Oncotype DX Breast Recurrence Score Research Articles

Abstract PO5-09-04: Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants

Abstract Background: The 21-gene assay (Oncotype DX Recurrence Score, RS) is the only clinically validated assay to determine the prognosis in hormone-positive, HER2-negative breast cancer (BC) patients treated with endocrine therapy alone by predicting locoregional and distant recurrence. Outcomes of Oncotype RS in BRCA-associated BC has been studied previously, but the results of RS analysis in BC patients with the other BC susceptibility genes have not been documented. This study evaluates the clinical and pathological characteristics of BC patients with ATM, CHEK2 and PALB2 germline pathogenic variants (PV). Methods: Patients with invasive hormone-positive, HER2-negative BC who have had Oncotype DX Breast Recurrence Score® testing and who underwent genetic testing in the Breast Medical Oncology and the Breast Clinical Cancer Genetics Clinic at the University of Texas MD Anderson Cancer Center (MDACC) were identified from the prospectively maintained research database. Clinical and tumor characteristics were analyzed using descriptive statistics. Results: Between 1996 and June 2023, 5652 patients with Oncotype RS were included in this analysis. Amongst those 828 BC patients had genetic testing and 81 patients were found to have a pathogenic variant: 17 patients with a CHEK2 mutation, 10 patients with an ATM mutation, and 18 patients with a PALB2 mutation. Among patients with CHEK2 PV, median Oncotype RS was 17 (5–32) overall, 21 (13–32) for patients age < 50, and 14.5 (5–28) for patients age ≥50 (p= 0.2). Among patients with ATM PV, median RS was 16.5 (3–54) overall, 25 (10–54) for patients age < 50, and 14.5 (3–29) for patients age ≥50 (p= 0.19). Among patients with PALB2 PV, median RS was 26.5 (15–40) overall, 20 (15–40) for patients age < 50, and 31 (26–37) for patients age ≥50 (p= 0.012). Further patient and tumor characteristics are shown in Table 1. Conclusion: This is a single-institutional cohort of hormone-positive, HER2-negative BC patients who had Oncotype RS and who underwent genetic testing. Further analysis on clinical and tumor pathological characteristics and long-term outcome is ongoing. Table1. Patient and tumor characteristics Citation Format: Fatma Akkoc Mustafayev, Angelica Gutierrez Barrera, Diane Liu, Banu Arun. Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and 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 PO5-09-04.

Abstract PO4-08-09: Concordance analysis of paired breast cancer core needle biopsies and surgical excision samples using the Oncotype DX Breast Recurrence Score® assay

Abstract INTRODUCTION: The Oncotype DX Breast Recurrence Score® (RS) assay is validated to predict risk of distant recurrence at 10 years and the benefit of adjuvant chemotherapy in patients with estrogen receptor (ER)+, HER2- early breast cancer who receive 5 years of endocrine therapy. The feasibility of Oncotype DX® testing with diagnostic core needle biopsies (CNB) was demonstrated through analysis of a large commercial laboratory experience. The neoadjuvant ADAPT study showed the clinical utility of deriving the Recurrence Score® (RS) result from CNB as well. However, data are limited on concordance of RS results from paired CNB and surgical samples. Our primary objective was to determine the degree of concordance of RS results between paired tissue samples from the same primary breast tumor of patients with early stage, ER+, HER2- invasive breast cancer who had a CNB and subsequent surgical excision (SE; lumpectomy or mastectomy) without intervening systemic therapy. METHODS: Patients with a commercial RS result on either CNB or subsequent SE were identified through medical record and clinical database review. A pathologist reviewed archival tissue samples to confirm eligibility and selected the other paired CNB or SE block most representative of the tumor tissue for subsequent study Oncotype DX testing. Descriptive statistics were used to summarize patient and tumor characteristics. Wilcoxon signed rank, McNemar’s and Cochran-Mantel-Haenszel tests were used to compare RS between SE and CNB paired samples. Cohen’s Kappa and 95% confidence intervals (CIs) were used to compare the agreement of categorical RS (0-25 and 26-100) result between SE and CNB paired samples. Lin’s concordance correlation and 95% CIs were used to compare agreement of continuous RS between paired samples. RESULTS: A total of 134 patients were identified with paired CNB and SE samples with a median time of 34 (range 5-103) days between collections. Of the 134 patients, a commercial RS result was available for 25 (18.7%) with CNB and 109 (81.3%) with SE. A study RS result was then generated on the other paired sample. Median age was 62 years (range 33-99; 23 patients [17%] were age ≤50 vs. 111 [83%] age >50). Cases were predominantly node negative (107/134 node negative vs. 26/134 node positive; 1/134 unknown) invasive ductal carcinomas (104/134 ductal vs. 18/134 classic lobular vs. 12/134 other). Mean RS results were 15.6 (range 0-56) and 16.6 (range 0-59) for CNB and SE, respectively (p = 0.003), with no statistically significant differences in RS category defined as low vs. high risk (119/134 CNB vs. 114/134 SE for RS 0-25 and 15/134 CNB vs 20/134 SE for RS 26-100; p = 0.13) or low vs. intermediate vs. high risk (85/134 CNB vs. 78/134 SE for RS 0-17 and 43/134 CNB vs. 48/134 SE for RS 18-30 and 6/134 CNB vs. 8/134 SE for RS 31-100; p = 0.19). No differences were observed based on age relative to 50 years or nodal status (data not shown). Cohen’s Kappa statistic k = 0.64 (95% CI, 0.44-0.83) supports substantial agreement between the CNB and SE samples. Lin’s concordance correlation coefficient (CCC) demonstrates similar agreement for the continuous RS result between paired samples (CCC = 0.86 [0.80-0.90]). Overall percent agreement was 91.8% (87.1-96.4%). CONCLUSIONS: Studies evaluating the level of concordance of ER, progesterone receptor, and HER2 biomarker status between CNB and SE samples have found high concordance rates, albeit varied. We now provide data demonstrating high concordance of RS results between CNB and SE specimens obtained from the same breast primary tumor without intervening systemic therapy. This supports use of either biopsy source for testing with a genomic predictor to identify those patients who will most likely benefit from chemotherapy and which patients may be spared. Citation Format: Aziza Nassar, Jodi Carter, Paige Innis, Satish Seerapu, Christy Russell, Helena Hanna, Abigail Lochala, Minetta Liu. Concordance analysis of paired breast cancer core needle biopsies and surgical excision samples using the Oncotype DX Breast Recurrence Score® assay [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 PO4-08-09.

