at this meeting in 2017. Here we present a comparison of 9-year BCSM of ILC vs IDC from a linkage update in 2019. These results will be updated further based on a new linkage of RS data to be completed in April 2023. Methods: Eligible pts had 0-3 axillary nodes at initial surgery, were hormone receptor positive and HER2-negative with a RS result, had no prior malignancy, and were diagnosed between January 2004 and December 2012. Pts with ICD-O-3 code 8520 were categorized as ILC and those with code 8500 as IDC. 9-year BCSM of both cohorts was estimated using actuarial methods. Multivariable Cox proportional hazards models characterized association between RS results and BCSM. Results: Of 89818 pts, 9835 (11.0%) had ILC and 64669 (72.0%) had IDC. Among pts with ILC, median age was 60 years; 12.5% were N1 and 28.4%, 63.7% and 7.9% were grade 1, 2 and 3. Median follow-up was 84 months. Chemotherapy (CT) use and BCSM increased with increasing RS result in both cohorts. After adjusting for age, race, tumor grade, tumor size, nodal status, and histologic subtype, the RS result was independently associated with BCSM ( p &lt; .001) in both ILC and IDC. Conclusions: In this linked SEER analysis of pts with ILC or IDC, the RS results were prognostic for 9-year BCSM, regardless of nodal status. [Table: see text]

P088 The evaluation of the 21-gene Breast Recurrence Score assay as a prognostic factor for locoregional recurrence in early breast cancer treated by lumpectomy and intraoperative radiotherapy only

P088 The evaluation of the 21-gene Breast Recurrence Score assay as a prognostic factor for locoregional recurrence in early breast cancer treated by lumpectomy and intraoperative radiotherapy only

Abstract P2-11-31: FAVORABLE LOCOREGIONAL CONTROL IN CLINICALLY NODE-NEGATIVE HORMONE-RECEPTOR POSITIVE BREAST CANCER WITH LOW 21-GENE RECURRENCE SCORES: A SINGLE INSTITUTIONAL STUDY WITH 10-YEAR FOLLOW-UP

Abstract Background: Recent studies have shown a lower likelihood of locoregional recurrences in patients with low 21-gene recurrence score (RS). In this single institutional study, we investigated any associations between different cut-off values of 21-gene RS and histopathological factors and outcome in patients with long-term follow-up. Methods: Between February 2010 to February 2013, 61 patients with early stage clinically node-negative hormone receptor-positive and HER2-negative breast cancer tested for the 21-gene RS assay, were included into the study. The clinicopathological, treatment and outcome characteristics were analyzed. Results: Median age was 48 (range, 29-72). Of those, 53 patients were diagnosed with Stage 1 (86.9%) and 8 patients were Stage 2 (13.1%) following surgery. Patients with high histologic grade (HG), or with Ki-67&amp;gt;=25% were significantly more likely to have intermediate/high RS based on RS &amp;gt;11 and &amp;gt;18 (Table 1). Based on the 21-gene RS assay, only 19 patients (31%) received adjuvant chemotherapy. At a median follow-up of 112 months, 3 patients developed local recurrences (4.9%) treated with endocrine therapy alone. Among patients treated with endocrine treatment alone (n=42), the clinicopathological characteristics including age &amp;lt; 40, age &amp;lt; 50, high histologic or nuclear grade, high Ki67-scores (&amp;gt;=20%, &amp;gt;=25%, &amp;gt;=30%), presence of lymphovascular invasion, luminal-A type tumor, multifocality, lymph node positivity, tumor size more than 2 cm, RS&amp;gt;=18 or RS&amp;gt;11 were not significantly found to be associated with 10-year locoregional recurrence free survival (LRRFS). However, patients with a RS &amp;gt;=16 have significantly shown a poorer 10-year LRRFS cpmpared to those with RS &amp;lt; 16 (RS &amp;lt; 16; 100% vs RS&amp;gt;=16; 75%, p=0.039, Table 2). Conclusions: These results suggest that Oncotype DX assay may be of little value in patients with high histologic grade or high Ki67 scores (&amp;gt;= 25%) as treatment decision criteria to determine any benefit from chemotherapy. Furthermore, patients with a RS &amp;gt;=16 are more likely to benefit from adjuvant chemotherapies, whereas those with a RS &amp;lt; 16 have an excellent outcome and local control on long term follow-up with endocrine treatment alone. Further prospective studies should be performed to validate these findings in future. Table 1. Correlation of 21-gene Recurrence Score (RS) including different cut-off values with Ki-67 scores and histopathological factors Table 2. Clinicopathologic factors and 21-gene Recurrence Score (=RS) associated with disease free survival (DFS) and locoregional recurrence free survival free survival (=LRRFS). (DFS is equal to LRRFS since none of the patients developed distant metastases) Citation Format: Cihan Uras, Neslihan Cabıoğlu, Fatma Tokat, Halil Kara, Ozlem ER, Taner Korkmaz, Nuran Bese, Umit Ince. FAVORABLE LOCOREGIONAL CONTROL IN CLINICALLY NODE-NEGATIVE HORMONE-RECEPTOR POSITIVE BREAST CANCER WITH LOW 21-GENE RECURRENCE SCORES: A SINGLE INSTITUTIONAL STUDY WITH 10-YEAR FOLLOW-UP [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-31.

