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Purpose The use of the 21-gene Recurrence Score (RS) assay is emerging in node-positive estrogen receptor (ER)+ HER2-negative breast cancer (BC), particularly as initial data from the RxPONDER trial are now available. We investigated the impact of the RS result on adjuvant treatment decisions in such patients. Patients and Methods This prospective, multi-center study enrolled patients with ER+, HER2-negative BC and 1 to 3 positive nodes (microscopic [N1mi] or macroscopic [N1]). Treating oncologists documented treatment recommendations/plan before and after knowing the RS result. Sample size was determined assuming an overall treatment change rate (from chemohormonal therapy [CHT] to hormone therapy [HT] and vice-versa) of ≥30%. Results The study included 84 patients across 5 regional cancer centers, of whom 82 underwent 21-gene testing (77%, N1 disease; 63% grade 2 tumors). Of the RS-tested patients, 60%, 33%, and 7% had RS 0 to 17, 18 to 30, and 31 to 100, respectively. In 43 patients (52%), treatment changed post-RS: 40 patients (49%) from CHT to HT and 3 patients (4%) from HT to CHT. The net change was a 45% reduction in chemotherapy use. Treatment recommendation changes were consistent with the RS result. In RS 0 to 17 patients, the only documented change was from CHT to HT (27 patients). In RS 18-30 patients, change was noted in both directions (CHT-to-HT, 13 patients; HT-to-CHT, 3 patients). No treatment change was reported for the RS 31 to 100 patients, all of whom were recommended CHT pre-testing. Conclusion Our results support the clinical utility of the RS assay in ER+ HER2-negative BC with 1 to 3 positive nodes.

Introduction: The aim of the present study was to analyze the performance of Oncotype DX® multigene assay (ODX®) in patients with 0–3 lymph nodes in a high-volume community hospital. Methods: Patients with non-metastatic HR+/HER2– EBC and 0–3 positive lymph nodes, who underwent primary surgery at the Red Cross Hospital Munich, Germany and consecutively had ODX® testing were included in this retrospective study. The distribution of clinicopathologic characteristics, recurrence score (RS) risk, and use of systemic therapy were compared among patients without positive lymph nodes (N0) and patients with micrometastases or 1 to 3 positive lymph nodes (N1). Disease-free survival (DFS) and overall survival (OS) were estimated. Results: From 2012 to 2017 ODX® was consecutively performed in 575 (16.4%) of 3,492 women with HR+/HER– EBC, of which 553 were eligible for this analysis (N0: 60.8%; N1: 39.2%). Among the patients included, 441 (79.7%) had an RS of 0 to 25 and 112 (20.3%) had an RS of 26 or higher. In patients with RS 0 to 25 the rate of chemotherapy use was low, independent from nodal status (N0: 17.1% and N1: 19.1%) and 5-year DFS was 90.5% and 91.7% for N0 and N1 patients, respectively. There was no significant difference in DFS (90.5% vs. 93.3%; p = 0.101) or OS (97.2% vs. 96.0%; p = 0.737) for patients with an RS of 0 to 25 when treated with chemo-endocrine therapy or endocrine therapy alone, independent from nodal status. Conclusions: The results of the study confirm the observations from randomized studies on the use of the ODX® in a real-world population in terms of risk distribution and patient outcome. Adjuvant chemotherapy could be safely omitted in patients with HR+/HER2– breast cancer with 0–3 positive lymph nodes and RS

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

Results from TAILOR-X suggest that up to 70% of hormone receptor-positive (HR+) node-negative (N0) ESBC patients (pts) may avoid chemotherapy (CT) with RS ≤ 25. We assess clinical and economic impacts of RS testing on treatment using real-world data. From October 2011 to February 2019, a retrospective, cross-sectional observational study was conducted of HR+ N0 ESBC pts who had RS testing in Ireland. Pts were classified low risk (RS ≤ 25) and high risk (RS > 25). Clinical risk was calculated. Data were collected via electronic patient records. Cost data were supplied by the National Healthcare Pricing Regulatory Authority. 963 pts. Mean age is 56 years. Mean tumour size is 1.7 cm. 114 (11.8%), 635 (66%), 211 (22%), 3 (0.2%) pts had G1, G2, G3 and unknown G, respectively. 796 pts (82.8%) low RS, 159 (16.5%) high RS and 8 pts (0.7%) unknown RS. 263 pts (26%) were aged ≤ 50 at diagnosis; 117 (45%) had RS 0–15, 63 (24.5%) 16–20, 39 (15.3%) 21–25 and 40 (15.2%) RS 26–100. 4 pts (1.5%) had unknown RS. Post-RS testing, 602 pts (62.5%) had a change in CT decision; 593 changed to hormone therapy (HT) alone. In total, 262 pts received CT. Of pts receiving CT; 138 (53%) had RS > 25, 124 (47%) had RS ≤ 25. Of pts aged ≤ 50, 153 (58%) had high clinical risk, of whom 28 had RS 16–20. Assay use achieved a 62.5% change in treatment with 73% of pts avoiding CT. This resulted in savings of €4 million in treatment costs. Deducting assay costs, savings of €1.9 million were achieved. Over the 8 years of the study, a 62.5% reduction in CT use was achieved with savings of over €1,900,000.

Lymphovascular invasion (LVI) and Black race are associated with poorer prognosis in early breast cancer (EBC). We evaluated the association between LVI and race, and whether LVI adds prognostic benefit to the 21-gene recurrence score (RS) in EBC. Women with ER+ HER2− EBC measuring up to 5 cm, with 0–3 involved axillary nodes, diagnosed between 1 January 2010 and 1 January 2014, who underwent surgery as first treatment and had available RS, were identified in the NCDB database. Bivariate associations between two categorical variables were examined using chi-square test. Multivariate Cox proportional hazards model were used to assess the association of LVI, race, and other covariates with overall survival (OS). 77,425 women, 65,018 node-negative (N0), and 12,407 with 1–3 positive (N+) nodes, were included. LVI was present in 12.7%, and associated with poor grade, RS 26–100, and N+ (all p p = 0.009) and N+ (HR 1.37, p = 0.015) disease. LVI adds prognostic information in ER+, HER2−, N0 BCA with RS 11–100, but does not predict chemotherapy benefit. Black race is associated with worse OS, but not LVI.

Objectives The influence of older age at diagnosis in combination with race/ethnicity on utilization and results of the 21-gene recurrence score (RS) assay for breast cancer (BC) patients is not fully understood. Our objectives were to evaluate the utilization of RS among older women with BC, the likelihood of a high-risk RS, and factors associated with breast cancer-specific mortality (BCSM) among older patients across different races. Materials and methods We utilized the Surveillance, Epidemiology, and Results (SEER) database with linked RS results to evaluate women with estrogen receptor-positive BC diagnosed 2004–2015. Multivariable logistic regression was used to describe the differences in utilization of RS testing and the association of high-risk RS according to patient characteristics. The Cox proportional hazards model was used to analyze factors associated with BCSM. Results We found that 20.4% (109,244/536,555) of all women ≥18 and 14.3% (33,584/235,171) of women ≥65 underwent RS testing. Non-whites had lower odds of RS testing at younger ages whereas among women ≥65 there was no significant difference. After taking into account stage and grade, being ≥65 reduced the odds of high-risk RS in all races except American Indian/Alaskan Native. Age ≥ 65 was independently associated with increased hazard BCSM. Among women ≥65 with high-risk RS, chemotherapy was associated with lower hazard of BCSM in all races. Conclusions Older women are less likely to be tested for RS, but also less likely to have high-risk RS. Older women with high-risk RS, when given chemotherapy have reduced BCSM across all races.