Abstract PO1-07-01: Artificial intelligence-based prediction of Oncotype DX Score from whole slide images using human-interpretable features and breast biomarkers

Abstract Background The Oncotype DX Breast Recurrence Score assay (ODX) is a commonly used genomic test for patients with estrogen receptor (ER)-positive, HER2-negative, early-stage invasive breast cancer. While ODX predicts patients’ recurrence risk and benefit from chemotherapy, it is tissue and time-consuming, and expensive. Previous deep-learning or non-linear ODX prediction models achieved promising performance using whole-slide images (WSI) or with other covariates (e.g., ER, progesterone receptor (PR), HER-2, Ki-67 scores and tumor stage) but systematic quantification of the contribution of individual histological features to the ODX score remained challenging. Here, we extracted a rich set of human-interpretable features (HIFs) quantifying nuclear morphology and the distribution of cells and tissues in the tumor microenvironment. We used these HIFs, along with manually assessed ER, PR, HER-2 scores, and tumor stage, to predict ODX scores. We also explored the role of Ki-67 features in augmenting our model predictions Methods We developed machine learning models to extract cell, tissue, and nuclear HIFs from WSI stained with hematoxylin and eosin (H&E) and immunohistochemistry (IHC) against Ki-67. These models were deployed on 353 H&E WSI to extract 276 HIFs quantifying cell densities, tissue areas, relative cell counts, and nuclei size, shape and color. Hierarchical agglomerative clustering was applied to cluster these features into 11 groups. Univariate regression was performed to identify correlations between ODX scores and feature clusters. To predict ODX score using HIFs, a multivariable regression model was fitted to the data where regressors are representative features from each cluster, in addition to ER, PR, HER-2 scores and stage as covariates. The model was fitted on the training set (N=266 slides) and evaluated on the held-out test set (N=87 slides). To examine the utility of Ki-67 IHC features in ODX prediction, a Ki-67 model was deployed on a subset of 194 matched Ki-67 IHC WSI to extract count proportions and densities of Ki-67 positive cells in cancer epithelium and stroma. Results Significant positive correlations were identified between ODX scores and feature clusters corresponding to cancer cell density (p < 10-7), macrophage density (p < 10-4), immune cell density (p < 10-16), and variations in cancer nuclear size (p < 10-5) and color (p < 10-3). Significant negative correlations were observed between ODX scores and clusters related to fibroblast density (p < 10-3), and variations of non-cancer cell nuclear color (p = 0.02). Evaluation of our model’s ability to predict ODX scores revealed an association between predicted and observed scores (Pearson r = 0.74). The AUROC for model predictions of high/low classifications (with reference to a cutoff ODX score of 20) was 0.80. Ki-67 features were clustered together with H&E cancer cell density features and showed a stronger correlation with ODX scores compared to the H&E features alone. Combining Ki-67 cell density features with H&E features led to increased performance of the multivariable regression model on the test set compared to H&E features only (r = 0.62 vs. r = 0.59). However, a model combining Ki-67, H&E and covariates performed similarly to a model with H&E and covariates (r = 0.73), suggesting that Ki-67 features may not be needed for ODX prediction when H&E and covariate information is available. Conclusions Our model predicts ODX recurrence scores with comparable performance to other black-box approaches using WSI and breast biomarker status and without the need for, Ki-67 features. Using readily available information, our model has the potential to be a convenient screening tool for patient stratification, which may lead to better patient care, lower costs, and faster treatment. Citation Format: Nhat Le, John Van Arnam, Christian Kirkup, Ylaine Gerardin, Michael Drage, Neha Khaitan, Anurag Sharma, Georgi Galev, Nicholas Indorf, Emily Sansevere, Ilan Wapinski, Stephanie Hennek, Gloria Zhang. Artificial intelligence-based prediction of Oncotype DX Score from whole slide images using human-interpretable features and breast biomarkers [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 PO1-07-01.

A UK prospective multicentre decision impact, decision conflict and economic evaluation of the 21-gene assay in women with node+ve, hormone receptor+ve, HER2-ve breast cancer

BackgroundFor a tumour profiling test to be of value, it needs to demonstrate that it is changing clinical decisions, improving clinical confidence, and of economic benefit. This trial evaluated the use of the Oncotype DX Breast Recurrence Score® assay against these criteria in 680 women with hormone receptor-positive (HR+), HER2-negative early breast cancer with 1–3 lymph nodes positive (LN+) in the UK National Health Service (NHS).MethodsPrior to receipt of the Recurrence Score (RS) result, both the physician and the patient were asked to state their preference for or against chemotherapy and their level of confidence on a scale of 1–5. Following receipt of the RS result, the physician and patient were asked to make a final decision regarding chemotherapy and record their post-test level of confidence.ResultsReceipt of the RS result led to a 51.5% (95% CI, 47.2–55.8%) reduction in chemotherapy, significantly increased the relative and absolute confidence for both physicians and patients and led to an estimated saving to the NHS of £787 per patient.ConclusionThe use of the Oncotype DX assay fulfils the criteria of changing clinical decisions, improving confidence and saving money.