Abstract P6-01-39: The impact of the 21-gene Recurrence Score® assay upon physician treatment recommendations in the neoadjuvant setting in lymph node-negative breast cancer patients in a multicenter prospective study in Quebec

Abstract Background: Although the role of the 21-gene Breast Recurrence Score® assay is well established to predict response to adjuvant chemotherapy in the setting of node-negative hormone receptor (HR)-positive, HER2-negative breast cancers (BC), fewer studies have evaluated the assay in the neoadjuvant setting. Due to the correlation between a high Recurrence Score® (RS) result and pathological complete response (pCR), the Breast Recurrence Score assay has been used to aid in selecting between chemotherapy (CT) or endocrine therapy. We wanted to further understand the impact of the assay upon physician treatment recommendations and the use of chemotherapy in this patient cohort. Methods: We conducted a multicenter, prospective, observational study in patients with clinically node-negative HR-positive, HER2-negative BC with T2-T3 disease being considered for neoadjuvant therapy. Physicians were required to complete two questionnaires indicating treatment choice, including CT, endocrine therapy, or surgery, prior to and post availability of RS result. Patients were followed up for 6 months after commencement of neoadjuvant therapy. The primary objective was to evaluate the change in the physician’s recommendation for neoadjuvant CT prior to and post assay results. As a secondary objective, we also evaluated the impact of the RS result on physician’s expressed level of confidence. Results: A total of 70 patients were enrolled between April 2018 and November 2021 at five hospital centers, as part of the McPeak Sirois Group of Quebec. The median age of the cohort was 60 years (range, 30 to 79 years). 24.3 % (n=17) of the cohort consisted of patients aged &amp;lt; 50 years, and 75.7% (n=53) were ≥ to 50 years. 29.0% (n=20) of the patients had a RS &amp;lt; 16, 39.1% (n=27) had a RS between 16-25, and 31.9% (n=22) had a RS &amp;gt; 25. For the entire cohort, the RS result led to a net reduction in chemotherapy recommendation by 33.3% (OR (odds of having CT post-RS recommendation versus pre-RS recommendation) = 0.23 [95% CI: 0.12-0.44]; P&amp;lt; 0.0001), and 39.2% net reduction in the use of chemotherapy at 6-month follow-up (OR = 0.18 [95% CI: 0.09-0.35]; P&amp;lt; 0.0001). Furthermore, the RS result led to a 35.3% net reduction in physician recommendation of CT for patients &amp;lt; 50 years (OR = 0.19 [95% CI: 0.04-0.83]; P=0.027) and a 32.7% net reduction for patients ≥ 50 years (OR = 0.24 [95% CI: 0.11-0.50]; P=0.0001). For patients with a RS &amp;lt; 16, there was a reduction in CT recommendation by 75.0%, and by 44.4% for patients with a RS between 16 - 25 (OR = 0.15 [95% CI: 0.06-0.38]; P&amp;lt; 0.0001). Moreover, RS results led to an increase in confidence in physician treatment decisions for 59.4% of patients (OR = 12.53 [95% CI: 5.46-28.78]; P&amp;lt; 0.0001). Conclusion: We determined that the 21-gene Breast Recurrence Score assay altered neoadjuvant treatment decisions, leading to a reduction in the use of chemotherapy by about one-third, regardless of age. Additionally, the assay increased physician confidence in their treatment recommendation for about 60% of patients. This demonstrates the potential clinical utility of the assay to decrease the use of CT in the neoadjuvant setting amongst HR-positive, node-negative BC patients in Quebec. Citation Format: Mariya Yordanova, Lucas Sideris, Pierre Dubé, Jean-Francois Boileau, Julie Lemieux, Catalin Mihalcioiu, Sylvie Levesque, Marie-Claude Guertin, Erica Patocskai, Rami Younan, André Robidoux, Saima Hassan. The impact of the 21-gene Recurrence Score® assay upon physician treatment recommendations in the neoadjuvant setting in lymph node-negative breast cancer patients in a multicenter prospective study in Quebec [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-39.