Background: The association between 21-gene recurrence score (RS) and host factors such as overweight remains unclear for breast cancer patients. The objectives of the current study are to comprehensively analyze the distribution, single gene expression, and prognostic predictive value of RS between overweight or non-overweight patients.Patients and methods: Luminal-like patients receiving surgery between January 2009 and December 2018 in the Comprehensive Breast Health Center, Shanghai Ruijin Hospital, with 21-gene RS results were retrospectively retrieved. Association and subgroup analysis between BMI and 21-gene RS were conducted. Single-gene expression in 21-gene RS panel was compared between overweight and non-overweight groups. Recurrence-free survival (RFS) and overall survival (OS) were calculated according to RS category and BMI status.Results: Among 1876 patients included, 442 (23.56%), 995 (53.04%) and 439 (23.40%) were classified into low, intermediate and high risk groups. RS category was significantly differently distributed between overweight and non-overweight patients (P=0.035). Overweight patients had a trend of lower RS score than patients with normal weight (25.13 vs 26.17, P=0.080). The effect of BMI on RS significantly varied according to age (P=0.012) and menstruation status (P Citation Format: Yiwei Tong, Weiqi Gao, Jiayi Wu, Siji Zhu, Ou Huang, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen, Xiaosong Chen. Comprehensive association analysis of 21-gene recurrence score and overweight in breast cancer patients [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 PS17-38.

Background: The use of the 21-gene recurrence score assay (RS) has reduced chemotherapy (CT) administration in patients with hormone receptor (HR)-positive, HER-2 negative, lymph-node negative, early stage breast cancer (ESBC). Invasive lobular carcinoma (ILC) accounts for up to 15% of all breast cancers. This study uses real world data to assess (1) the effect of RS testing on treatment decision making in patients with ILC and (2) the economic benefit of testing in this subgroup. Methods: From October 2011 to February 2019, a retrospective, cross-sectional, observational study was conducted on HR+, HER-2 negative, lymph-node negative, ESBC patients with ILC who had RS testing in Ireland. For the decision impact analysis, a survey of Irish breast medical oncologists presumed that, without RS testing, CT would be recommended to patients with histological grade (G) 2 and 3 tumours and not for G1 tumours. In accordance with TAILOR-x results, patients were classified overall as low risk (RS≤25) and high risk (RS>25) and patients ≤50 years old were low risk (RS 0-15), intermediate risk (RS 16-25), and high risk (RS>25). Data were collected from electronic patient records. Descriptive statistics were used. Cost data were obtained from the National Healthcare Pricing Regulatory Authority. The economic analysis was adjusted for changing treatment and assay costs over the study period. Results: 166 patients with ILC were identified. Mean age was 59 years. Mean tumour size was 2.3cm (range 0.7-5.8). The majority had G2 tumors (n=152, 92%) with a small number of G3 (n=7, 4%) and G1 (n=7,4%). Overall, 153 patients (92.2%) had a low RS (≤25), 12 (7.2%) had high RS (>25), and 1(0.6%) was unknown. All 12 patients with RS>25 had G2 tumours, 6/12 (50%) had tumour size >3cm, 4(33.3%) were PR+ and 8(66.7%) were PR negative. In 29/166 (17.5%) patients, aged ≤50 at diagnosis, RS was ≤15 in 16(55%), 16-20 in 6(21%), 21-25 in 5(17%), >25 in 1(3.5%) and unknown in 1(3.5%). The majority of these patients (27, 93%) had G2 tumours, 1 had G1 and 1 had G3. Post RS testing 124 patients (74.5%) had a change in CT recommendation; all from CT to hormone therapy. In total, only 35 patients (21%) received CT. In this group, RS was 0-15 in 3(9%), RS 16-25 in 19(54%), RS >25 in 12 (34%) and unknown in 1(3%). Eight of 35 patients (23%) were aged ≤50. The most common CT regimen administered was docetaxel plus cyclophosphamide (TC). RS testing achieved a 78% reduction in chemotherapy use. This resulted in savings of €900,000 in treatment costs. With the incorporation of the assay cost, the net savings totalled approximately €400,000. Conclusions: Ireland was the first public health care system to reimburse the 21-gene recurrence score assay in Europe. There is limited evidence demonstrating the benefits of RS in ILC. In our study, the use of the test has resulted in a 78% reduction in chemotherapy use in an Irish ILC patient population and a substantial cost saving (greater than €400,000) to the Irish Healthcare System. Citation Format: Mehala Tharmabala, Lynda McSorley, Fathiya Al Rahbi, Evoy Denis, James G Geraghty, Rothwell Jane, Damian McCartan, Enda McDermott, Maccon M Keane, John Kennedy, Seamus O'Reilly, Steve Millen, John Crown, Lilian Mary Smyth, Catherine Margaret Kelly, Prichard Ruth, Cecily Quinn, Janice M Walshe. An analysis of the clinical and economic impact of the 21-gene recurrence score (RS) in invasive lobular early-stage breast cancer (ESBC) in Ireland [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-23.

Background: The 21-gene recurrence score (RS) can predict chemotherapy benefit in estrogen receptor (ER)-positive, human epidermal growth factor receptor-2 (HER2)-negative early breast cancer patients. The TAILORx showed that age would influence the interaction between RS and chemotherapy effect, and patients ≤50 years with RS >15 can benefit from chemotherapy. The current study aimed to determine the RS threshold that can predict chemotherapy benefit in both young and elder women. Methods: Patients diagnosed with pN0-1, ER+/HER2- breast cancer between 2009 and 2016 at Shanghai Ruijin hospital were retrospectively reviewed. A one-to-one propensity score matching (PSM) was performed between women receiving chemotherapy or not. Patients were then stratified by different cutoffs of age (range, 30-65 years). In each prespecified strata of age, cox proportional hazards models were used to determine the RS threshold which was predictive of chemotherapy benefit. Results: A total of 1227 patients were included. The median age was 58 years and the median RS was 24. After matching, the RS values that can manifest the chemotherapy benefit varied with age. For patients at 55 years of age or younger, apparent chemotherapy benefit was observed in those who had RS >25 (P = 0.03), with 4-year invasive disease-free survival (IDFS) rate of 97.0% and 89.3% in patients receiving chemotherapy or not. While patients derived no benefit from chemotherapy if they had RS ≤25 (P = 0.66, 4-year IDFS rate: 95.3% vs. 94.6%). However, for patients older than 55 years, adjuvant chemotherapy was associated with better prognosis in those with RS >36 (P = 0.014, 4-year IDFS rate: 94.7% vs. 76.2%), but not in those having RS ≤36 (P = 0.13, 4-year IDFS rate: 92.3% vs. 95.8%). Conclusions: The RS threshold to demonstrate the chemotherapy benefit differed with age. Young patients with RS >25 and old patients with RS >36 could benefit from adjuvant chemotherapy. Survival of breast cancer patients receiving adjuvant chemotherapy or not stratified by age and theChemoendocrine therapyEndocrine therapyP-value4-year IDFS rate (%)95% CI (%)4-year IDFS rate (%)95% CI (%)≤55 yearsRS ≤2595.390.7-100.094.689.6-100.00.66RS >2597.091.3-100.089.382.0-97.30.03>55 yearsRS ≤3692.387.7-97.295.892.1-99.60.13RS >3694.787.9-100.076.252.1-100.00.014 Citation Format: Jing Yu, Caijin Lin, Jiahui Huang, Jin Hong, Weiqi Gao, Siji Zhu, Hui Wang, Ou Huang, Xiaosong Chen, Jianrong He, Li Zhu, Weiguo Chen, Yafen Li, Kunwei Shen, Jiayi Wu. Efficacy of adjuvant chemotherapy stratified by age and the 21 gene recurrence score in estrogen receptor positive 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 PS4-28.

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 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.