Biomarcadores en resonancia magnética y su correlación con el test Oncotype

Breast cancer (BC) has high rates of incidence and prevalence, causing significant impact in our society. Magnetic resonance imaging (MRI) plays a crucial role in its detection and staging. The Oncotype DX Breast Recurrence Score (ODXRS) test can be used to guide decision making regarding adjuvant chemotherapy (CT) in early-stage luminal BC to allow for more tailored cancer treatment. The aim of this article is to review knowledge regarding MRI biomarkers to date according to the BI-RADS® classification and the use of artificial intelligence (AI) in this imaging technique to establish its correlation with the ODXRS test. The latest studies published on AI and MRI present promising findings, and their standardisation could mark a turning point in breast radiology.

Defining the Biology of Estrogen Receptor-Low-Positive Breast Cancer.

We sought to better define estrogen receptor-low-positive (ER-low+) breast cancer biology and determine the utility of the Oncotype DXBreast Recurrence Score® (RS) assay in this population. Patients with information regarding percentage ER positivity and PAM50 subtype were identified in The Cancer Genome Atlas (TCGA) and subtype distribution was determined. Next, patients with ER-low+ (ER 1-10%), HER2- breast cancer undergoing upfront surgery with known RS result were identified in the National Cancer Database (NCDB) and our institutional Dana-Farber Brigham Cancer Center (DF/BCC) database; RS distribution was examined. Finally, patients with ER-low+, HER2- breast cancer treated at DF/BCC from 2011 to 2020 without prior RS results and in whom tissue was available to perform the assay were identified. RS results, treatment, recurrence and breast cancer-specific survival (BCSS) were determined. Of 1033 patients in TCGA, ER percentage and PAM50 subtype were available for 342 (33.1%) patients. Forty-six (13.5%) had ER-low+/HER2- tumors, among whom 82.6% were basal and 4.3% were luminal A. Among 3423 patients with ER-low+/HER2- disease in the NCDB, RS results were available for 689 (20.1%) patients; 67% had an RS ≥26. In our institutional database, only two patients with ER-low+/HER2- disease and an RS were identified, both with RS ≥26. Among 37 patients in our institutional cohort without prior RS, 35 (97.4%) had an RS ≥26, determined with testing. After a median follow-up of 40 months (range 3-106), three patients, all treated with chemotherapy, recurred. Three-year BCSS was 97.0% (95% confidence interval 96.9-97.1%). Most ER-low+/HER2- breast cancers are basal-like, with RS ≥26 suggesting these tumors are similar to triple-negative disease.

Budget Impact of the Oncotype DX Breast Recurrence Score® Test in Patients with Early Primary Hormone-Receptor-Positive, HER2-Negative, Node-Positive Breast Cancer in Germany

Background: Gene expression tests can inform decisions on whether to recommend or omit chemotherapy for patients with early HR+, HER2− breast cancer. The benefit of these tests is well established and fully reimbursed by sickness funds for lymph node-negative (pN0) patients in Germany. A budget impact model was built to evaluate the effect of using the Oncotype DX Breast Recurrence Score^® test also for node-positive (pN1: 1–3 positive lymph nodes) patients. Methods: The prospective randomized clinical trial, RxPONDER, defined conditions (Recurrence Score result 0–25 for postmenopausal patients with 1–3 positive lymph nodes) under which omitting chemotherapy does not significantly impact invasive disease-free survival with results currently reported for 5-year follow-up. The present budget impact model calculates average total cost per node-positive patient versus no testing from a sickness funds perspective, taking into account not only the budgetary impact of avoiding chemotherapy and associated side effects, but also the costs of treating those patients who develop distant metastasis. The stability of the results was investigated by probabilistic multivariate sensitivity analysis. Results: After deducting testing cost, applying the Oncotype DX Breast Recurrence Score test yielded an average savings per node-positive patient of EUR 4,272. Without the test costs, the greatest savings resulted from reductions in direct treatment costs and costs arising from the treatment of chemotherapy-related side effects, which together averaged EUR 6,677. The targeted use of chemotherapy after testing also resulted in slightly lower costs for treatment of distant metastasis, if it did occur. The multivariate sensitivity analysis also almost exclusively resulted in cost savings. Conclusion: Analogous to the pN0 situation, this budget impact model demonstrates that the Oncotype DX Breast Recurrence Score test can also reduce healthcare costs in Germany in treatment of node-positive (pN1: 1–3 positive lymph nodes) patients by minimizing both unnecessary chemotherapy and undertreatment. Additional benefits to patients would include reduced morbidity and improved quality of life for those patients who can safely avoid chemotherapy or undertreatment.

The budget impact of utilizing the Oncotype DX Breast Recurrence Score test from a US healthcare payer perspective

