Axillary Node-negative Breast Cancer Research Articles

Abstract PO1-01-10: Comparison of the cost-effectiveness of multigene assays for HR+/HER2- node-negative early-stage breast cancer in the US

Abstract Background Traditional clinico-pathologic features, such as tumor grade and size, age, and menopausal status, may provide incomplete prognostic information, and have limited ability to predict chemotherapy benefit for patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2)-, axillary lymph node-negative (N0) early-stage breast cancer, leading to both under- and over-treatment with adjuvant chemotherapy. Multigene expression profile tests have been used in clinical practice to complement clinico-pathologic information to optimize treatment decisions. To date, the Oncotype DX Breast Recurrence ScoreÒ test is the only multigene assay with the ability to predict chemotherapy benefit validated by evidence from randomized clinical trials and supported by NCCN and ASCO guidelines. Other commercially available assays in the US include MammaPrintÒ, EndoPredictÒ and Prosigna RORÒ, which offer prognostic information beyond traditional clinico-pathologic features to improve treatment decisions. The relative cost-effectiveness of the four multigene assays compared to using clinico-pathologic risk alone to guide chemotherapy decisions was assessed from a societal perspective in the US. Methods A cost-effectiveness model built in Microsoft Excel estimated the cost-effectiveness of the Oncotype DXÒ test, MammaPrint, EndoPredict and Prosigna ROR compared to using clinical-pathological risk alone over a lifetime horizon. The model structure consisted of a decision-tree portion informed using published studies for the distribution of distant recurrence risk categories as defined by each test (low, intermediate, and high risk for the Oncotype DX test and Prosigna ROR, low and high risk for MammaPrint and EndoPredict). Decision impact studies and clinical expert opinion informed the proportion of patients allocated to adjuvant chemotherapy conditional on test result category. A Markov discrete health state model then simulated the future risk of distant recurrence, and long-term adverse effects of chemotherapy: acute myeloid leukemia (AML), and congestive heart failure (CHF), and aggregated the costs and outcomes of treatment decisions over a patient’s lifetime. The probability of distant recurrence of breast cancer conditional on test result category was derived from the most up-to-date studies assessing the performance of tests: TAILORx for the Oncotype DX test, MINDACT for MammaPrint, and TransATAC for EndoPredict and Prosigna ROR. Costs were estimated from a US societal perspective in 2020 US dollars (including Medicare healthcare costs, lost productivity and patient out-of-pocket chemotherapy costs from literature), and outcomes were expressed in terms of life-years, quality-adjusted life-years (QALYs), and net monetary benefit (NMB). The cost-effectiveness of each multigene assay compared to using clinico-pathologic risk alone was presented using the incremental cost-effectiveness ratio (ICER). Results Using the Oncotype DX test resulted in the largest lifetime cost savings (-$13,395) and generated the largest QALY gain (0.25) out of the four multigene assays included in the model, when compared to using clinico-pathologic risk alone (Table 1). All four multigene assays represented a cost-effective use of resources from a societal perspective (based on the accepted willingness-to-pay threshold of $100,000 per QALY gained), with a low net lifetime cost or net cost savings with positive QALY gain. Conclusion These results support the use of multigene assays to guide treatment decisions in node-negative HR+/HER2- early-stage breast cancer to improve treatment outcomes, and also result in substantial net cost savings from a societal perspective. The prediction of chemotherapy benefit using the Oncotype DX test resulted in substantially higher cost savings and improved breast cancer outcomes. Citation Format: Vladislav Berdunov, Gebra Cuyun Carter, Christy Russell, Sara Campbell, Jennifer Racz, Yara Abdou. Comparison of the cost-effectiveness of multigene assays for HR+/HER2- node-negative early-stage breast cancer in the US [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 PO1-01-10.

Carbon nanoparticles versus patent blue dye for detection of sentinel lymph node in patients with early breast cancer

Background Sentinel lymph nodes biopsy (SLNB) has replaced axillary lymph node dissection (ALND) in a considerable percentage of patients with early-stage breast cancer which was a great advance in preventing many surgical complications and enhancing their health welfare. Although there are different sentinel lymph nodes (SLNs) tracers with different identification rates, there is no agreement about the idealistic method. Aim The study was designed to compare carbon nanoparticles and patent blue v dye regarding SLNs detection rate, number of SLNs, time of detection, metastatic SLNs, cost, and safety in patients with early breast cancer and clinically node-negative axilla. Patients and methods A total of 40 patients with axillary lymph node-negative early-stage breast cancer patients were divided into two groups and subjected to carbon nanoparticles and patent blue V dye in group A and group B, respectively. Patients who were pregnant or lactating had node-positive axilla (N1-3) or metastatic breast cancer (M1) or had neoadjuvant chemotherapy were excluded. Results The mean age was 48.3±9.5 and 47 ±8.9, while the mean BMI of 33.3±4.8 and 32.834±4.862, the SLN detection rates were 95% and 90% in groups A and B, respectively. A total of 128 sentinel lymph nodes (SLNs) were removed from patients in the two groups (65 with Carbon Nanoparticles and 63 with patent blue dye). The mean number of SLNs was 3.4±0.7 (range, 2–5) and 3.5±1.2 (range, 2–7), mean time of SLNs detection was 13.5±4.5 (range, 7–22) and 12.7± 3.6 (range, 7–18 min) between group A and B, respectively. Conclusion There is no significant difference between carbon nanoparticles and patent blue dye regarding axillary SLNs in early breast cancer regarding identification rate, number of SLNs, time of detection, metastatic SLNs, cost, and safety with slight preference to carbon nanoparticles regarding postoperative skin staining and Egyptian market availability.

Reduction in Breast Cancer Death With Adjuvant Chemotherapy Among US Women According to Race, Ethnicity, and the 21-Gene Recurrence Score.