Background: The Oncotype DX 21-gene expression assay (ODX) is prognostic for recurrence and predictive of chemotherapy benefit in early estrogen receptor-positive (ER+) HER2-negative (HER2-) breast cancer (BCA). Invasive ductal carcinoma (IDC) comprises approximately 80% of BCA. Invasive lobular carcinoma (ILC) is a subtype of BCA with distinct pathologic features, and often has low to intermediate ODX Recurrence Score (RS). We evaluated differences in clinicopathologic characteristics, RS and chemotherapy benefit between IDC, ILC, and carcinomas of mixed histologies (ductal + lobular (DLC), ductal + other (DOC), and lobular + other (LOC)) in the National Cancer Database (NCDB). Methods: Female patients (pts) diagnosed between 1/1/2010 and 1/1/2014 with ER+ HER2- BCA, measuring up to 5 cm, with 0-3 involved axillary lymph nodes (LN), treated with definitive surgery as first treatment, and with numeric ODX recurrence score (RS) available were identified from the 2005-2016 NCDB database. Associations between categorical variables were examined using the chi-square test. The Cox proportional hazards model was used to examine the difference in overall survival between histology subtypes while controlling for age, race/ethnicity, RS, tumor size, grade, LN involvement and treatment. Results: 77,472 pts met inclusion criteria, 62,395 (83.8%) node negative (N0) and 12,077 (16.2%) node positive (N+). 57,615 pts (77.4%) had IDC; 8693 (11.7%) ILC; 5393 (7.2%) DLC; 2457 (3.3%) DOC; and 312 (0.4%) LOC. DOC and LOC were more common in Black than White pts (p26. Presence of lobular histology (ILC, DLC and LOC) was associated with lower incidence of RS >26. ILC was least likely to have both low RS (0-10) and high RS (p Citation Format: Della Makower, Jiyue Qin, Juan Lin, Xiaonan Xue, Joseph A Sparano. The 21-gene recurrence score in early non-ductal breast cancer: A national cancer database analysis [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 PS6-20.

OBJECTIVE: Women with early-stage, ER+ breast cancer are recommend to receive genomic profiling tests, such as the 21-gene Recurrence Score (RS) test, to guide treatment decisions. We examined test- and treatment-related information discussed and the associations between RS categories and aspects of communication during patient-oncologist clinical encounters. METHODS: As part of a larger trial, clinical encounters (N=46) were audiorecorded and coded for 1) RS- and treatment-related information, 2) shared decision making, 3) patient active participation, and 4) oncologist patient-centered communication. We examined differences by RS category using mixed models, adjusting for nesting within oncologist. RESULTS: Patients with a high RS were more likely to receive a chemotherapy recommendation (p

Multi-gene assays have emerged as crucial tools for risk stratification in early-stage breast cancer. This study aimed to evaluate the prognostic significance of the 21-gene recurrence score (RS) in Chinese patients with pN0-1, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Among 800 patients recruited between 2009 and 2016, the median RS was 24 (0-69), with 27.4%, 46.8%, and 25.9% patients classified into low-, intermediate-, and high-risk groups. Cox regression analysis demonstrated that the high-risk category was associated with significantly higher odds of invasive disease-free survival (IDFS) and distant disease-free survival (DDFS) events compared with the low-risk category (IDFS: HR = 2.450, 95% CI 1.017-5.902, P = 0.046; DDFS: HR = 2.829, 95% CI 1.013-7.901, P = 0.047). No significant association between RS category and overall survival (OS) was found (intermediate vs. low: HR= 1.244, 95% CI 0.292-5.297, P = 0.768; high vs. low: HR = 2.933, 95% CI 0.759-11.327, P = 0.119). RS, as a continuous variable, was a highly significant predictor for IDFS (HR= 1.028, 95% CI 1.010-1.047, P = 0.002), DDFS (HR= 1.030, 95% CI 1.010-1.051, P = 0.003), and OS (HR= 1.034, 95% CI 1.007-1.063, P = 0.014). Our findings suggested that RS may predict IDFS in Chinese patients with ER+/HER2- breast cancer with N0 or N1 disease.

Background Invasive ductal carcinoma (IDC) is often accompanied by ductal carcinoma in situ (DCIS). Whether the DCIS component affects the 21-gene recurrence score (RS) is unclear. Methods Consecutive ER-positive, HER2-negative, N0–1 patients with RS results were included. Patients were divided into pure IDC and IDC with DCIS (IDC/DCIS) groups. The RS, the expression of its 16 cancer genes and prognosis were compared between IDC and IDC/DCIS patients. Results A total of 1458 patients were enrolled, 320 of whom had concomitant DCIS. DCIS component was independently associated with lower RS (P = 0.038). IDC/DCIS patients more often had a low-risk RS (P = 0.018) or intermediate-risk RS (P = 0.024). Regarding individual genes in the RS panel, Ki67, CCNB1 and MYBL2 in the proliferation group and MMP11 and CTSL2 in the invasion group were significantly lower among IDC/DCIS patients than pure IDC patients. Among IDC/DCIS patients, lower RS was independently correlated with a higher DCIS proportion and lower DCIS grade. Within a median follow-up of 31 months, the DCIS component in IDC did not significantly influence prognosis. Conclusions IDC with DCIS component is associated with a lower 21-gene RS, possibly due to lower expression of proliferation and invasion genes. DCIS proportion and grade independently influenced the 21-gene RS in IDC/DCIS patients. Due to the relatively short follow-up period and low recurrence rate, the impact of the DCIS component in IDC on prognosis needs further evaluation.

Purpose To evaluate the effect of the 21-gene recurrence score (RS) assay in breast cancer-specific mortality (BCSM) and decision-making for chemotherapy in older (aged ≥65 years) breast cancer. Methods We retrospectively included older patients with T1-2N0 and estrogen receptor-positive breast cancer in the Surveillance, Epidemiology, and End Results database. Cox regression model and competing-risks model were used for data analysis. Results This study included 8524 patients, 1987 (23.3%) had low RS, 5059 (59.4%) had intermediate RS, and 1478 (17.3%) had high RS. Chemotherapy was administrated in 2.0%, 8.6%, and 51.2% for low, intermediate, and high RS cohorts, respectively (P, Highlights • ODX testing should be considered in older breast cancer patients. • RS was independently correlated with BCSM in both prognostic models. • Chemotherapy was not correlated with a lower risk of BCSM in intermediate and high RS cohorts.

To evaluate the role of 21-gene recurrence score (RS) assay in adjuvant chemotherapy decision-making among older patients with early breast cancer.Consecutive hormonal receptor-positive, aged ≥60 patients with breast cancer were enrolled from Shanghai Ruijin Hospital between January 2014 and December 2017. Treatment decisions were made by multi-disciplinary team (MDT) before and after 21-gene RS testing, and the actual treatment for each patient was also analyzed.A total of 511 patients were enrolled, with 331 (64.8%) aged between 60 and 69, 140 (27.4%) between 70 and 79, and 40 (7.8%) over 80 years. There were 138 (27.0%), 287 (56.2%), and 86 (16.8%) patients classified as low, intermediate, and high risk RS, respectively. Multivariable analysis demonstrated that age, tumor stage, nodal status, PR expression, Ki-67, and 21-gene RS were independent impact factors for chemotherapy recommendations (P .05). Patients with high risk RS and intermediate risk RS (both P .001) were more often recommended to receive chemotherapy than patients with low risk RS. Treatment recommendations changed in 74 (14.5%) patients after 21-gene RS testing: 17 (3.3%) from chemotherapy to no chemotherapy and 57 (11.2%) from no chemotherapy to chemotherapy. Overall compliance rate to MDT recommendation after 21-gene RS testing was 95.7%.An intermediate and/or high risk 21-gene RS assay was independently associated with receiving adjuvant chemotherapy among older patients with breast cancer. However, it showed a limited impact on adjuvant chemotherapy decision-making. After 21-gene RS testing, compliance with MDT recommendation was relatively high in older patients with breast cancer.