Background and objectivesThe Oncotype DX Breast Recurrence Score test is used to estimate distant recurrence risk of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2–) early-stage breast cancer and inform decisions on the use of adjuvant chemotherapy. A model-based budget impact analysis compared the Oncotype DX test in combination with clinical–pathological risk against using clinical–pathological risk alone for HR+/HER2– node-negative (N0) and node-positive (N1; 1–3 axillary lymph nodes) early-stage breast cancer patients.Materials and methodsTest and medical costs associated with treatment of breast cancer were assessed through a US healthcare payer perspective. Distributions of patients by Recurrence Score result and distant recurrence probabilities with chemo-endocrine and endocrine therapy were derived from the TAILORx (N0) and RxPONDER (N1) trials. Changes in budget impact were evaluated over a 5-year horizon for a 1,000,000-member hypothetical health plan.ResultsWith the Oncotype DX test, there was an incremental budget impact of $261,067 (per member per month (PMPM): $0.004), in the N0 population, and $56,143 (PMPM: $0.001) in the N1 population over the 5-year period. The largest budget impact reduction in the N0 population was attributed to reduced breast cancer recurrence costs (incremental: −$633,457, PMPM: −$0.011), while chemotherapy sparing reduced costs in the N1 population (incremental: −$94,884, PMPM: −$0.002).ConclusionThe clinical benefit of using the Oncotype DX test to inform adjuvant chemotherapy decisions has been shown in multiple randomized controlled trials. This analysis demonstrated that while using the Oncotype DX test to inform adjuvant chemotherapy decisions may slightly increase US healthcare costs over an initial 5-year time horizon (driven by a cost increase in the first year with cost savings reflected in remaining 4 years), there is significant scope for cost savings when assessing beyond this period due to avoided downstream costs of distant recurrence and long-term chemotherapy adverse events. PMPM costs also remain low across all populations examined, demonstrating a close-to-neutral budget impact.

Benefits and Applications of Oncotype DX Breast Recurrence Score Testing among Breast Cancer Patients: Current Recommendations and Controversies.

Benefits and Applications of Oncotype DX Breast Recurrence Score Testing among Breast Cancer Patients: Current Recommendations and Controversies.

Correlation between Oncotype DX, Predict, and Nottingham Prognostic Index on HR+, HER2- early breast cancer treatment: The current value of molecular testing.

1601 Background: The Oncotype DX Breast Recurrence Score (ODX) assay is a 21-gene assay validated in hormone receptor-positive, HER2 negative invasive breast cancer (BC) to predict chemotherapy benefit and risk of distant recurrence at 10 years regardless of node status and is also a strong predictor of mortality. ODX can minimize the misuse of chemotherapy, financial burden, and improve clinical outcomes. ODX is not widely used in Ecuador due to socioeconomic and healthcare access disparities; instead, many physicians stratify patients' risk according to clinicopathological and immunohistochemical features. We aim to compare the differences between ODX and two of the most common stratification clinical tools: Predict Score (PS) and Nottingham prognostic index (NPI). Methods: Retrospective analysis of women with early BC who underwent ODX testing in Ecuador from May 2020 to January 2023. Inclusion criteria: early BC (T1-T3 / N0-N1a); estrogen receptor (ER) positive; HER2 negative by immunohistochemistry; and available data of tumor size, grade, lymph node status, and Ki67 proliferation index. Exclusion criteria: patients with recurrent BC, incomplete pathology, or immunohistochemistry data. PS and NPI were calculated using online tools. The correlation between PS, NPI, and ODX scores was analyzed using Spearman's correlation coefficient in SPSS. Results: 77 patients underwent ODX testing, of which 58 patients (mean age 55 years old) met the inclusion criteria. Invasive breast carcinoma not otherwise specified was the most common type (48 patients (82%). Risk scores generated by PS correlated strongly with NPI for all patients (r=0.47; p ≤ 0.001). A strong correlation was also found between ODX and NPI (0.79, p<0.027). Risk scores were then stratified by patient risk category. For low-risk patients, 68% of correspondence between ODX and PS was found, and 98% between ODX and NPI. Intermediate-risk patients showed a correspondence between ODX and PS of 5% and 9% for ODX and NPI. High-risk patients showed a correspondence of 50% between ODX and PS and 17% between ODX and NPI. Conclusions: ODX risk recurrence for low-risk patients is highly correlated with PS and NPI. For Intermediate and high-risk patients determined by PS and NPI, ODX testing provided valuable and prognostic information and should be considered to guide adjuvant treatment. [Table: see text]

A quality improvement initiative on the utility of the Oncotype DX breast cancer assay in a community hospital.

e13072 Background: Since the advent of Oncotype DX (ODX) breast recurrence score (RS) assay, the use of adjuvant chemotherapy (CT) in the treatment of breast cancer has significantly reduced. This test not only estimates the benefit of CT, but also determines the risk of distant recurrence in patients with early-stage breast cancer with hormone-receptor (ER/PR) positive, human epidermal growth factor receptor (HER) 2-negative, and axillary lymph node negative or positive (1-3 positive nodes) disease. All patients are categorized based on their scores ranging from 0-100 as follows: low (RS≤10), intermediate (RS11-25) and high risk (RS≥26). Further studies proved that adjuvant CT is beneficial in pre-menopausal women with RS 0-25, however offered no benefit to post-menopausal women in the same category. The aim of our study was to assess the implementation of these guidelines in a community hospital in an underserved area. Methods: At Mercy Catholic Medical Center, we performed a retrospective analysis on 303 female patients with newly diagnosed breast cancer, identified between January 2017 – October 2022. We included patients with ER/PR+, HER2-, lymph node negative or positive, who had undergone surgery and were to receive endocrine therapy with or without adjuvant CT. Patients who were lost to follow-up or did not undergo the genetic testing were excluded from the study. We then analyzed the treatment strategies based on RS categories. All patients who did not receive CT was either because it was not indicated (old age, post-menopausal) or patients refused. Results: 81 patients underwent ODX testing among whom, 60.5%, 35.8%, and 3.7% patients were Black, White and Hispanic/Asian, respectively. 1.2%, 9.8%, 18.51%, 34.56%, 35.08% were aged ≤40, 41-50, 51-60, 61-70 and ≥71 years, respectively. Based on the RS, we identified 29.62% in low risk, 56.79% in intermediate risk, and 13.5% in high-risk categories. 100% patients in the high-risk category were prescribed CT and only 7.4% patients with RS 0-25 received CT. 12 patients were found to be lymph node positive, among whom, 3 had RS≥26 and 2 were pre-menopausal, all of whom were prescribed CT. Out of these, 7 were post-menopausal with RS 0-25 and only 1 received CT. Conclusions: Our hospital data suggests that implementation of ODX and adherence to its guidelines has significantly helped avoid CT and its related side effects in the low and intermediate risk categories. Implementation of this cost-effective test has consistently increased in the last two decades and is now an imperative tool in clinical decision-making specially in community hospitals serving underprivileged populations. [Table: see text]