We previously showed the 21-gene breast recurrence score (RS) has lower prognostic accuracy for non-Hispanic Black (NHB) compared with non-Hispanic White (NHW) women with estrogen receptor (ER)-positive/HER2-negative breast cancer. The purpose of this study was to determine the clinical validity of the RS for predicting chemotherapy benefit as recommended in the current NCCN Guidelines for Breast Cancer among women from diverse racial/ethnic groups. Using the SEER Oncotype database, we estimated propensity score-weighted hazard ratios (HRs) and 95% confidence intervals for breast cancer death with chemotherapy for women with ER-positive/HER2-negative, AJCC stages I-II, axillary node-negative, invasive breast cancer according to race/ethnicity. We included 6,033 (8.2%) Asian/Pacific Islander (API), 5,697 (7.8%) NHB, 6,688 (9.1%) Hispanic, and 54,945 (74.9%) NHW women. Breast cancer death was reduced with chemotherapy for NHB (HR, 0.48, 95% CI, 0.28-0.81), Hispanic (HR, 0.48; 95% CI, 0.25-0.94), and NHW (HR, 0.80; 95% CI, 0.65-0.99) women with an RS of 26 to 100. There was a nonsignificant reduction for API women (HR, 0.59; 95% CI, 0.28-1.24). For women with an RS of 11 to 25, there was no reduction in death for any racial/ethnic group. Among women aged ≤50 years, the reduction in breast cancer death with chemotherapy differed according to race (NHB: HR, 0.37 [95% CI, 0.20-0.67]; NHW: HR, 0.56 [95% CI, 0.44-0.74]; Pinteraction for chemotherapy * race <.0499). An exploratory subgroup analysis found that young NHB women may benefit from chemotherapy at a lower RS cutoff than other women. The RS was clinically validated as a predictive biomarker for NHB, Hispanic, and NHW women with ER-positive, axillary node-negative breast cancer, but it may underestimate the benefit of chemotherapy for young NHB women. If this finding is confirmed, the RS cutoff for recommending adjuvant chemotherapy for young NHB women with ER-positive, axillary node-negative breast cancer may need to be lower than for other women.

Real-world impact of TAILORx on chemotherapy use and SOFT/TEXT on ovarian function suppression uptake in a population based-cohort of women 40 years and under with HR-positive, HER2-negative, axillary lymph node negative breast cancer.

534 Background: Gene expression profiling (GEP) testing is prognostic for distant recurrence risk in women with hormone receptor positive (HR+), human epidermal growth factor receptor-2 negative (HER2-), axillary lymph node negative (LN-) breast cancer (BC). The TAILORx trial generated prospective evidence demonstrating the 21-gene recurrence score (RS) is also predictive of chemotherapy (CT) benefit. The literature suggests that GEP testing reduces adjuvant CT prescription and is cost-effective. In the same era, the SOFT/TEXT trials demonstrated disease-free survival benefit for the addition of ovarian function suppression (OFS) to endocrine therapy in premenopausal women. Real-world uptake and impact of these advances in the management of HR+, HER2-, LN- BC in young women may be limited due to complex reasons. This retrospective study evaluated GEP and CT use post TAILORx and OFS use post SOFT/TEXT in women 40 years old or younger diagnosed with HR+, HER2-, LN BC from 2011 to 2020 in Alberta, Canada. Methods: Clinical variables were retrieved from the Alberta Health Services Cancer Care Breast Data Mart and through review of the electronic medical record. GEP testing and CT use were compared between 3 cohorts of women defined by diagnosis: pre RS funding/pre TAILORx (before April 2014), post RS funding/pre TAILORx (April 2014-May 2018), post TAILORx (June 2018 and beyond). OFS use was compared between 2 cohorts of women defined by diagnosis pre- and post SOFT/TEXT (May 2015). In subgroup analyses, we compared CT use by GEP status and RS category and OFS use by CT status. Results: Among the 291 women identified, GEP testing increased by 37% post GEP funding (pre 2% vs. post 39%; P = &lt; .0001) and by additional 15% post TAILORx (pre 39% vs. post 54%; P &lt; .0001) whereas overall CT use declined by 15% post GEP funding (pre 85% vs. post 70%; P = .01) and by additional 16% post TAILORx (pre 70% vs. post 54%; P = .01). Although not significant, OFS use increased by 8% post SOFT/TEXT (pre 13% vs. post 21%; P = .08). In subgroup analyses, post TAILORx was associated with a significant reduction in CT use of 19.5% in non-GEP tested women (pre 85% vs. post 65% P = .01) and non-significant increase in CT use of 6% in RS tested women (pre 40% vs. post 46%; P = .61) mainly driven by high mid range RS 21-25 and lower high range RS 26-30. There was no significant change in OFS use in non-CT treated women post SOFT/TEXT (Pre 5.3% vs. Post 8%, P = .68) whereas OFS use increased by 15% in women treated with CT post SOFT/TEXT (pre 15% vs. post 30%; P = .01). Conclusions: Public GEP funding and TAILORx led to widespread adoption of GEP and real-world decline in CT use in women 40 years of age or younger diagnosed with HR+, HER2-, LN- BC in Alberta. SOFT/TEXT led to real-world incline in OFS use in those treated with CT but adoption remained suboptimal.