Most invasive breast cancers express hormone receptors (HR) and typically have a favorable prognosis following endocrine therapy. Patients at a higher risk of recurrence can be identified by multigene prognostic classifiers such as the 21-gene recurrence score (RS) assay, 70-gene prognostic signature, PAM-50, 12-gene molecular score, and others. The 21-gene RS assay (Oncotype Dx™, Genomic Health, Redwood City, CA) has level I clinical evidence and is the most widely used multigene assay in North America. The RS assay is based on reverse transcriptase polymerase chain reaction that can be performed on the RNA isolated from formalin-fixed paraffin-embedded tissue. It evaluates the expression of 16 cancer-related genes developed based on a multi-step approach. Due to its ability to assess recurrence risk and predict potential benefit from chemotherapy, the assay is recommended for patients with node-negative, HR-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer by the American Society of Clinical Oncology, National Comprehensive Cancer Network clinical practice guidelines in oncology, European Society for Medical Oncology clinical practice guidelines, and St. Gallen consensus panel guidelines. The RS assay has also been incorporated in the prognostic stage groups in the 8th edition of the American Joint Commission of Cancer staging manual in order to provide essential genomic information for optimal treatment decisions. This review will focus on the utility of the RS assay in HR-positive and HER2-negative breast cancer patients, including risk of distant and locoregional recurrence in node-negative and node-positive tumors, association with radiotherapy, special subtypes of breast cancer, practical issues related to selecting tumors for testing, and overview of the recently published TailorX (Trial Assigning IndividuaLized Options for treatment [Rx]) results.

Purpose To investigate the effect of 21-gene recurrence score (RS) on chemotherapy-decision making and prognosis in breast cancer patients aged, Highlights • Intermediate-risk patients were less likely to receive chemotherapy over time. • The 21-gene RS was an independent prognostic indicator for BCSS. • Survival benefit of chemotherapy was observed in the high-risk cohort.

Background: Clinical-pathological factors and 21-gene recurrence score (RS) influence adjuvant chemotherapy (ACT) decision for early breast cancer patients. We investigated the decision-making of ACT in patients with discordant risk classifications of clinical-pathological factors and RS. Methods: Patients with hormonal receptor (HR)+/ human epidermal growth factor receptor 2 (HER2)-, early breast cancer, who underwent 21-gene RS testing were identified from Ruijin Hospital (RJBC) and the Surveillance, Epidemiology, and End Results (SEER) database. According to Adjuvant! Online and RS (≤25 or >25), discordant risk classifications were defined as: clinical low-risk/ RS high-risk (C-low/ RS-high) and clinical high-risk/ RS low-risk (C-high/RS-low). McNemar's test was used to assess the changes between pre- and post-RS recommendations. Breast cancer-specific survival (BCSS) was estimated using the Kaplan-Meier methods. Results: Among 727 RJBC patients, the C-low/RS-high group and the C-high/RS-low group represented 19.7% and 21.3% of the cohort. After receiving 21-gene RS results, treatment recommendations were changed for 22.1% patients with discordant risk classifications: ACT rate increased from 41.9% to 75.5% in the C-low/RS-high group and decreased from 63.9% to 60.0% in the C-high/RS-low group. Among 2958 patients from the SEER cohort, 18.4% of the C-high/RS-low group and 59.2% of the C-low/RS-high group received ACT. There was no significant difference in the estimated 3-year BCSS between ACT or not among the C-low/RS-high group (p=0.708) and the C-high/RS-low groups (p=0.391). Conclusion: For patients with discordant risk classifications, physicians were apt to adopt the 21-gene RS rather than routine clinical-pathological factors to guide ACT selection.

PURPOSE The 21-gene recurrence score (RS) is used to identify patients with hormone receptor–positive early-stage breast cancer who may benefit from the addition of chemotherapy to endocrine therapy. We hypothesized that many women with poor prognostic histopathologic grade 3 disease may be offered chemotherapy irrespective of RS results, of whom a subset may not benefit from adjuvant chemotherapy. PATIENTS AND METHODS A total of 30,864 women in the National Cancer Database were diagnosed with pT1c to pT2, pN0 to pN1, grade 3 estrogen receptor–positive, human epidermal growth factor receptor 2–negative invasive breast carcinoma from 2010 to 2015. RS was stratified as low (less than 18), intermediate (18 to 30), and high (31 or more). Overall survival by RS was evaluated by Kaplan-Meier, log-rank, and multivariable proportional hazards, with adjustment for relevant clinical and demographic variables. RESULTS RS testing in grade 3 cancers increased between 2010 and 2015 (pN0, 53% to 72%; pN1, 16% to 36%). Among the 13,558 women with pN0 and the 2,840 with pN1 disease with RS testing, 27.1% and 30.0%, respectively, had low scores (less than 18). The 5-year overall survival rate for patients with a high RS, but not low RS, was significantly higher with chemotherapy ( v no chemotherapy; absolute differences: high RS pN0 = 12.2% and pN1 = 25.5%, both P < .001; low RS pN0 = 2.5%, P = .07; and pN1 = 1.0%, P = .27), findings that were reinforced in multivariable analyses risk adjusted by clinicopathologic characteristics. CONCLUSION Increased use of RS may help to better tailor treatment recommendations by stratifying patients with grade 3 disease into those who will and will not derive survival benefit and should be considered in all patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative T1c to T2, N0 to N1 disease.

BACKGROUND The trial assigning individualized options for treatment (Rx) (TAILORx) confirmed the predictive value of the 21-gene recurrence score (RS) assay in hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer and established thresholds for chemotherapy benefit in younger and older patients. Real-world chemotherapy use and RS-guided treatment costs in British Columbia post-TAILORx were examined. METHODS The authors assembled 3 cohorts of HR-positive, HER2-negative, node-negative patients with breast cancer defined by diagnosis: before RS funding (cohort 1 [C1]: January 2013-December 2013), after introduction of public RS funding (cohort 2 [C2]: July 2015-June 2016), and after TAILORx results (cohort 3 [C3]: July 2018-June 2019). Chemotherapy use was compared between cohorts by age and RS. Budgetary impacts of RS testing on chemotherapy costs were evaluated pre- and post-TAILORx. RESULTS Among the 2066 patients included, chemotherapy use declined by 19% after RS funding was introduced and by an additional 23% after TAILORx publication (P = .001). Reduction in chemotherapy use was significant for RS 11-20 tumors (C3 vs C2, P = .004). There was no significant change in chemotherapy use in patients >50 years old (C2:12% vs C3:10%, P = .22). RS testing was associated with higher cost savings post-TAILORx, except in patients 70 to 80 years old, where testing led to excess costs when adjusting for the low rate of RS-concordant chemotherapy prescribed. CONCLUSIONS TAILORx has had population-based impacts on chemotherapy prescribing in intermediate RS tumors and patients ≤50 years old. The lower clinical use of RS and increased spending in patients 70-80 years old highlights the importance of careful selection of older candidates for high-cost genomic testing. LAY SUMMARY The 21-gene recurrence score (RS) test helps predict whether patients with hormone-positive, HER2-negative, lymph node-negative breast cancer are likely to benefit from chemotherapy. The recent trial assigning individualized options for treatment (Rx) (TAILORx) found that patients with intermediate RS tumors did not benefit from chemotherapy. The authors assessed whether TAILORx results translated to real-world changes in chemotherapy prescribing patterns. In this study, chemotherapy use decreased by 23% after TAILORx, with the greatest reductions seen among intermediate RS tumors and younger patients. In contrast, RS testing had lower clinical value and increased treatment costs in elderly patients, which requires further study to ensure optimal care for this age group.

Purpose To compare the distribution, chemotherapy-decision making, and prognosis of the 21-gene recurrence score (RS) between Chinese breast cancer (BC) in the United States and White American (WA) BC. Materials and methods We identified early-stage and estrogen receptor-positive BC patients diagnosed between 2004 and 2015. Multivariate logistic regression, Kaplan-Meier analysis, and multivariate Cox proportional hazards models were used for statistical analyses. Results A total of 67486 patients were identified, including 66215 (98.1%) WA patients and 1271 (1.9%) Chinese patients. Regarding the RS, 38894 (57.6%) had low RS, 23882 (35.4%) had intermediate RS, and 4710 (7.0%) had high RS. A similar distribution of RS was found between WA and Chinese BC (P=0.280). Race was not the predictor associated with high RS. Similar trends of chemotherapy use were found in Chinese and WA BC. In WA BC, there were 4.1%, 31.5%, and 72.2% of patients receiving chemotherapy in low, intermediate, and high RS cohorts, respectively (P Conclusion Our results demonstrate similar distribution, chemotherapy use, and outcome of the 21-gene RS between Chinese and WA BC in the United States.