177P Oncotype DX breast recurrence score (ODX RS) and gBRCAm in pts with HR+/HER2-negative early breast cancer (eBC) in a retrospective cohort

Up to 50% of pts with breast cancer and germline pathogenic/likely pathogenic BRCA variants are missed by current testing guidelines. Timely determination of germline BRCA mutation (gBRCAm) status is integral to facilitating an effective treatment strategy. Prior studies suggest that gBRCAm-associated HR+ HER2-negative eBC has a higher ODX RS vs gBRCA wild type (gBRCAwt). However, data from large cohorts are limited. We conducted a retrospective cohort study using the US Electronic Health Record-derived de-identified Flatiron Health database. We selected pts ≥18 years with HR+ HER2-negative eBC, diagnosed from March 2007–October 2022 with a confirmed ODX RS. gBRCA testing rates were calculated by year of eBC diagnosis. Prevalence of gBRCAm was described by ODX RS category (low <11, intermediate 11–25, high >25). A total of 3672 pts with a confirmed ODX RS (category: low n=961; intermediate n=2172; high n=539) were included. Median age was 62 years (IQR 53, 69), 75.6% were white and 83.4% received treatment at community oncology clinics. Of 1163 pts (31.7%) tested, 37 (3.2%) had gBRCAm. Prevalence of gBRCAm was highest in the high ODX RS category (n=14, 7.5%) vs intermediate (n=19, 2.8%) and low (n=4, 1.4%). gBRCA testing increased over time from 2011–2014 (13.7%) to 2019–2022 (32.4%) for eBC pts. The testing rates were similar across ODX RS categories.Table: 177PRates of gBRCA testing in pts with HR+ HER2-negative eBC with a confirmed ODX RS*Rate of gBRCA testing within 6 months of eBC diagnosis2011–20142015–20182019–2022Overall13.7%22.4%32.4%ODX RS High12.1%26.3%30.8%ODX RS Intermediate14.5%21.5%32.9%ODX RS Low12.4%22.2%32.1%*Between 2007 and 2010 only 8 ODX RS tests were performed, and so data are not shown. ODX RS, Oncotype DX Recurrence Score. Open table in a new tab *Between 2007 and 2010 only 8 ODX RS tests were performed, and so data are not shown. ODX RS, Oncotype DX Recurrence Score. In this modern retrospective cohort, ODX RS appeared higher in gBRCAm-associated HR+ HER2-negative eBC vs sporadic/untested pt tumors. Despite an increasing trend in gBRCA testing, around two-thirds of HR+ HER2-negative eBC pts in this cohort did not undergo genetic testing, including 351 pts with high ODX RS who may benefit from newer risk-reducing strategies. Based on the recently demonstrated improved survival from adjuvant olaparib in gBRCAm pts, wider implementation of genetic testing may be warranted in this population.

Abstract 90: Exploring the role of common circulating tumor cell-associated genes in estrogen receptor-positive breast cancer recurrence

Abstract Despite having the best survival among the molecular subtypes, estrogen receptor-positive (ER+) breast cancer has a tendency for late recurrence. Circulating tumor cells (CTCs) are responsible for disease recurrence by seeding tumors at secondary sites. We have previously developed a CTC signature of 90 common regions of gene copy number gain and demonstrated that this signature is significantly more widespread among cells in metastases than primary tumors.1,2 The objective of our current work is to establish whether the expression data from a 133 gene panel largely derived from the CTC signature can be used to assess the risk of recurrence (ROR) in early ER+ breast cancer patients to help guide treatment decisions following surgery. Formalin-fixed, paraffin-embedded (FFPE) ER+ breast tumor biopsies and linked normal (control) tissues from 192 patients are being analyzed with a custom NanoString nCounter probe set of our 133 CTC genes. From data gathered to date, several genes were shown to be significantly overexpressed in tumors compared to reference normal tissues. This includes MMP11, MKI67, LILRB4, UBE2T, BIRC5, CDC6, MYBL2, and NUF2, which had a log2 fold-change of at least 3.5 (n = 34, p &amp;lt; 0.01). The correlation of our CTC genes to ROR is being evaluated by comparison to the results of the Oncotype DX Breast Recurrence Score Test, a well-established clinical test for ROR in ER+ breast cancer, for each patient. So far, it has been shown that the intratumor heterogeneity (ITH) of CTC genes as established by DEPTH2, an ITH algorithm which evaluates mRNA levels, is significantly positively corelated to Oncotype DX score (n = 23, r = 0.41, p = 0.0495). Moving forward, we will create our own ROR scoring system based on gene expression and copy number data from the CTC gene panel and validate it by comparison to Oncotype DX score and other available clinical data for each of the 192 patient samples. The goal of our work is to gain a deeper understanding of the molecular mechanisms that drive metastasis and recurrence in ER+ breast cancer by focusing on CTCs which play a pivotal role in driving these events. 1. Kanwar N, Hu P, Bedard P, Clemons M, McCready D, Done SJ. Identification of genomic signatures in circulating tumor cells from breast cancer. International Journal of Cancer. 2015;137(2):332-344. doi:10.1002/ijc.29399 2. Kanwar N, Balde Z, Nair R, et al. Heterogeneity of Circulating Tumor Cell-Associated Genomic Gains in Breast Cancer and Its Association with the Host Immune Response. Cancer Research. 2021;81(24):6196-6206. doi:10.1158/0008-5472.can-21-1079‌ Citation Format: Martin Rotbauer, Melanie Dawe, Philippe Bedard, David Cescon, Susan Done. Exploring the role of common circulating tumor cell-associated genes in estrogen receptor-positive breast cancer recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 90.