Association of Social Determinants and Tumor Biology With Racial Disparity in Survival From Early-Stage, Hormone-Dependent Breast Cancer

Black women with hormone receptor-positive breast cancer experience the greatest racial disparity in survival of all breast cancer subtypes. The relative contributions of social determinants of health and tumor biology to this disparity are uncertain. To determine the proportion of the Black-White disparity in breast cancer survival from estrogen receptor (ER)-positive, axillary node-negative breast cancer that is associated with adverse social determinants and high-risk tumor biology. A retrospective mediation analysis of factors associated with the racial disparity in breast cancer death for cases diagnosed between 2004 and 2015 with follow-up through 2016 was carried out using the Surveillance, Epidemiology, and End Results (SEER) Oncotype registry. The study included women in the SEER-18 registry who were aged 18 years or older at diagnosis of a first primary invasive breast cancer tumor that was axillary node-negative and ER-positive, who were Black (Black), non-Hispanic White (White), and for whom the 21-gene breast recurrence score was available. Data analysis took place between March 4, 2021, and November 15, 2022. Census tract socioeconomic disadvantage, insurance status, tumor characteristics including the recurrence score, and treatment variables. Death due to breast cancer. The analysis with 60 137 women (mean [IQR] age 58.1 [50-66] years) included 5648 (9.4%) Black women and 54 489 (90.6%) White women. With a median (IQR) follow-up time of 56 (32-86) months, the age-adjusted hazard ratio (HR) for breast cancer death among Black compared with White women was 1.82 (95% CI, 1.51-2.20). Neighborhood disadvantage and insurance status together mediated 19% of the disparity (mediated HR, 1.62; 95% CI, 1.31-2.00; P < .001) and tumor biological characteristics mediated 20% (mediated HR, 1.56; 95% CI, 1.28-1.90; P < .001). A fully adjusted model that included all covariates accounted for 44% of the racial disparity (mediated HR, 1.38; 95% CI, 1.11-1.71; P < .001). Neighborhood disadvantage mediated 8% of the racial difference in the probability of a high-risk recurrence score (P = .02). In this study, racial differences in social determinants of health and indicators of aggressive tumor biology including a genomic biomarker were equally associated with the survival disparity in early-stage, ER-positive breast cancer among US women. Future research should examine more comprehensive measures of socioecological disadvantage, molecular mechanisms underlying aggressive tumor biology among Black women, and the role of ancestry-related genetic variants.

Effect, sensitivity, specificity and accuracy of ultrasonic assessment of axillary lymph node-negative breast cancer.

To investigate the diagnostic value of ultrasound for patients with axillary lymph node-negative breast cancer (ALNNBC). A retrospective analysis was performed on the clinical data of 204 breast cancer patients who were admitted by Quanzhou First Hospital Affiliated to Fujian Medical University between October 2020 and May 2022. According to the results of axillary lymph node (ALN) examination, the patients were assigned to a positive group(n=102) and a negative group(n=102). All patients underwent diagnosis with color Doppler ultrasound, with pathological diagnosis as the "gold standard" to determine the sensitivity and specificity of ultrasonic diagnosis. A receiver operating characteristic(ROC) curve was established to analyze the efficiency of ultrasonic diagnosis and compare the ultrasonographic features and flow grades between the two groups. Differences were statistically significant between the two groups in ultrasonographic features of lesions(negative vs positive, all p<0.05), including morphological irregularity(59.8% vs 85.3%), spiky margins(19.6% vs 63.7%), posterior echo attenuation(19.6% vs 44.1%) and microcalcification(40.2% vs 55.89%). The negative group had a lower proportion of patients with grade 2-3 ultrasound blood flow when compared with the positive group(32.4% vs 56.86%), and the difference was statistically significant(p<0.05). Ultrasonic diagnosis of ALNNBC had a sensitivity of 88.24%(90/102), a specificity of 92.16%(94/102), a coincidence rate of 90.20% (184/204), a 95% CI of 0.845-0.928, and an AUC of 0.879. Ultrasonic diagnosis of ALNNBC is relatively efficient as ultrasonographic features and ultrasound blood flow signals can provide a scientific basis for the diagnosis of ALNNBC.

Assessment of Racial Disparity in Survival Outcomes for Early Hormone Receptor–Positive Breast Cancer After Adjusting for Insurance Status and Neighborhood Deprivation

Racial disparities in survival outcomes among Black women with hormone receptor-positive breast cancer have been reported. However, the association between individual-level and neighborhood-level social determinants of health on such disparities has not been well studied. To evaluate the association between race and clinical outcomes (ie, relapse-free interval and overall survival) adjusting for individual insurance coverage and neighborhood deprivation index (NDI), measured using zip code of residence, in women with breast cancer. This was a post hoc analysis of 9719 women with breast cancer in the Trial Assigning Individualized Options for Treatment, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer. The present data analysis was conducted from April 1 to October 22, 2021. A multivariate model was developed to evaluate the association between race and relapse-free interval and overall survival adjusting for insurance and NDI level at study entry, early discontinuation of endocrine therapy 4 years after initiation, and clinicopathologic characteristics of cancer. Median follow-up for clinical outcomes was 96 months. A total of 9719 women (4.2% [n = 405] Asian; 7.1% [n = 693] Black; 84.3% [n = 8189] White; 4.4% [n = 403] others/not specified) were included; 9.1% of included women [n = 889] were Hispanic or Latino. Median (SD) age was 56 (9.2) years. In multivariate models, Black race compared with White race was associated with statistically significant shorter relapse-free interval (hazard ratio [HR], 1.39; 95% CI, 1.05-1.84; P = .02) and overall survival (HR, 1.49; 95% CI, 1.10-2.99; P = .009), adjusting for insurance and NDI level at study entry and other factors. Although uninsured status was not associated with clinical outcomes, patients with Medicare (HR, 1.30; 95% CI, 1.01-1.68; P = .04) and Medicaid (HR, 1.44; 95% CI, 1.01-2.05; P = .05) had shorter overall survival compared with those with private insurance. Participants living in neighborhoods in the highest NDI quartile experienced shorter overall survival compared with those in the lowest quartile (HR, 1.34; 95% CI, 1.01-1.77; P = .04), regardless of self-identified race. The findings of this post hoc analysis of a randomized clinical trial suggest that Black women with breast cancer have significantly shorter relapse-free interval and overall survival compared with White women. Early discontinuation of endocrine therapy, clinicopathologic characteristics, insurance coverage, and NDI do not fully explain the observed disparity. ClinicalTrials.gov Identifier: NCT00310180.