BackgroundThe 21-gene recurrence score (RS) can predict chemotherapy benefit in estrogen receptor-positive, human epidermal growth factor receptor-2-negative (ER+/HER2-) early breast cancer patients. Age would influence the interaction between RS and chemotherapy effect. The current study aimed to determine RS thresholds which were predictive of chemotherapy benefit in young and old women, respectively.MethodsPatients diagnosed with pN0–1, ER+/HER2- breast cancer between 2009 and 2016 were retrospectively reviewed. Propensity score matching was performed according to chemotherapy usage. After stratifying patients with different cutoffs of age, the RS threshold indicating chemotherapy benefit in each age strata were determined by cox proportional hazard models.ResultsA total of 1227 patients were included. The median age was 58 years and the median RS was 24. After matching, the RS thresholds suggesting chemotherapy benefit varied with age. For patients ≤55 years, chemotherapy benefit was observed in those having RS > 25 (P = 0.03), with 4-year invasive disease-free survival (IDFS) of 97.0 and 89.3% in patients receiving chemotherapy or not. While patients derived no benefit from chemotherapy if they had RS ≤25 (P = 0.66, 4-year IDFS: 95.3% vs. 94.6%). For patients > 55 years, adjuvant chemotherapy was associated with better prognosis in those with RS > 36 (P = 0.014, 4-year IDFS: 94.7% vs. 76.2%), but not in those having RS ≤36 (P = 0.13, 4-year IDFS: 92.3% vs. 95.8%).ConclusionsOld patients need higher RS thresholds to demonstrate the chemotherapy benefit. Further efforts are warranted to investigate the association between age and predictive RS thresholds.

The 21-gene recurrence score (RS) assay is prognostic and predictive for hormone receptor (HR)+/HER2-/node- breast cancer (BC) patients. However, its clinical value in node + patients hasn’t been elucidated. HR+/HER2-/pN1 patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital from January 2014 to December 2018, with available RS results were retrospectively included. Clinico-pathological characteristics were compared. Adjuvant chemotherapy recommendations pre-/post- RS assay and actual usage were analyzed. A total of 303 patients were included, with 59, 178, 66 RS P P = 0.013), and RS category (P P P = 0.003) RS were more likely to be recommended with chemotherapy. RS independently influence chemotherapy decision in postmenopausal population as well. Chemotherapy recommendation changed for 9.57% patients after RS assay. Patient adherence rate to chemotherapy recommendation was 94.72% (287/303). The 21-gene RS independently influenced chemotherapy recommendation in pN1 BC patients, which could provide additional information to guide chemotherapy decision with relatively good treatment adherence rate.

Aim: To investigate the associations with the 21-gene recurrence score (RS) and effect of adjuvant radiotherapy (RT) for early-stage breast cancer after breast conserving surgery. Methods: We included 13,246 patients in the SEER database. Results: Patients with a higher RS were independently related to nonreceipt of RT (p < 0.001). In both the traditional and Trial Assigning Individualized Options for Treatment (TAILORx) RS cut-offs, the receipt of RT was not related to better breast cancer-specific survival in low- and high-risk RS groups, but was independently related to better breast cancer-specific survival in intermediate-risk RS group before (p = 0.029) and after (p = 0.001) propensity score matching. Conclusion: The 21-gene-RS may impact the decision-making of adjuvant RT in early-stage breast cancer after breast conserving surgery. The survival benefit of adjuvant RT may be limited to patients with intermediate-risk RS.

We evaluated 328 patients (34.8% African American [AA]; 65.2% White American [WA]) with hormone receptor-positive, HER2/neu-negative breast cancer. Mean age (60 years); mean tumor size (1.6 and 1.7 cm for AA and WA, respectively) were similar, and mean BMI was higher for AA (33 vs 29.8; P = 0.001). Recurrence score (RS) distribution was similar- 8.3% AA and 5.9% WA with high RS (≥31). No significant differences were observed in delivery of chemotherapy stratified by score. With median follow-up 27.2 months for AA and 33.4 months for WA, distant recurrence occurred in 1.0% and 1.6%, respectively (P = 1). Our results suggest comparable RS utility in AA and WA patients.

Purpose The 21-gene recurrence score (Oncotype DX) (RS) informs systemic therapy decision making in ER-positive HER2-negative early breast cancer (BC). To date no study has described the more nuanced discussions that take place regarding systemic therapy or the impact of the RS on concordance in such decision making. Here we utilized a novel decision making tool to assess the impact of the RS on decision making as well as concordance of treatment recommendations. Patients and methods The clinicopathological information (CPI) of 50 BCs without and with the RS were presented to a panel of breast oncologists in a simulated MDT. The Liverpool Adjuvant Systemic Therapy Decision Tool (LASTDT) was developed and used to categorize treatment recommendations. Outcome measures included the impact of the RS on decisiveness and concordance in decision making and its impact on treatment recommendations. Results Availability of the RS increased definitive decision making from 8% (4/50) to 56% (28/50) [χ2 = 79.35, p Conclusions The RS improves certainty of decision making as well as concordance amongst oncologists. This provides evidence that the availability of the RS can improve consistency of decision making amongst oncologists and thus helps to ensure patients are managed consistently. This is particularly important when patients are managed in a loco-regional, multidisciplinary team manner where heterogeneous decisions can lead to disparity in care.

PURPOSE The purpose of this study was to investigate the effect of 21-gene recurrence score (RS) on predicting prognosis and chemotherapy decision in node micrometastases (N1mi) breast invasive ductal carcinoma (IDC). Methods Patients with stage T1-2N1mi and estrogen receptor-positive IDC diagnosed between 2004 and 2015 were included. The associations of 21-gene RS with breast cancer-specific survival (BCSS), chemotherapy decision, and benefit of chemotherapy were analyzed. RESULTS We identified 4,758 patients including 1,403 patients (29.5%) treated with adjuvant chemotherapy. In the traditional RS cutoffs, 2,831 (59.5%), 1,634 (34.3%), and 293 (6.2%) patients were in the low-, intermediate-, and high-risk RS groups, respectively. In 3,853 patients with human epidermal growth factor receptor-2 (HER2) status available, most patients were HER2-negative disease (98.3%). A higher RS was independently related to chemotherapy receipt, and 14.0%, 47.7%, and 77.8% of patients in the low-, intermediate-, and high-risk RS groups received chemotherapy, respectively. The multivariate analysis indicated that a higher RS was related to worse BCSS (p < 0.001). The 5-year BCSS rates were 99.3%, 97.4%, and 91.9% in patients with low-, intermediate-, and high-risk RS groups, respectively (p < 0.001). However, chemotherapy receipt did not correlate with better BCSS in low-, intermediate-, or high-risk RS groups. There were similar trends using Trial Assigning Individualized Options for Treatment RS cutoffs. CONCLUSION The 21-gene RS does predict outcome and impact on chemotherapy decision of N1mi breast IDC. Large cohort and long-term outcomes studies are needed to identify the effects of chemotherapy in N1mi patients by different 21-gene RS groups.