Using Oncotype DX breast recurrence score® assay to define the role of neoadjuvant endocrine therapy in early-stage hormone receptor-positive breast cancer

PurposeThe role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need.MethodsWe assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay.ResultsWe observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0–25 may omit chemotherapy without compromising outcomes.ConclusionThese data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting.

Abstract P3-05-48: Prediction of disease recurrence in low risk Oncotype Dx breast cancers from digital H&amp;E-stained whole slide images of pre-treatment resections alone

Abstract Background Breast cancer patients with estrogen receptor (ER)+/HER2- (and usually node-negative) tumors can avail themselves of Oncotype DX Breast Recurrence Score (ODXRS) testing to predict their risk of distant recurrence within 9 years and, consequently, putative chemotherapy benefit. However, ODXRS testing requires sufficient tumour availability and specimen shipping, which imposes time and financial burdens to testing which have to be met by healthcare systems. The advent of digital pathology offers a potential avenue for exploring computer-aided diagnostic solutions which may overcome these hurdles by extracting the requisite information from hematoxylin and eosin (H&amp;E)-stained tissue whole slide images (WSIs) alone. In turn, this technology could significantly reduce diagnostic turnaround times and cost, and improve accessibility and test reproducibility, thereby enabling healthcare systems to run more efficiently and offer patients more timely results. Ideally, such a platform should incorporate a measure of the underlying tumor biology to provide a fully explainable, white box solution, and may offer further insights into the identification of early recurrence events. Aims The aim of this study was to establish whether our computer-aided solution’s (Q-Plasia OncoReader Breast, QPORB) digital biomarker representing G1/S cell cycle deformations extracted from H&amp;E WSIs was prognostic for disease-free survival (DFS) and could predict disease recurrence, particularly in the setting of low risk ODXRS breast cancers. Methods Primary breast cancer resection/excision specimens (n=70 cases) sent for ODXRS testing from St James’s University Hospital, UK (2016-2019) were collected. Anonymised diagnostic glass slides (n=198 slides) of H&amp;E-stained tumors were scanned at x20 magnification on an Aperio AT2 scanner. In parallel, relevant clinical and histological data were collected from pathology reports and electronic patient records, including both ODXRS and recurrence events during follow-up. The QPORB recurrence scale (QPORB-RS), which combines statistical physics and tumor biology to identify image-based malignant cell cycle deformation, extracts prognostic information from WSIs. The contribution of potential confounders (age, stage, grade, lesion size, Nottingham prognostic index and Charlson score) were accounted for. Results The QPORB-RS was prognostic for DFS for patients with predominantly node-negative (including node micro-metastases) HR+/HER2- tumors over a median follow-up period of 5 years (P=0.02; dichotomized Kaplan Meyer with median cut-off). The QPORB-RS concurred with ODXRS’s high vs. low recurrence risk in 73% (19/26) and 61% (27/44) of cases, respectively, with an overall agreement of 66% (46/70). Moreover, the QPORB-RS identified all 5 patients who had recurrences (with ODXRS of 6, 9, 10, 21 and 26, and ages of 55, 66, 42, 35 and 50 years, respectively) as being high risk in the subset of those given a low (including historically intermediate) ODXRS and who did not receive chemotherapy. Conclusion The QPORB-RS is a good prognostic test of risk of disease recurrence in breast cancer patients with predominantly node-negative (including node micro-metastases) HR+/HER2- tumors within a median 5-year follow-up period. Our efforts are now focussed on extending this cohort and establishing the prognostic value of the QPORB-RS across all breast carcinomas, regardless of molecular subtype, stage/node positivity and menopausal status. Citation Format: Satabhisa Mukhopadhyay, Tathagata Dasgupta, Elizabeth Walsh, Rebecca Millican-Slater, Andrew hanby, Joanne Stephenson, Craig A. Bunnell, Nicolas M. Orsi. Prediction of disease recurrence in low risk Oncotype Dx breast cancers from digital H&amp;E-stained whole slide images of pre-treatment resections alone [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 P3-05-48.

Abstract P6-01-11: A UK prospective multicentre decision impact, decision conflict and economic evaluation of the use of Oncotype DX® to guide chemotherapy in 680 women with hormone receptor positive, HER2 negative breast cancer and 1 to 3 nodes involved