Abstract P3-14-02: Racial/ethnic differences in the benefit of adjuvant chemotherapy for breast cancer patients with an intermediate risk 21-gene recurrence score

Abstract Background: The Oncotype 21-gene Recurrence Score (RS) is the most commonly ordered genomic biomarker used to inform decisions on adjuvant chemotherapy for patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer. Representation of racial/ethnic minority patients in the population used to develop the assay was poor, with only 5% of study participants identified as Black. This raises concern about the accuracy of the RS in underrepresented populations. In earlier work (Hoskins et al, JAMA Oncology 2021), we showed that the RS has less prognostic accuracy in Black compared with non-Hispanic White (NHW) women. This finding is concerning in light of persistent racial disparities in breast cancer mortality. Here we examine the predictive accuracy of the RS according to race/ethnicity for identifying patients with ER+, axillary node-negative breast cancer who benefit from adjuvant chemotherapy.Methods: We conducted a large, population-based retrospective cohort study of women 18+ years diagnosed with ER+, axillary node-negative breast cancer from 2004 to 2010 using Surveillance, Epidemiology and End Results Oncotype DX Database (2004-2015). This analysis included women with a minimum of 7 yrs follow-up and an RS of 11-25, since this is the group with the most uncertainty regarding the benefit of chemotherapy. Demographic and clinical characteristics were collected from cancer registry data. Propensity score weighted Cox models determined the association between chemotherapy use and breast cancer death. Age, insurance status, tumor grade, tumor size, progesterone receptor status, and RS were included as predictors of the propensity score. Associations between chemotherapy use and breast cancer death were determined using overall, race/ethnicity, and age stratum-specific hazard ratios (HR) and 95% confidence intervals (CI). Results: The analysis included 22,693 NHW, 5,657 Black, and 3,348 Hispanic women. The overall result is consistent with the prospective TAILORx trial, showing greater benefit from chemotherapy in women under age 50. There is a greater reduction in the hazard of breast cancer death associated with chemotherapy use for Black (HR 0.31, 95% CI, 0.15, 0.66) and Hispanic (HR 0.07, 95% CI, 0.02, 0.31) compared with NHW women under age 50 (HR 0.43, 95% CI,0.32, 0.59). In models combining Black and NHW patients, an interaction term for race*chemotherapy was significant (p=0.022), indicating a differential association between chemotherapy use and breast cancer death according to race/ethnicity. Visual comparison of breast cancer mortality curves that plot 7-year breast cancer death rate as a function of the continuous RS, stratified by chemotherapy administration (yes/no), shows that the curves begin to diverge at a lower RS for Black (RS 17) compared with NHW women (RS 24). Conclusions: This observational study found that Black women under age 50 with ER+, axillary node-negative breast cancer and an RS of 11-25 derive significantly more benefit from adjuvant chemotherapy than NHW women. National practice guidelines do not recommend routine use of adjuvant chemotherapy for patients in this risk category, indicating that many Black patients may be undertreated. Results need to be confirmed in prospective studies, but they suggest that RS cut-offs used to recommend adjuvant chemotherapy may need to be modified for racial/ethnic minority women. Hazard of Breast Cancer Death (95% Confidence Interval)Race/EthnicityChemotherapyAll AgesAge &amp;lt; 50Age 50+OverallYes0.71 (0.63, 0.81)0.32 (0.25, 0.41)1.01 (0.87, 1.18)NoRefRefRefNHWYes0.73 (0.62,0.84)0.43 (0.32, 0.59)0.87 (0.74, 1.04)NoRefRefRefBlackYes0.83 (0.60, 1.16)0.31 (0.15, 0.66)1.26 (0.84, 1.89)NoRefRefRefHispanicYes0.33 (0.20, 0.57)0.07 (0.02, 0.31)0.61 (0.33, 1.12)NoRefRefRef Citation Format: Hsiao- Ching Huang, Gregory S. Calip, Jennifer Weiss, Yael Simons, V.K. Gadi, Oana C. Danciu, Garth H. Rauscher, Kent F. Hoskins. Racial/ethnic differences in the benefit of adjuvant chemotherapy for breast cancer patients with an intermediate risk 21-gene recurrence score [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-02.

Use of methylene blue dye for lymphatic basin mapping and sentinel lymph node biopsy in breast cancer patients in Enugu, Nigeria.

Sentinel lymph node biopsy is the current standard of care for axillary staging and further treatment planning in patients with clinical axillary node-negative breast cancer. Sentinel node (SN) biopsy was designed to accurately stage the axilla and minimize the side effects of conventional axillary-lymph-node dissection without sacrificing oncologic outcomes. Sentinel lymph node biopsy is normally performed with nuclear scan and patent blue violet or isosulfan blue. These are expensive and not commonly available in resource-poor regions such as West Africa. Methylene blue dye is a commonly used agent in a wide range of clinical diagnostic procedures and has been used by other investigators to perform this procedure. This study was designed to demonstrate the feasibility and effectiveness of SN biopsy in the management of axillary node-negative breast cancer in resource-limited populations using methylene blue dye. To determine the efficacy of methylene blue dye as a single tracer in lymphatic basin mapping and sentinel lymph node biopsy in patients with clinical axillary node-negative breast cancer. This was a prospective, case-controlled study involving 28 consecutively presenting female patients with clinical axillary node-negative breast cancer at the University of Nigeria Teaching Hospital, Enugu. Each of the patients had lymphatic basin mapping and sentinel lymph node biopsy with a sub-areola-subdermal injection of methylene blue dye. The SN (s) were then removed using the dye as the marker. Each patient then had a mastectomy or wide local excision as appropriately planned and conventional levels I and II axillary dissection was performed in the same sitting. The SNs and other axillary nodes were reviewed independently by our institution's pathologist. Each patient's axillary dissection specimen acted as her control for the study. The SNs were identified in 24 (85.7%) patients. There was a demonstrable learning curve with an improvement in identification rate in the later half of the cases (92.9%) compared to the earlier half of the cases (78.6%). A range of 1-3 nodes and a mean of 1.78 nodes were obtained. A sensitivity of 90.9%, specificity of 79.6%, false-positive rate of 28.6%, false-negative rate of 9.1%, and accuracy of 95.8% were obtained. There was no incidence of allergic/hypersensitivity reaction. Sentinel lymph node biopsy with methylene blue dye can be applied with high accuracy within resource-limited environments. However, there is a definite short learning curve that must be overcome and the procedure validated before clinical application in decision-making.