Aim We aimed to assess the role of 21-gene recurrence score (RS) in the decision-making for surgical treatment in early stage breast cancer and compared the outcomes between breast-conserving surgery (BCS) and mastectomy (MAST) among various 21-gene RS groups. Methods We included patients with stage T1-2M0M0 and estrogen receptor-positive breast invasive ductal carcinoma who underwent BCS + radiotherapy or MAST between 2004 and 2012 as part of the Surveillance, Epidemiology, and End Results program. Data were analyzed using binomial logistic regression, multivariate Cox proportional hazards models, and propensity score matching (PSM). Results We enrolled 34,447 patients including 22,681 (65.8%) and 11,766 (34.2%) who underwent BCS and MAST, respectively. Patients with high-risk RS were more likely to receive MAST. Multivariate analysis indicated that patients with intermediate-risk (P

Background The 21-gene (Oncotype DX) Recurrence Score (RS) is a multi-gene expression assay that is both prognostic and predictive of adjuvant chemotherapy (AdjCT) benefit in estrogen receptor (ER) positive/HER2 negative breast cancer (BC). Use of the RS in TNBC and HER2+ BC is not recommended by national guidelines. Using the National Cancer Database (NCDB), we sought to evaluate whether oncologists use the RS in these subtypes. Additionally, we assessed the prognostic effects of the RS in node negative patients (pts) who did or did not receive adjuvant chemotherapy. Methods Pts with TN and HER2+ BC diagnosed from 2010-2015 in the NCDB were analyzed. Pts with neoadjuvant therapy or stage IV were excluded. Cases with RS testing were classified as low (RS 0-17), intermediate (RS 18-30) or high (RS 31+). Analysis was performed using multivariable logistic regression; overall survival (OS) was analyzed using the Kaplan-Meier method with log-rank tests. Results 142,330 pts were evaluable: 64,830 TNBC and 77,500 HER2+ (21,768 ER-/HER2+ and 55,732 ER+/HER2+). In these subtypes, RS was performed in 5,369 (3.8%) pts as follows: 1,479 (2.3%) TNBC, 185 (0.8%) ER-/HER2+, and 3,705 (6.6%) ER+/HER2+. Given the small ER-/HER2+ cohort, we focused on TNBC and ER+/HER2+. Within these subtypes, factors associated with RS testing included lower grade, smaller pathologic tumor size, pathologic N0 status, white race, age 60-69, and ILC or IMC histology (each p Of the TNBC pts tested, the RS distribution was: low 16.3%, intermediate 13.1% and high 70.6%, while for ER+/HER2+ it was low 30.5%, intermediate 30.7% and high 38.8% (p AdjCT was less frequently recommended in pts with low RS; however, this varied by tumor subtype with AdjCT recommended for 66.8% of TNBC with low RS and 37.9% of ER+/HER2+ with low RS. For intermediate RS, rates of AdjCT recommendation were 74.3% and 73.7%, and for high RS were 94.0% and 93.2% for TNBC and ER+/HER2+ respectively. In a multivariable analysis among pts with low RS, factors associated with AdjCT recommendation included younger age, larger pathologic tumor size, node positive disease, and higher grade. In AdjCT untreated TNBC, 5 yr OS did not differ for low RS (96.5%) vs intermediate RS (95.2%, p=0.82). In contrast OS was significantly worse for high RS (76.7%) than the other two groups, each p≤0.04. In AdjCT untreated ER+/HER2+, 5 yr OS was significantly better for low RS (96.7%) vs intermediate RS (92.5%, p=0.03) and vs high RS (92.1%, p=0.003), with no difference between intermediate RS vs high RS (p=0.32). Evaluating pts who did receive AdjCT, there was no significant difference in 5 yr OS for either subtype according to RS (p=0.46 and p=0.83). Interestingly, in patients with low RS, 5 yr OS was similar with or without AdjCT in both TNBC (89.5% vs 96.5%, p=0.25) and ER+/HER2+ (97.6% vs 96.7%, p=0.47). Conclusions RS testing is being conducted in a small fraction of pts with TN and HER2+ BC with lower clinical risk features. The observation that RS is prognostic for survival in AdjCT untreated patients is hypothesis generating, and suggests that further evaluation of the RS and other multigene assays in ER negative and HER2+ BC is warranted. Citation Format: Boughey JC, Hoskin TL, Cocco D, Day CN, Leon-Ferre R, Habermann EB, Goetz MP. The 21-gene recurrence score and chemotherapy use in triple negative breast cancer (TNBC) and HER2 positive breast cancer: A National Cancer Database study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-09.

Background: The 21-gene Recurrence Score (RS) assay is prognostic among women with early-stage estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) and is used to select patients for chemotherapy (CT). Young women (age Methods: In the Young Women's Breast Cancer Study, a prospective cohort study of women diagnosed with BC at age Results: Among eligible women (N=577), 189 (33%) had undergone RS testing and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6 years. Median age at diagnosis was 37, most had N0 BC (300/509, 59%), and the majority had RS 11-25 (306/509, 60%). RS result was significantly associated with DRFI in N0 BC, with hazard ratio (HR) (95% CI) of 0.29 (0.07,1.30) and 0.21 (0.09,0.50) for RS26 (and trended towards significance in N1 BC). Results were similar using conventional RS groups. Among women with N0 BC and RS 11-25, 44% received CT, with two events in the 86 receiving CT (2.3%) and 6 events in the 109 without CT (5.5%); 5/8 (63%) occurred in those with RS 20-25. Table 1 N0N1Total Cohort N%N%N% 3005916332509100Median Age37.137.537.2Tumor Stage T120869694229358T28227784817635T3103159357T4001151Grade I4716855711II16555794926652III8829754618536Not assessed 1 1 PR status by IHC Negative (=1%)280931469047092Chemotherapy No1414712715430Yes159531519335570Ovarian Suppression No263881499145289Yes37121495711TAILORx RS Groups RS =267224613714929Conventional RS Groups RS =31481640259919 Table 2 6-year freedom from distant recurrence or breast cancer deathDRFI HR (95% CI) N0N1N0N1TAILORx RS Groups RS =2685.1%71.3%RefRefConventional RS Groups RS =3186.4%62.8%RefRef Conclusions: The RS is prognostic among young women with node-negative and node-positive BC, and is a valuable tool for risk stratification. Disease outcomes among young women with N0 disease and RS 11-25, a minority of whom received CT, are very good. Evaluation of the effect of ovarian suppression/CT-induced amenorrhea by RS/treatment strata is ongoing. Citation Format: Poorvu PD, Gelber SI, Rosenberg SM, Ruddy KJ, Tamimi RM, Collins LC, Peppercorn J, Schapira L, Borges VF, Come SE, Warner E, Jakubowski DM, Russell C, Winer EP, Partridge AH. Prognostic impact of the 21-gene recurrence score assay among young women with node-negative and node-positive ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-07.

Many genomic assays that assess recurrence risk in early breast cancer (EBC) are prognostic, but they differ in risk group stratification, which can affect clinical utility. Prospective outcomes of >60K patients treated based on the 21-gene assay results have shown that chemotherapy may be safely omitted in EBC patents with low Recurrence Score (RS) results (RS

Context.— Recurrence score (RS) testing was developed and validated in invasive ductal and rare lobular carcinomas, although it is used for all special types of breast cancers. Objective.— To determine association of histologic type (HT) and RS, specifically high-risk RS. Design.— We used RSs linked to Surveillance, Epidemiology, and End Results Program registries of invasive breast cancers diagnosed in 2004 through 2015. Multivariable logistic regression was used to evaluate association between HT and high-risk RS. Relationships between HT and low-, intermediate-, and high-risk RS were compared with χ2 test. Kaplan-Meier curves were compared using log-rank test. Results.— A total of 110 318 patients had RS testing. Of these, 23 220 (21%) had low, 70 822 (64.2%) intermediate, and 16 276 (14.8%) high RS. Histologic types were 80 476 (73%) ductal, 12 713 (11.5%) lobular, 12 449 (11.3%) mixed, 2151 (2%) mucinous, 610 (0.6%) tubular, 382 (0.4%) micropapillary, 365 (0.3%) salivary, 208 (0.2%) papillary, 49 (0.04%) medullary, 26 (0.02%) metaplastic, 26 (0.02%) neuroendocrine, and 863 (0.8%) unknown. The distribution of low-, intermediate-, and high-risk RS was significantly different among HTs. Higher percentages of high-risk RS were identified in patients with ductal, medullary, and metaplastic types (P < .001). The odds of having high-risk RS were lower for some HTs, including micropapillary, after multivariable adjustment (P < .05). The low number of estrogen receptor–positive medullary and metaplastic carcinomas tested had higher odds of having high-risk RS. In T1 and T2 tumors, when ductal, lobular, mixed, and other types combined were compared, the mortality was different. Conclusions.— This population-based study of RS in HTs showed high-risk RSs are identified in traditionally good prognostic subtypes. Micropapillary carcinoma has lower odds of high-risk RS even after multivariable adjustment.