Abstract Introduction: For a test to be of value, it needs to demonstrate that it is changing clinical decisions, improving clinical confidence and of economic benefit. This trial looked at the use of Oncotype DX Breast Recurrence Score ® (RS) assay against these criteria in 680 women with hormone receptor positive (HR+), HER2 negative early breast cancer with 1 to 3 lymph nodes positive (LN+) in the UK National Health Service (NHS) (5 teaching and 9 district general hospitals) between 2017 and 2022. Methods: Patients with LN+ early breast cancer who were willing and fit to receive chemotherapy (CT) were consented to join the trial. At the initial oncologists’ appointment, physicians were asked to state their preference for or against CT and their level of confidence in their decision on a scale of 1 to 5. Following receipt of the RS result physicians were asked to make a final decision for or against CT and similarly record their level of confidence. Descriptive analyses were used to characterize (1) patient and tumour characteristics, (2) change in treatment recommendations post-RS testing (by RS result and nodal status), and (3) change in physicians’ level of confidence post-RS testing (by RS result and nodal status). Average cost for chemotherapy and RS test price were used to estimate overall cost savings. Results: A total of 680 patients were recruited. 16 patients were excluded (5 failed samples, 5 withdrew consent, 3 HER2 positives, 2 with advanced disease, and 1 specimen delayed in transit), leaving 664 assessable patients. The median age was 58 years and 77.1% of women were post-menopausal. Most patients had a RS of 0-17 (n=400, 60.2%); while 206 (31%) had a RS of 18-30 and 58 (8.7%) had a RS of 31-100. Using post-RxPONDER cutoffs, 566 (85.2%) had an RS of 0-25; 98 (14.8%) had an RS of 26-100. Decision impact results: The decision impact results broken down by RS result and nodal status are detailed in Table 1. Of the 662 patients with complete decision impact data, in 359 (54.2%) the recommendation by the physician changed from CT+ hormone therapy (HT) to HT alone. In 286 (43.2%) cases the decision was unchanged and in 17 (2.6%) the recommendation changed from HT alone to CT+HT. Overall 342 (51.7%) cases were spared chemotherapy. Decision conflict results: The change in the physicians’ level of confidence by RS result and nodal status are detailed in Table 2. Of the 660 cases with complete decision conflict data, physicians reported an increase in confidence in their recommendations after receiving the RS in 363 (55.0%), confidence was unchanged in 219 (33.2%) and decreased confidence in 78 (11.8%) cases. Economic analysis: Using the estimates of Burdanov et al, the average costs of a course of chemotherapy in the UK is £6,000 to £7,000. An estimate of the overall cost saving of 342 courses is £2,064,00 to £2,408,000 and the overall cost of 664 RS assays at the list price of about £2580 (although an undisclosed discount applies to the NHS) is £1,713,120. This suggests that the use of RS assay represents a significant saving to the NHS. Conclusion: The use of Oncotype DX assay in node positive early breast cancer leads to about half of women being spared chemotherapy, a significant improvement in clinical confidence for oncologists and an economic saving to the health care system. Table 1 Pre- vs Post-Oncotype DX Treatment Recommendation by Physician According to Recurrence Score and Nodal Status Table 2 Change in Physicians’ Level of Confidence Post-Oncotype DX Testing According to Recurrence Score and Nodal Status Citation Format: Simon D. Holt, Priyadharshini Sai-Giridhar, Mark Verrill, Laura Pettit, Anna Rigg, Tamas Hickish, Caroline D. Archer, Anshu Wadhawan, Marianne Dillon, Jo Dent, Mark R. Nathan, Ludger Barthelmes, Shazza rehman, Paige Innis, Saira Khawaja. A UK prospective multicentre decision impact, decision conflict and economic evaluation of the use of Oncotype DX® to guide chemotherapy in 680 women with hormone receptor positive, HER2 negative breast cancer and 1 to 3 nodes involved [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 P6-01-11.

Abstract P3-05-27: The impact of co-existing ductal carcinoma in situ in invasive early hormone receptor positive breast cancer on the genomic and clinical risk of recurrence

Abstract Background: Invasive early breast cancer (IBC) often presents with a co-existing ductal carcinoma in situ (DCIS) component, while about 5% of the cases present with an extensive (&amp;gt;25%) intraductal component (EIC). The presence of a DCIS component was previously shown to be associated with favorable clinico-pathological characteristics and survival outcomes. However, the association between co-existing DCIS and genomic risk of recurrence is unclear. Methods: Patients with early hormone receptor positive (HR+) HER2neu-negative (HER2-) breast cancer and known OncotypeDX breast recurrence score (RS), who underwent breast surgery in our institute, were included. A natural language processing (NLP) algorithm was used to identify co-existence of extensive DCIS (DCIS-H) and non-extensive DCIS (DCIS-L) in surgical pathological reports. Genomic risk was determined using OncotypeDX RS, while clinical risk was calculated according to the MINDACT criteria, based on tumor size and grade. The genomic and clinical risks of DCIS-H, DCIS-L and pure IBC (No-DCIS) were compared. Results: A total of 45 (5%) DCIS-H cases, 468 (56%) DCIS-L cases and 328 (39%) No-DCIS cases were identified. DCIS-H cases presented with less aggressive clinico-pathological characteristics, such as lower proportions of histologic grade III (10% vs 26% vs 21%) and lower proportions of node-positive disease (13% vs 18% vs 21%), compared to DCIS-L and No-DCIS cases, respectively. The distribution of OncotypeDX RS significantly varied between the groups. DCIS-H tumors were less likely to have a high RS and more likely to have a low or intermediate RS compared to DCIS-L and No-DCIS tumors (High RS: 4% vs 20% vs 20%, Low + intermediate RS: 96% vs 80% vs 80%, respectively; p=0.04). Additionally, the proportions of high clinical risk cases were lower in the DCIS-H group compared to the DCIS-L and No-DCIS groups (42% vs 53% vs 50%, respectively; p=0.002). Based on genomic and clinical risk and current guidelines, we found that women presented with an extensive DCIS component (DCIS-H) had a lower probability of receiving an adjuvant chemotherapy recommendation compared to women presented with a non-extensive DCIS component (DCIS-L) or pure IBC (No-DCIS) (11% vs 29% vs 25%, respectively; p=.035). No differences in disease recurrence were detected between the groups. Conclusions: Co-existing extensive DCIS in invasive early HR+Her2- breast cancer is significantly correlated with lower genomic and clinical risk of recurrence and a smaller chance for chemotherapy recommendation. The rarity of this condition (5% of cases) limited our ability to detect differences in outcomes. These findings warrant future studies of the underlying genomic landscape of co-existing extensive DCIS. Citation Format: Yael Bar, Kfir Bar, Judith Ben- Dror, Didi Feldman, Meishar Shahoha, Ahuva Weiss-Meilik, Nachum Dershowitz, Wolf Ido, Amir Sonnenblick. The impact of co-existing ductal carcinoma in situ in invasive early hormone receptor positive breast cancer on the genomic and clinical risk of recurrence [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 P3-05-27.