Recent Advances in the Tracer Technology Used for Sentinel Lymph Node Biopsy in Breast Cancer

The high incidence of breast cancer poses one of the greatest risks to female health worldwide. Sentinel lymph node biopsy (SLNB) is the standard of treatment for patients with axillary lymph node-negative early-stage breast cancer. Herein, the precise use of tracers is the key to ensuring the success of SLNB. However, owing to select-few limitations of traditional tracers, their clinical application is limited. New tracer techniques, such as the near-infrared fluorescent dye method (using indocyanine green), contrast-enhanced ultrasound, and superparamagnetic iron oxide nanoparticles are being applied in clinical practice. In this paper, we review the recent progress in SLNB tracer technology.

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer

BackgroundThe recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary lymph-node–negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.MethodsIn a prospective trial, we randomly assigned women with hormone-receptor–positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease–free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse–free survival.ResultsA total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease–free survival differed according to menopausal status (P=0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease–free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P=0.89). Among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P=0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.ConclusionsAmong premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease–free survival and distant relapse–free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)

Association of Modifiable Risk Factors With Early Discontinuation of Adjuvant Endocrine Therapy

Early discontinuation of adjuvant endocrine therapy (ET) is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the recommended full 5 years of ET treatment. To identify the association between early discontinuation of ET in the Trial Assigning Individualized Options for Treatment (TAILORx) and modifiable risk factors, polypharmacy, and types of additional medications such as antidepressants and opioids. This post hoc analysis includes a subgroup of 954 patients with breast cancer in TAILORx, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer and started ET within a year of study entry. Analyses were conducted in the intent-to-treat population. Statistical analysis took place from January 15, 2020, to April 6, 2021. Participants completed measures on cancer-related health-related quality of life including physical well-being and social well-being prior to initiating ET. Early discontinuation of ET was defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence. Kaplan-Meier estimates were used to calculate discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET with patient-level factors. A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. In a joint model, receipt of chemoendocrine therapy (vs receipt of ET only; hazard ratio [HR], 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005), worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002), and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were individually and significantly associated with a higher probability of early discontinuation of ET. Only antidepressant use at study baseline was associated with early discontinuation (HR, 1.87; 95% CI, 1.23-2.84; P = .003). In this post hoc analysis of a randomized clinical trial, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies. These results support systematic screening for patient-reported outcomes and depressive symptoms to identify women at risk for discontinuation of ET. ClinicalTrials.gov Identifier: NCT00310180.

What accounts for the racial disparity in survival from estrogen receptor-positive, axillary node-negative breast cancer in the United States? An analysis of the SEER-Oncotype database.

6534 Background: In a previous analysis of the SEER-Oncotype database (Hoskins, et al. JAMA Oncol, 2021), we reported that among women with estrogen receptor (ER)-positive, axillary node-negative breast cancer (BC), Black women were more likely than non-Hispanic White (White) women to have a high risk Oncotype Recurrence Score (RS), and the adjusted hazard for BC-specific death was 1.5-2.5 times higher for Black than for White women within each RS risk category. In this study we examined the role of health insurance, census tract socioeconomic status and tumor biology in the racial disparity in ER-positive BC mortality among US women. Methods: We obtained BC-specific survival data from the SEER-Oncotype database for women diagnosed with first primary, stages I-II, ER-positive, node-negative BC between 1/1/2004 -12/31/2015 who had an Oncotype Recurrence Score (RS) through Genomic Health Laboratory. The racial (Black:White) BC mortality disparity was estimated as a disparity hazard ratio (HR) from a series of Cox proportional hazards models of time to BC death. The baseline model adjusted for SEER registry and age at diagnosis (included in all models). We estimated the disparity HR after controlling for variable domains one at a time, as well as cumulatively in this order: neighborhood SES index (a composite measure including census tract education, income and poverty) and insurance (none, public, private); tumor biology (RS, PR status, tumor grade); tumor size; and treatment (surgery type, initiation of radiation and chemotherapy). Results: The analysis included 57,428 White and 6,003 Black women with node-negative, ER-positive BC (median follow-up = 54 months). The total disparity HR for BC death was 1.67 (95% CI: 1.37, 2.02). Tract SES and insurance together accounted for 21% of the disparity HR (adjusted HR 1.52, 95% CI: 1.22, 1.88); most of this was due to differences in insurance status, with tract SES accounting for 7% of the disparity when considered in isolation. Tumor biology (RS, PR status and grade) accounted for 30% of the disparity (adjusted HR = 1.41, 95% CI:1.14, 1.75); together, the domains of social determinants and tumor biology accounted for 50% of the disparity HR (adjusted HR = 1.30, 95% CI: 1.04, 1.62). Tumor size and treatment initiation each explained roughly 10% of the disparity HR when considered in isolation but did not account for any of the disparity once other factors were accounted for. Results obtained from additional methods for mediation analyses, including a method of rescaled coefficients and structural equation modeling (SEM) applied to discrete-time survival analysis will also be presented. Conclusions: In this study of node-negative, ER-positive BC, much of the BC survival disparity among US women could be explained by racial differences in measured tumor biology and social determinants of health.