Background:Oncotype Dx is used to predict the long-term recurrence risk in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer (BC). This study aimed at establishing a correlation between clinicopathological parameters and recurrence score (RS), subsequently improving predictability and ultimately justifying the use of the multigene assay.Materials and methods:A retrospective analysis of the pathology and clinical data of 114 female patients with BC who had Oncotype Dx testing between 2012 and 2019. The pathological parameters included are tumor cell type, tumor grade, pathological stage, and mitotic index (MI). The expression of ER, progesterone receptor (PR), HER2, and Ki67 was assessed by immunohistochemistry. A univariate and multivariate linear regression analysis was performed to assess the correlation between these parameters and the RS.Results:In univariate analysis, age (˂40 years), higher tumor grade, and low PR expression were significantly associated with higher RS ( P = .02; ˂.001; and ˂.001, respectively). Both MI and Ki67 were also strongly correlated with an increase in the RS with a P value of .01 (Spearman correlation 0.34 and 0.33). In multivariate linear regression analysis, age, MI, and Ki67 lost their significance, but both higher grade and PR remained significantly associated with a higher RS along with the tumor stage ( P ˂ .001; ˂.001; and .04, respectively).Conclusions:Tumor grade and PR immunohistochemical expression are the main predictors of RS in our study population. Other clinicopathological features were not significant predictors of change in RS in multivariate analysis.

Background: The 21-gene recurrence score (RS) assay has been proven prognostic and predictive for hormone receptor-positive/HER2-negative, node-negative early breast cancer patients. However, whether primary 21-gene RS can predict prognosis in recurrent breast cancer patients remained unknown.Patients and Methods: Consecutive breast cancer patients operated in Comprehensive Breast Health Center, Shanghai Ruijin Hospital between January 2009 and December 2018 were retrospectively analyzed. Patients with available 21-gene RS result for the primary tumor and reporting disease recurrence during follow-up were included. Association of 21-gene RS and overall survival (OS), post-recurrence overall survival (PR-OS), post-recurrence progression-free survival (PR-PFS), and first-line systemic treatment after recurrence were compared among different groups.Results: A total of 74 recurrent patients were included, with 10, 27, 37 patients in the RS

Purpose: Hormone receptor (HR)-positive breast cancer patients with tumor size ≤1.0 cm and negative node have favorable outcomes. The 21-gene Recurrence Score (RS) could predict response to chemotherapy for HR+ breast cancer, but its role in T1bN0 disease is challenging.Methods: T1bN0 breast cancer patients diagnosed between January 2014 and June 2019 with RS results were included and categorized as Low- (RS < 18), Intermediate- (RS 18–30), or High-risk (RS > 30) groups. Univariate and multivariate analysis were used to assess factors associated with RS distribution and chemotherapy recommendation. Chemotherapy decisions change and patient adherence after 21-gene RS testing were also evaluated.Results: Among 237 patients with T1bN0 tumors, proportions of Low-, Intermediate-, and High-risk RS were 19.8, 63.3, and 16.9%, respectively. Multivariate analysis found that ER expression (P = 0.011), PR expression (P < 0.001), and Ki-67 index (P = 0.001) were independently associated with RS distribution. Adjuvant chemotherapy was recommended for 31.6% of patients, which was more frequently given to patients with higher tumor grade [Odds ratio (OR) = 2.99 for grade II, OR = 59.19 for grade III, P = 0.006], lymph vascular invasion (OR = 8.22, P = 0.032), Luminal-B subtype (OR = 5.68, P < 0.001), and Intermediate-to High-risk RS (OR = 10.01 for Intermediate-risk, OR = 192.42 for High-risk, P < 0.001). Chemotherapy decision change was found in 18.6% of patients, mainly in those with Intermediate- to High-risk RS tumor with the majority from no-chemotherapy to chemotherapy. The treatment compliance rate after the 21-gene RS testing with MDT was 95.4%.Conclusion: RS category was related to ER, PR, and Ki-67 expression, which was recognized as an independent factor of chemotherapy recommendation in T1bN0 breast cancer. The 21-gene RS testing would lead to a chemotherapy decision change rate of 18.6% as well as a high treatment adherence, which can be applied in T1bN0 patients.

Although Ki67 labeling index is a potential predictive marker for chemotherapy benefit, its clinical utility has been limited by the lack of a standard scoring method resulting in poor interobserver reproducibility. Especially, there is no consensus on the use of average versus hotspot score for reporting. In order to determine the best method for Ki67 scoring and validate manual scoring method proposed by the International Ki67 Working Group (IKWG), we systematically compared average versus hotspot score in 240 cases with a public domain image analysis program QuPath. We used OncotypeDx Recurrence Score (RS) as a benchmark to compare the potential clinical utility of each scoring methods. Both average and hotspot scores showed statistically significant but only modest correlation with OncotypeDx RS. Only hotspot score could meaningfully distinguish RS low-risk versus high-risk patients. However, hotspot score was less reproducible limiting its clinical utility. In summary, our data demonstrate that utility of the Ki67 labeling index is influenced by the choice of scoring method.

PURPOSE The 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor–positive (ER+) and human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles. METHODS The Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2− breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node–negative (N0) and limited node–positive (N1) breast cancer. RESULTS Among eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively. CONCLUSION The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.

Background Recent studies have shown that tumors with extensive tumor-infiltrating lymphocytes (TILs) have a higher probability of pathologic complete response, even in luminal/human epidermal growth factor 2 (HER2)-negative breast cancer. We compared TIL levels and the 21-gene recurrence score (RS) in estrogen receptor (ER)-positive/HER2-negative breast cancer. Methods We evaluated the percentage of stromal TILs in 198 ER-positive/HER2-negative patients in whom RS was obtained by examining slides of surgical specimens by standardized methodology proposed by the international TIL Working Group. TIL levels were categorized as high (≥ 60%), intermediate (11–59%), or low (≤ 10%). All tumors were treatment-naïve. Results Ninety-seven (49.0%), 88 (44.4%), and 13 patients (6.6%) had low, intermediate, and high TIL levels, respectively. There was a significant but weak correlation between continuous RS and continuous TIL levels (Pearson’s R = 0.201, p = 0.004). The mean RS was significantly highest in high TIL tumors (17.8 ± 10.7 in low TIL tumors, 19.4 ± 8.7 in intermediate TIL tumors, and 26.2 ± 8.2 in high TIL tumors; p = 0.014). However, when we compared categorized RS and TIL levels, we found that tumors with high TIL levels tended to have higher RS (≥ 26) but it was not significant (p = 0.155). Furthermore, multivariate analysis revealed that high RS was not an independent factor associated with high TIL levels. Chemo-endocrine therapy was more frequently performed among patients with high TILs and less frequently among those with low or intermediate TILs (p

Background: The 21-gene Recurrence Score (RS) Assay (Oncotype DX®) is a validated prognosticator and predictive of chemotherapy (CT) benefit in patients with hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In Israel, the RS assay has been reimbursed by Clalit Health Services (CHS, the largest HMO in Israel) since 2006, and the assay is widely used in eligible estrogen receptor (ER)+ patients. Notably, ER+ breast cancer patients have a protracted risk of recurrence with approximately half of all distant recurrences occurring after 5 years from diagnosis. The goal of the current ongoing analysis was to investigate early (≤5 years) and late (>5 years) distant recurrence in N0/N1mi ER+ HER2-negative breast cancer patients who were RS-tested through CHS. Methods: This analysis of the CHS registry included breast cancer patients with ER+ HER2-negative N0/N1mi disease who underwent RS testing from 1/2006 (CHS approval of the assay) through 1/2009. Data sources included CHS claims arms (for patient/tumor characteristics), Teva Pharmaceuticals (for tumor characteristics, RS result), and medical records (for treatment/recurrence/survival). The study was approved by the institutional review boards of the CHS Community Division and was granted a waiver for obtaining patient consent. Results: The analysis included 1026 patients with median (interquartile range) follow up of 9.3 (8.8-10.2) years. Most patients were females (99%). Median (range) age was 59 (25-84) years; 92% had N0 and 8% had N1mi disease; 14%, 52%, and 16% had grade 1, 2, and 3 tumors, respectively (grade information was not available for 18% of patients); median (range) tumor size was 1.5 (0.3-6.5) cm. The majority of patients (78%) had invasive ductal carcinoma and 12% had invasive lobular carcinoma. Overall, 489 patients (48%) had RS Conclusions: These will be the first late recurrence data from over 1000 patients for whom the RS result was used in real-life clinical decision making. Consistent with previous analyses of the CHS registry, CT use was appropriately based on the RS result, and the recurrence/survival outcomes (for the first 5 years) demonstrated the prognostic performance of the RS. Distant recurrence and breast cancer death data beyond 5 years will be presented at the meeting. Citation Format: Stemmer SM, Rizel S, Steiner M, Geffen DB, Soussan-Gutman L, Bareket-Samish A, McCullough D, Svedman C, Nisenbaum B, Ryvo L, Peretz T, Fried G, Rosengarten O, Liebermann N, Ben Baruch N. Real-life analysis evaluating >1000 N0/N1mi estrogen receptor (ER)+ breast cancer patients for whom treatment decisions incorporated the 21-gene recurrence score (RS) result: Clinical outcomes with median follow up of > 9 years [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-14.