Impact of the 21-Gene Assay in Patients with High-Clinical Risk ER-Positive and HER2-Negative Early Breast Cancer: Results of the KARMA Dx Study

The 21-gene Oncotype DX Breast Recurrence Score® assay is prognostic and predictive of chemotherapy benefit for patients with estrogen receptor-positive, HER2- early breast cancer (EBC). The KARMA Dx study evaluated the impact of the Recurrence Score® results (RS) on the treatment decision for patients with EBC and high-risk clinicopathological characteristics for whom chemotherapy (CT) was considered. Eligible patients with EBC were candidates for the study if CT was considered standard recommendation by local guidelines. Three high-risk EBC cohorts were predefined: (A) pT1-2, pN0/N1mi, and grade 3; (B) pT1-2, pN1, and grades 1-2; and (C) neoadjuvant cT2-3, cN0, and Ki67 ≤ 30%. Treatment recommendations before and after 21-gene testing were registered, as well as treatment received and physicians' confidence levels in their final recommendations. A total of 219 consecutive patients were included from eight Spanish centers: 30 in cohort A, 158 in cohort B, and 31 in cohort C. Ten patients were excluded from the final analysis as CT was not initially recommended. After 21-gene testing, treatment decisions changed from CT + endocrine therapy (ET) to ET alone for 67% of the whole group. In total, 30% (95% confidence interval [CI] 15% to 49%), 73% (95% CI 65% to 80%), and 76% (95% CI 56% to 90%) of patients ultimately received ET alone in cohorts A, B, and C, respectively. Physicians' confidence in their final recommendations increased in 34% of cases. Use of the 21-gene test resulted in an overall 67% reduction in CT recommendation in patients considered candidates for CT. Our findings indicate the substantial potential of the 21-gene test to guide CT recommendations in patients with EBC considered to be at high risk of recurrence based on clinicopathological parameters, regardless of nodal status or treatment setting.

Neoadjuvant endocrine therapy with or without palbociclib in low-risk patients: a phase III randomized double-blind SAFIA trial.

The most prevalent subtype of breast cancer (BC) is luminal hormonal-positive breast cancer. The neoadjuvant chemotherapy regimens have side effects, emphasizing the need to identify new startegies. Analyze the complete pathologic response (pCR) rate and overall response in a low-risk hormone-positive subset of patients receiving neoadjuvant hormone treatment (NAHT) with or without Palbociclib (a CDK4/CDK6 inhibitor) to boost NAHT effectiveness. Based on the upfront 21-gene Oncotype DX or low-risk Breast Recurrence Score assay (RS™), the SAFIA trial is designed as a prospective multicenter international, double-blind neoadjuvant phase-III trial that selects operable with luminal BC patients that are HER2-negative for the induction hormonal therapy with Fulvestrant 500mg ± Goserelin (F/G) followed by randomization of responding patients to palbociclib versus placebo. The pCR rate served as the study's main outcome, while the secondary endpoint was a clinical benefit. Of the 354 patients enrolled, 253 initiallyresponded and were randomized to either F/G fulvestrant with palbociclib or placebo. Two hundred twenty-nine were eligible for the evaluation of the pathologic response. No statistically significant changes were observed in the pCR rates for the patients treated with the F/G therapy with placebo or palbociclib (7% versus 2%, respectively) per the Chevallier classification (Class1 + Class2) (p = 0.1464) and 3% versus 10% assessed per Sataloff Classification (TA, NA/NB) (p = 0.3108). Palbociclib did not increase the rate of complete pathological response. Neoadjuvant hormonal therapy is feasible in a selected population with a low RS score of < 31 CLINICAL TRIAL: NCT03447132.

Precision Medicine in Breast Cancer: Do MRI Biomarkers Identify Patients Who Truly Benefit from the Oncotype DX Recurrence Score® Test?

The aim of this study was to combine breast MRI-derived biomarkers with clinical-pathological parameters to identify patients who truly need an Oncotype DX Breast Recurrence Score® (ODXRS) genomic assay, currently used to predict the benefit of adjuvant chemotherapy in ER-positive/HER2-negative early breast cancer, with the ultimate goal of customizing therapeutic decisions while reducing healthcare costs. Patients who underwent a preoperative multiparametric MRI of the breast and ODXRS tumor profiling were retrospectively included in this study. Imaging sets were evaluated independently by two breast radiologists and classified according to the 2013 American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) lexicon. In a second step of the study, a combined oncologic and radiologic assessment based on clinical-pathological and radiological data was performed, in order to identify patients who may need adjuvant chemotherapy. Results were correlated with risk levels expressed by ODXRS, using the decision made on the basis of the ODXRS test as a gold standard. The χ2 test was used to evaluate associations between categorical variables, and significant ones were further investigated using logistic regression analyses. A total of 58 luminal-like, early-stage breast cancers were included. A positive correlation was found between ODXRS and tumor size (p = 0.003), staging (p = 0.001) and grading (p = 0.005), and between BI-RADS categories and ODXRS (p &lt; 0.05 for both readers), the latter being confirmed at multivariate regression analysis. Moreover, BI-RADS categories proved to be positive predictors of the therapeutic decision taken after performing an ODXRS assay. A statistically significant association was also found between the therapeutic decision based on the ODXRS and the results of combined onco-radiologic assessment (p &lt; 0.001). Our study suggests that there is a correlation between BI-RADS categories at MRI and ODXRS and that a combined onco-radiological assessment may predict the decision made on the basis of the results of ODXRS genomic test.