Four Cycles of Docetaxel-Cyclophosphamide versus Anthracycline-Taxane as Adjuvant Chemotherapy for HER2-Negative, Axillary Lymph Node Negative Breast Cancer: A Real-World Comparison of Alberta Patients Treated 2008-2012.

Uncertainty exists around the need to include an anthracycline if taxane-based adjuvant chemotherapy is being used for human epidermal growth factor receptor-2 (HER2) negative and axillary lymph node negative (LNN) breast cancer. We identified all patients who were diagnosed with HER2-negative, LNN breast cancer treated with docetaxel-cyclophosphamide for four cycles (DC4) or an anthracycline-taxane (AT) regimen following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with AT to up to four patients treated with DC4 on potentially confounding clinicopathologic and treatment variables. We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) and assessed the effect of the type of adjuvant chemotherapy on these outcomes using Cox regression. Of the 726 eligible patients, 657 (90.5%) were treated with DC4 and 69 (9.5%) were treated with AT. Matching created a group of 202 women treated with DC4 and eliminated differences in clinicopathologic and treatment factors. There was no statistically significant difference for the treatment effects of matched DC4 patients compared to the AT patients on iDFS (75.7% vs. 76.8%, p = 0.75; hazard ratio (HR) = 1.05, 95% CI = 0.65 to 1.8), BCSS (88.1% vs. 87%, p = 0.8; HR = 0.91, 95% CI = 0.42 to 1.9), or OS (87.1% vs. 86.9%, p= 0.96; HR = 0.98, 95% CI = 0.46 to 2.1). Four cycles of DC as compared with an AT regimen yielded similar 10-year iDFS, BCSS and OS amongst patients with HER2-negative, LNN breast cancer.

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

Abstract Background: The 21-gene recurrence score (RS) provides prognostic information for distant recurrence (DR) and predictive information for chemotherapy (CT) benefit in early breast cancer, whereas clinicopathologic features provide only prognostic information. We used patient-specific meta-analysis (PSMA) methods (Crager et al, J Appl Stat 2014 [PMID: 26664111]; Tang et al. J Clin Oncol 2011 [PMID: 22010013]) to develop an online tool that assesses individualized estimates of DR risk and absolute CT benefit. We also externally validated this new tool for estimating DR risk in an independent cohort.Methods: The PSMA included 10,004 women with hormone-receptor positive, HER2-negative, node-negative breast cancer from the NSABP B-14 (n=577) trial receiving endocrine therapy (ET) alone and TAILORx trial receiving ET alone (n=4854) or CT plus ET (n=4573). The baseline risk used TAILORx event rates with ET alone. A patient-specific estimator of absolute CT benefit was computed by combining PSMA of the individualized relative CT effect from the TAILORx and NSABP B-20 (n=550 HER2-negative) trials and risk estimates with ET alone. External validation of DR risk estimation was performed in an independent cohort of 1098 women enrolled in the Clalit Health Service registry who had a 21-gene RS performed, of whom 222 (20%) received CT in addition to ET as per the recommendation of their treating physician guided by the RS. Results: The new tool is more informative for DR risk than RS or clinicopathologic factors alone (p&amp;lt;0.001, likelihood ratio test). The risk estimate was significantly associated with DR risk in the independent Clalit cohort (p&amp;lt;0.001), and closely approximated the observed 10-year DR risk (Lin concordance 0.962). Since the RS strongly influenced CT use, propensity score matching could not appropriately be used for evaluation of CT benefit in Clalit. Using this tool for a 55-year-old woman with a low clinical risk 1.5 cm intermediate grade tumor, the absolute CT benefit estimate ranges from 0% to 15% as RS ranges from 11 to 50; this compares to a range of 2% to 8% if the relative CT benefit were held constant. Over the same RS range for a 55-year-old woman with high clinical risk 2.5 cm poor grade tumor, the tool’s absolute CT benefit estimate ranges from 1% to 33% compared to 4% to 17% if the relative CT benefit were held constant. This indicates that incremental CT benefit observed with higher RS is driven not only by a higher underlying recurrence risk, but also by prediction of relative CT benefit.Conclusions: We describe a validated clinical tool integrating clinicopathologic and genomic features to guide adjuvant chemotherapy of hormone-receptor positive, HER2-negative, axillary node-negative breast cancer with greater precision than using clinicopathologic or genomic data alone. The individualized CT effect prediction provided by the RS, based on contemporary treatments, contributes substantially to the estimate of absolute CT benefit. Support: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180822, U10CA180868, and UG1CA189859. The content is solely the responsibility of the authors. Mention of commercial products does not imply endorsement by the U.S. government. Additional support was provided by the Breast Cancer Research Foundation, the Komen Foundation, and the Breast Cancer Research Stamp (BCRS) issued by the United States Postal Service. Citation Format: Joseph A Sparano, Michael R Crager, Gong Tang, Robert J Gray, Salomon M Stemmer, Steve Shak. Development and validation of a tool integrating the 21-gene recurrence score and clinicopathlogic features to individualize prognosis for distant recurrence and prediction of absolute chemotherapy benefit in early breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-10.