Introduction: The 21-gene recurrence score (RS) assay categorizes hormone receptor positive, node negative breast cancers (BC) into 3 risk groups for recurrence. We previously showed that the AAMC Model, using only standard pathology data, accurately does the same. This study compares the recurrence rate of the AAMC Model's risk groups to RS-based risk groups. A 2-step approach then is used, in which the AAMC model is applied first, and the RS assay is used only for AAMC intermediate risk cases. AAMC intermediate cases were reclassified by RS into low or high risk groups. Methods: From a prospective registry of newly diagnosed BC, we selected invasive, hormone receptor positive, HER2 negative, lymph node negative cases from 2005 to 2015 tested with RS assay. Five-year Kaplan-Meier distant recurrence rates were calculated for each risk category. Results: 1268 cases were included. Five-year recurrence rates were similar between the AAMC Model's low risk group and RS30 high risk group. Applying the RS assay to the 715 cases in the AAMC Model's intermediate group resulted in re-classifying 417 (58%) as low risk and 41 (6%) as high risk. Using RS alone, 33% of cases were intermediate risk (n=424), whereas in the 2-step approach 20% were intermediate risk (n=257). For the 2-step approach, the 5-year distant recurrence rate was 3.3% for the low risk group (n=740) and 24.4% for the high risk group (n=271). Conclusions: Five-year recurrence rates in the AAMC Model's low and high risk groups were similar to those in RS-based risk groups. The 2-step approach, with RS used only for AAMC intermediate cases, resulted in larger low and high risk groups with equivalent prognostic accuracy, compared to use of the RS assay alone. The 2-step approach reliably identifies a large number of patients unlikely to benefit from 21 gene assay and provides substantial cost savings. Kaplan-Meier Calculated 5-year Distant Recurrences Rates for 4 Models: 1268 Patients Oncotype DXTAILORxAAMC Model2 Step Model with OncotypeDX for AAMC IntermediatesLow RiskRS < 18 (n=703)RS < 11 (n=250)Grade 1 and PR ≥ 1% (n=323)AAMC Low or AAMC intermediate/RS 30 (n=141)RS > 25 (n=231)Grade 3 or ER < 20% (n=230)AAMC High or AAMC intermediate/RS > 30 (n=271) 23.0% (95% CI 14.7 – 31.3%, nf=27)22.9% (95% CI 15.9 – 29.9%, nf=39)22.8% (95% CI 16.1 – 29.5%, nf=41)24.4% (95% CI 18.0 – 30.7%, nf=51)RS= Recurrence Score, nf=number of recurrences, CI = confidence interval. Citation Format: Mylander C, Rosman M, Gage M, Fujii T, Le Du F, Raghavendra A, Sinha A, Espinosa Fernandez JR, James A, Ueno N, Tafra L, Jackson R. Getting the most out of the 21-gene recurrence score assay: Increasing actionable results with a combined pathologic-genomic model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-09-05.

BACKGROUND: The Oncotype Dx Breast Cancer Assay (21-gene recurrence assay) is a prognostic tool that produces a recurrence score, which estimates the probability of distant recurrence within 10 years, given 5 years of adjuvant endocrine therapy as well as predicts benefit from adjuvant chemotherapy. The primary objective of this study was to explore if standard clinicopathologic variables independently correlate to the recurrence score. As a secondary objective, we explored if a model based on the clinicopathologic variables can accurately predict recurrence score. METHODS: We conducted a retrospective chart review of 507 patients with node-negative, estrogen receptor (ER) positive breast cancer from the UF Health Cancer Center at Orlando Health. Of the 507 patients, 84 did not meet inclusion criteria (n = 423). The following factors were correlated with recurrence score (RS): age, tumor size, ER, PR, ki67, HER2 (IHC), HER2 (FISH), and tumor grade. Although the RS is a continuous variable, scores are also used to categorize patients into three risk groups: low (RS RESULTS: In univariate analysis, there were no significant correlations between age, ER, tumor size, Ki67 and RS. There were statistically significant correlations between PR (r=-.42, p CONCLUSION: The data presented here suggests that it may be possible to create a model based on standard clinicopathologic parameters to predict the 21-gene recurrence score in node-negative, ER positive breast cancer patients. In practice, a 21-gene recurrence score assay is not always possible. We present an option to identify patients whose risk category can be confidently determined from the standard clinicopathologic variables alone, thereby reducing medical cost. Admittedly, this model has not undergone validation nonetheless, the data suggest the potential for a novel; low-cost; high reach diagnostic tool. Citation Format: Mankbadi MR, Luo Y, Yasin M, Ben Khallouq B, Moroose R. A prognostic predictive model based on the correlation of standard clinicopathologic characteristics with oncotype Dx 21-gene recurrence score for node-negative and ER positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-09-13.

Background: The 21-gene RS is routinely used in node negative ER+, HER2- BC to help guide chemotherapy treatment decision making. There is emerging use of the RS in limited N+ BC, though the results from the randomized clinical trial (RxPONDER) is pending. The objective of the study is to determine whether the results of the 21-gene RS will alter physician treatment decisions in ER+ HER2- limited N+ BC. Methods: Consenting patients (pts) with ER+, HER2-, 1-3 N+ (microscopic or macroscopic) early stage BC participated in this prospective, multi-center British Columbia Cancer Agency (BCCA) study. Treating physicians completed a questionnaire after an initial visit with the patient to document their treatment recommendation before obtaining the RS assay. At a subsequent visit, the assay result and final treatment recommendations were discussed and physicians completed a second questionnaire on the final treatment plan. The statistical assumption of the study was based upon anticipating an overall treatment decision change rate (from chemo-hormonal therapy to hormone only, or vice-versa) to be at least 30%. Results: Out of 84 pts enrolled, 82 went on to have RS testing. 57% of pts had T1 tumors, 40% T2 and 2% T3 tumors. The majority of pts (77%) had N1 macroscopic disease compared to 23% that had microscopic nodal involvement. 63% of cases were grade 2, followed by 23% grade 1 and 14% grade 3. 60% of RS were low (30). In 53% of cases there was an altered treatment plan (49% switched from chemo-hormonal therapy to hormone only, and 4% switched from hormone only to chemo-hormonal therapy). Of the 49% that switched to hormone only, 68% had a low RS and 33% had an intermediate RS. All 4% that switched to chemo-hormonal therapy had an intermittent RS. Conclusions: This multi-centered Canadian study showed that in 53% of cases, treatment recommendations were changed based on the RS. This suggests that there is clinical utility for the RS in 1-3 N+, ER+, and HER2- breast cancer. Citation Format: Sun J, Fenton D, Baxter S, Chan A, Roberts S, Feng X, Lohrisch C, Gelmon K, Shenkier T, Chia S. A prospective clinical utility study of the impact of the 21-gene recurrence score (RS) assay in the treatment of estrogen receptor positive (ER+), HER2 negative (HER2-), 1-3 node positive (N+) breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-07.