Abstract P6-01-43: Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: OncotypeDX versus MammaPrint versus Liquid Biopsy

Abstract Background: OncotypeDX (ODX) is a 21-gene recurrence score (RS) assay that is predictive of the benefit of adjuvant chemotherapy in early-stage hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer. MammaPrint (MP) is a 70-gene signature validated to prognosticate distant metastasis and survival. We have previously presented data suggesting that the presence of circulating tumor cells (CTCs) evaluated via liquid biopsy may also have prognostic and predictive utility in HR+/HER2- breast cancer. In this study, we compare the value of ODX, MP and liquid biopsy evaluating CTCs and disseminated tumor cells (DTCs) in predicting pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC). Methods: This retrospective analysis used the National Cancer Database (NCDB) 2004-2017 breast cancer dataset to identify a cohort of patients with HR+/HER2-, AJCC clinical stage I-III breast cancer who received NAC. A series of multiple logistic regression models were used to assess the value of a. ODX (RS &amp;lt; 26 versus ≥26), b. MP, c. the presence of CTCs, and d. the presence of DTCs in predicting pCR to NAC. Each model controlled for age, race, Charlson/Deyo comorbidity scoring, disease histology, grade, and nodal status. Results: A total of n=52,463 patients with stages I-III HR+/HER2- breast cancer received NAC. The patient characteristics of this cohort were as follows: the majority were White (n=42,826, 81.6%), between 50-70 years of age (n=27,683, 52.8%), and with invasive ductal carcinomas of the breast (n=40,197, 76.6%). N=6,111 (11.6%) had Grade I or well-differentiated disease, n=23,546 (44.9%) Grade II or moderately-differentiated disease, and n=2,605 (43.5%) had Grade III or poorly-differentiated disease. N=3,823 have documented recurrence scores based on ODX: with n=2,653 having RS &amp;lt; 26 (69.4%) and n=1,170 (30.6%) having RS ≥26. After controlling for age, race, comorbidity scoring, disease histology, grade and nodal status, RS ≥26 was found to be significantly associated with pCR to NAC (OR 1.85, 95% CI 1.46-2.35, p&amp;lt; 0.001). High-risk scoring per MP was also correlated with pCR but this relationship was not statistically-significant (OR 1.68, 95% CI 0.93-3.03, p=0.084), possibly due to the smaller size of this sample (n=828 patients underwent MP testing). Liquid biopsy data was also limited, with n=250 patients having documented CTC status and n=211 having documented DTC status. Neither the presence of CTCs (OR 0.96, 95% CI 0.44-2.09, p=0.908) nor DTCs (OR 0.61, 95% CI 0.25-1.50, p=0.279) was significantly associated with pCR to NAC. Conclusions: ODX is found to be predictive of pCR to NAC in early-stage, HR+/HER2- breast cancer. Utility of MP and liquid biopsy data in this context appears less robust, however, data is limited. More research is needed to validate existing data in a prospective trial setting, and explore for novel biomarkers across breast cancer subtypes. Citation Format: Nadeem Bilani, Mira Itani, Mohamed Mohanna, Neha Debnath, Barbara Dominguez, Hong Liang, Zeina Nahleh. Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: OncotypeDX versus MammaPrint versus Liquid Biopsy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-43.

Abstract P2-11-09: Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial

Abstract Background: The 21-gene recurrence score (RS) assay is a prognostic measurement originally established for distant recurrence in estrogen receptor-positive and node-negative breast cancer. Retrospective studies and the Trial Assigning Individualized Options for Treatment (TAILORx; ClinicalTrials.gov NCT00310180) validated its significance besides testing chemotherapy benefit in patients with midrange RS (11-25). However, unclarity remains as to whether RS has comparable prognostic value for overall survival (OS) in the TAILORx trial population. Methods: Association between the recurrence scores (midrange or high-range 26-100 vs. low-range 0-10) and OS was evaluated in all eligible patients with clinicopathological and treatment information by multivariable Cox proportional hazards regression model including RS, tumor size, tumor grades, chemotherapy, endocrine regimens, surgery type, progesterone receptor and demographics. We also evaluated the association between RS and invasive disease-free survival (DFS), recurrence-free interval (RFI) or distant recurrence-free interval (dRFI) by multivariable Cox analysis. Results: Median follow-up was 95.5 (range 0.1 to 138.6) months for OS, 89.6 months (range 0 to 134.8) for DFS, 87.7 (range 0 to 134.8) months for RFI or 87.6 (range 0-134.8) months for dRFI. Compared with low score group, midrange and high-range scores were associated with RFI and dRFI, respectively (P≤0.01 each). However, midrange score was neither associated with OS (adjusted HR 1.15; 95% CI 0.87-1.52; P=0.33) nor associated with DFS (HR 1.16; 95% CI 0.97-1.38; P=0.11). High-range score was associated with DFS (HR 1.58; 95% CI 1.21-2.06; P&amp;lt; 0.01) and had a trend towards association with OS (HR 1.44; 95% CI 0.95-2.19; P=0.08). Conclusions: The data indicate that the recurrence scores provide independent prognosis for breast cancer recurrence at both distant and locoregional sites and for distant recurrence, respectively. High-range score is prognostic of disease-free survival, with the midrange score showing marginal association. Midrange and high-range recurrence scores do not provide independent prognostic information for overall survival in hormone receptor-positive, HER2-negative, node-negative breast cancer in the TAILORx trial population. Citation Format: Sherry X. Yang, John Yu, Molin Wang. Association of 21-gene recurrence score with overall survival in phase 3 TAILORx trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-09.