Abstract PS6-34: Real life impact of TAILORx trial in a multi-center healthcare system: A comparison of management practice one year before and after the release of the trial

Abstract Introduction: Oncotype DX is a 21 gene assay which has been shown to be useful in predicting the risk of breast cancer recurrence. TAILORx trial compared survival with the use of hormonal therapy (HT) vs. chemo-hormonal therapy (CHT) in early-stage, Hormone receptor-positive, HER2-negative, axillary lymphnode-negative breast cancer who had an Oncotype DX recurrence score in the intermediate range (11-25), The study found HT to be non-inferior to CHT in that group, especially in women older than 50. Materials and methods: We studied 1084 patients with hormone receptor-positive, HER-2 negative early stage breast cancer at a multi-center setting in South Dakota and North Dakota who were diagnosed one year before and after the results of the TAILORx trial were presented. We aimed to identify any change in practice after the trial was published as compared to the year prior. Chi-square analysis was used to compare demographics of patients and management practices before and after the TAILORx trial publication. Results: We did not find any statistically significant change in Oncotype DX testing frequency across various age groups, tumor sizes, tumor grades or amongst patients who had lymphnode negative or one axillary lymph node positive disease (Table-1).We also did not find any statistically significant difference in management of early stage breast cancer patients (Table-2) that matched our inclusion criteria and had an intermediate risk Oncotype Dx score of 11-25(n=266). Conclusion: Our results indicate that management of early stage breast cancer at our center was not significantly impacted by the results of TAILORx. Rare use of CHT prior to TAILORx reporting suggests that practice prior to this trial was largely based on earlier trials suggesting minimal benefit for CHT in the intermediate risk group. Larger studies may be able to identify smaller changes in practice resulting from this study and should be pursued. Table-1: Frequency of Oncotype Dx testing one year before and after the TAILORx trial was released overall and in various sub-categories based on age of the patient, tumor size and tumor grade. Last row indicates the frequency comparison in patients who had one axillary lymph node positive status.Before TAILORx (N=512)After TAILORx (N=572)p-valuen (%)n (%)Overall204 (40)234 (41)0.7212Age&amp;lt; 5044 (46)31 (37)0.225450 - 69121 (46)146 (49)0.4519Equal or &amp;gt; 7039 (26)57 (30)0.3986Tumor Size&amp;lt; 1 cm41 (25)50 (28)0.53881 - 1.9 cm97 (51)122 (53)0.60552 - 2.9 cm40 (44)44 (42)0.77283+ cm24 (39)18 (32)0.4161Tumor Grade156 (39)63 (42)0.62002113 (48)135 (47)0.8542334 (26)35 (27)0.9768LN Positive31 (33)36 (32)0.9403 Table-2: Comparison of treatment received by patients in the intermediate risk group (score:11-25) based on Oncotype Dx test before and after the release of TAILORx trial , Chi sq p-value=0.5635, HT (Hormonal Therapy), CT (Chemotherapy).Before TAILORxAfter TAILORxHT + CTn=15n=135.91%5.12%HT Alonen=108n=11842.52%46.46% Citation Format: Mahum Shahid, Moataz Ellithi, Mohamed Abdallah, Arsalan Arshad, Mansi Oberoi, Mckenna L Eisenbeisz, Christopher M VanHove, Ty A Moody, Isaak N Ailts, Andrew J Foley, Morgan Nelson, Jonathan Bleeker. Real life impact of TAILORx trial in a multi-center healthcare system: A comparison of management practice one year before and after the release of the trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-34.

Association of Race/Ethnicity and the 21-Gene Recurrence Score With Breast Cancer–Specific Mortality Among US Women

Given the widespread use of the 21-gene recurrence score for identifying candidates for adjuvant chemotherapy, it is important to examine the performance of the Oncotype DX Breast Recurrence Score test in diverse patient populations to validate this approach for tailoring treatment in women in racial/ethnic minority groups. To examine whether breast cancer-specific mortality for women with hormone-dependent breast cancer differs by race/ethnicity across risk categories defined by the Oncotype DX Breast Recurrence Score test and whether the prognostic accuracy of the 21-gene recurrence score differs by race/ethnicity. This retrospective, population-based cohort study used the Surveillance, Epidemiology, and End Results Oncotype DX 2004-2015 database to obtain breast cancer-specific survival data on US women 18 years and older who were diagnosed with first primary stage I to III, estrogen receptor-positive breast cancer between January 1, 2004, and December 31, 2015, and had tumor testing through the Genomic Health Clinical Laboratory. Data were analyzed from April 20 to September 27, 2020. The primary outcome was breast cancer-specific mortality among women from different racial/ethnic groups stratified by the 21-gene recurrence score risk categories. Secondary analyses compared the prognostic accuracy of the recurrence score among the different racial/ethnic groups. A total of 86 033 patients with breast cancer (mean [SD] age, 57.6 [10.6] years) with Oncotype DX Breast Recurrence Score test information were available for the analysis, including 64 069 non-Hispanic White women (74.4%), 6719 non-Hispanic Black women (7.8%), 7944 Hispanic women (9.2%), 6950 Asian/Pacific Islander women (8.0%), and 351 American Indian/Alaska Native women (0.4%). Black women were significantly more likely than non-Hispanic White women to have a recurrence score greater than 25 (17.7% vs 13.7%; P < .001). Among women with axillary node-negative tumors, competing risk models adjusted for age, tumor characteristics, and treatment found higher breast cancer-specific mortality for Black compared with non-Hispanic White women within each recurrence score risk stratum, with subdistribution hazard ratios of 2.54 (95% CI, 1.44-4.50) for Black women with recurrence scores of 0 to 10, 1.64 (95% CI, 1.23-2.18) for Black women with recurrence scores of 11 to 25, and 1.48 (95% CI, 1.10-1.98) for Black women with scores greater than 25. The prognostic accuracy of the recurrence score was significantly lower for Black women, with a C index of 0.656 (95% CI, 0.592-0.720) compared with 0.700 (95% CI, 0.677-0.722) (P = .002) for non-Hispanic Whites. In this cohort study, Black women in the US were more likely to have a high-risk recurrence score and to die of axillary node-negative breast cancer compared with non-Hispanic White women with comparable recurrence scores. The Oncotype DX Breast Recurrence Score test has lower prognostic accuracy in Black women, suggesting that genomic assays used to identify candidates for adjuvant chemotherapy may require model calibration in populations with greater racial/ethnic diversity.

Adjuvant Chemotherapy for Low-Clinical-Risk Breast Cancer Defined by Modified Version of Adjuvant! Online: A Propensity Score Matched SEER Analysis

Background: The purpose of this research was to investigate whether the modified version of Adjuvant! Online was able to omit chemotherapy (CT) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, and axillary node-negative breast cancer, who are defined as low clinical risk. Methods: From 2010 to 2014, HR-positive, HER2-negative, and node-negative breast cancer patients aged 50 years and older were retrieved from the Surveillance, Epidemiology, and End Results (SEER) 18 database. The propensity score matching method was applied between the no-CT and CT groups. Overall survival (OS) was evaluated using Kaplan-Meier analysis and compared across groups using a log-rank test. Results: A total of 48,857 patients were enrolled. After propensity score matching, the numbers of patients in the no-CT and CT groups were both 3,102. The median follow-up period was 37 months. The 5-year OS rates in the no-CT and CT groups were 92 and 91%, respectively (p = 0.066). In the subgroup with a tumor score (tumor size added to tumor grade) of 2–3, OS was significantly higher in the no-CT group than in the CT group (93 vs. 90%, p < 0.001). In the subgroup with a tumor score of 4, OS was not different between these 2 groups (92 vs. 93%, p = 0.47). Conclusion: This retrospective study provides evidence that CT may not be beneficial to patients 50 years of age or older with HR-positive, HER2-negative, axillary node-negative breast cancer and additionally defined as low clinical risk by a modified version of Adjuvant! Online.

Early discontinuation to adjuvant endocrine therapy in the ECOG-ACRIN TAILORx Trial.

7004 Background: The TAILORx study demonstrated women with an intermediate Oncotype DX score receive the same benefit with endocrine therapy (ET) compared to chemoendocrine therapy (CET). However, early discontinuation of adjuvant ET is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the full 5 years of recommended ET treatment. The aim of this study was to identify patient-level risk factors associated with early discontinuation of ET in the TAILORx study. Methods: TAILORx was coordinated by the ECOG-ACRIN Cancer Research Group. Participants were a subgroup of 954 women who completed additional measures on health-related quality of life (HRQoL) including endocrine symptoms (ES) physical well-being (PWB) and social well-being (SWB) prior to initiating ET, which categorized into three groups by tertile for analysis. All participants were diagnosed with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer who started ET within a year of study entry. Early discontinuation of ET, defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence, was assessed by clinician report. Rate of discontinuation was calculated using Kaplan-Meier estimates, and Cox-proportional hazards joint models were used to analyze the association between rates of adherence to ET with patient-level factors. Results: In a joint model, receipt of CET therapy (vs receipt of ET only; HR = .59, 95% CI .38-.94, p = .02) and age above 40 (versus age &lt; = 40; HR = .30, 95% CI .14-.66, p = .003) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared to no history of depression (HR 1.82, 95% CI 1.19-2.77, p = 0.005), worse ES compared to better ES (HR 1.70, 95% CI 1.06-2.74, p = 0.03), worse PWB compared to better PWB (HR 2.12, 95% CI 1.30-3.45,p = 0.003), and worse SWB compared to better SWB (HR 1.94, 95% CI 1.20-3.13, p = 0.007) were individually and significantly associated with a higher probability of early discontinuation of ET, although none reached statistical significance when all were included in a joint model. Conclusions: Younger women are at risk for early discontinuation and modifiable characteristics such as HRQoL and history of depression are potential risk factors for early discontinuation of ET. These results support systematic screening for HRQoL and depressive symptoms to identify women at risk for discontinuation of ET. Clinical trial information: NCT00310180 .

Statistical machine learning model to predict Oncotype DX risk category in women over age 50.

524 Background: The 21-gene Oncotype DX Breast Recurrence Score multigene assay (RS) identifies women with ER positive, HER negative, axillary node-negative breast cancer (BC) for whom chemotherapy provides no invasive disease-free survival benefit compared to endocrine therapy alone. International adoption of RS testing is limited by cost and resource availability. We created a supervised statistical machine learning model using standard clinicopathologic data to predict RS risk category in women &gt; 50 years old. Methods: From 2012 to 2018, women with ER positive, HER2 negative, pathologically node-negative BC of all ages were retrospectively identified from a prospective institutional database. Standard clinicopathologic data and RS were collected. Per institutional protocol, RS are ordered for all early-stage, ER positive tumors &gt; 5 mm. Data were randomly split into training (n=3755) and validation sets (n=1609). A random forest model with 500 trees was developed on the training set, then evaluated on the validation set. Model predictors included age, tumor size, histologic subtype, hormone receptor status, lymphovascular invasion, and overall grade. The model was used to predict RS category (low risk: RS ≤ 25, high risk: RS &gt; 25) in women &gt; 50 years old. Results: 5364 unique tumors in 5189 women were identified. 3731 (70%) of tumors were identified in women &gt; 50 years; median age was 63 years (IQR 57-69). In women &gt; 50, median tumor size was 12 mm (IQR 9-17). Most tumors were invasive ductal (79%), low or intermediate grade (79%), and LVI was absent in 82% of tumors. Median ER staining by IHC was 95%; 28% of tumors had negative or weakly positive PR staining (1-20%). The model correctly classified 96.8% of patients as low risk (95% CI: 95.7-97.7). Negative predictive value for identifying low risk category was also high (92.3%, 90.7-93.6). Sensitivity for identifying high-risk women was 44.7% (37.4-52.1) and positive predictive value was 67.2% (58.2-75.3). A classification table on the validation set includes tumors with complete data available, including predictors and RS. Conclusions: Our model was highly specific (96.8%) for identifying women &gt; 50 with RS ≤ 25 who do not benefit from adjuvant chemotherapy. This model may be utilized in lieu of RS testing if cost and availability are prohibitive. True RS &gt; 25 was not as well predicted. The model will be refined following pathologic review of discordant cases to reduce false negatives. [Table: see text]