Recurrence Score Score Research Articles

Abstract P5-06-04: Prognostic value of EndoPredict and Oncotype Recurrence Score according to patient's age

Abstract Background: EndoPredict (EPclin) and Oncotype Recurrence Score (RS) have both shown their prognostic ability for women with estrogen receptor positive (ER), HER2-negative breast cancer, with EPclin outperforming RS specifically in node-positive population and for the prediction of late distant recurrence (DR). Age is an important risk factor for breast cancer but no data is available on the performance of genomic assays according to patient’s age. Here, we investigate whether EPclin and RS provide differential prognostic value in different age groups. Methods: 928 postmenopausal women with ER-positive, HER2-negative breast cancer were included in this analysis for whom information on EPclin and RS were available. None of the patients included in this analysis received chemotherapy. Age at diagnosis was treated as a categorical variable (≤60 years, 60-70 years, >70 years). Primary endpoint was DR and we used Cox regression models to assess the prediction of DR by EPclin and RS according to age. Results: 300 (32.3%) women were aged 60 years or younger, 377 (40.6%) between 60 and 70 years, and 251 (27.1%) were older than 70 years. Women aged 60 years or older had significantly more node-positive disease, higher grade tumors, and more DR than those aged 60 or younger. RS scores were similar between age groups whereas EPclin scores were significantly higher in older women compared to younger women, reflecting the combined molecular plus clinical nature of the EPclin. Overall, both RS and EPclin were prognostic but with decreasing prognostic value with increasing age (Table). We observed a significant interaction between continuous age and both tests (RS: P=0.004; EPclin: P=0.026). In women aged 70 years and older, RS did not provide any prognostic information (HR=1.22 (0.96-1.55); LR-χ2=2.5) whereas EPclin showed significant prognostic ability in this age group (HR=2.02 (1.59-2.57); LR-χ2=30.4) (Table). Kaplan-Meier estimates were significantly different between low and high risk groups for both tests in women aged less than 70 years. No significant risk stratification was achieved by RS in women aged 70 years or older whereas EPclin distinctively stratified older patients into low and high risk groups with significant different 10-year DR risks. Conclusion: Genomic assays are increasingly used in the clinic to determine prognosis for women with ER-positive, HER2-negative breast cancer. Here, we show that the effect sizes and prognostic value of EPclin and RS are different across age groups, and only the EPclin was prognostic in elderly patients. Our results indicate that tests that incorporate clinical parameters in their score are likely to be more prognostic in elderly patients and should be used in the decision-making process when using genomic assays. Hazard Ratios (HRs (95% CI)) for continuous EPclin/RS scores and risk groups according to age groups≤60 years60-70 years>70 years(N=300)(N=377)(N=251)RS2.23 (1.57-3.15)1.59 (1.32-1.91)1.22 (0.96-1.55)LowReferenceReferenceReferenceIntermediate3.79 (1.40-10.24)2.74 (1.44-5.23)1.75 (0.97-3.15)High8.86 (3.07-25.57)6.55 (3.25-13.19)1.63 (0.67-3.96)EPclin3.47 (2.28-5.27)2.74 (2.17-3.45)2.02 (1.59-2.57)LowReferenceReferenceReferenceHigh9.60 (3.60-25.57)5.55 (2.91-10.61)3.68 (1.89-7.17) Citation Format: Ivana Sestak, Ralf Kronenwett, Richard Buus, Jack Cuzick, Mitchell Dowsett. Prognostic value of EndoPredict and Oncotype Recurrence Score according to patient's age [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-04.

Abstract P3-07-05: Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study

Abstract Background: Oncotype DX Recurrence Score (RS), Prosigna PAM50 ROR score, the EndoPredict score (EP, EPclin) and the Breast Cancer Index (BCI) all provide substantial molecular prognostic information and are used in clinical practice for guiding the treatment for large numbers of patients with primary ER+/HER2- breast cancer. Despite this, there is incomplete information on the concordance between these scores and very little understanding of the molecular features that drive the individual scores. Here we report from a unique database (i) the correlation between all 4 scores when measured by the respective manufacturers in the TransATAC set of samples and (ii) the degree to which each of the scores is driven by proliferation, oestrogen signalling, HER2 signalling and invasive properties insomuch as these are reflected by each component module of the RS test (PM, EM, HM and IM, respectively). Methods: The TransATAC tumour sample set was collected from patients in the tamoxifen or anastrozole arms from the ATAC clinical trial of 5 years of endocrine therapy in postmenopausal patients with primary hormone receptor positive breast cancer. Cases were included if HER2- and all 4 scores were available. None of the patients received adjuvant chemotherapy. EP and ROR both include some clinical features in their final score but components were excluded for the purposes of this study. The RS module scores were provided by the manufacturer. The genes that contribute to the module scores are as follows: PM: Ki67, STK15, Survivin, CCNB1, MYBL2; EM: ER, PGR, BCL2, SCUBE2; HM: GRB7, HER2; IM: MMP11, CTSL2). Spearman rank correlation was used to study the association between molecular components. Results: Data was available for all four molecular scores for 785 TransATAC patients. Correlations were moderate to strong for RS vs EP (r=0.63), ROR vs EP (r=0.68), ROR vs BCI (r=0.74) and EP vs BCI (r=0.67) but were weak for RS vs ROR (r=0.32) and RS vs BCI (r=0.35). The correlation between each score with the RS module scores are shown in the Table. Molecular scoreRS moduleRSROREPBCIPM0.360.860.710.74EM-0.790.00-0.38-0.10HM-0.04-0.14-0.15-0.18IM0.260.380.340.32 The RS had a strong negative correlation with its EM (r= -0.79) and a weak positive correlation with its PM (r= 0.36) although the latter was stronger when the PM was thresholded; 78% of the cases had a PM score below the threshold of 6.5 and were assigned a value of 6.5 in the RS with no correlation between RS and PM in these samples (r=-0.03). ROR showed a very strong correlation with the PM (r=0.86), but none with the EM (r: 0.00). EP and BCI both showed strong correlation with the PM (r= 0.71 and 0.74, respectively) and with low or near absent correlation with EM (r= -0.38 and -0.10, respectively). There was little correlation between the HM with each of the scores while the IM correlation was similar for each score varying from 0.26 to 0.38. Of the two module components of BCI, MGI was strongly associated with the PM (r= 0.84) and not at all with the EM while H/I moderately correlated with PM (r=0.51) and weakly correlated with EM (r= -0.31). Conclusion: EP scores are moderately correlated with each of the other 3 scores while RS scores are dissimilar to those from the ROR and BCI. In contrast to common thinking the RS is driven only weakly by proliferative features and more by those related to ER/PR pathways. The EP, BCI and particularly ROR are dominated by proliferative features. These relationships provide and explanation for the differences that we and others have reported in the prognostic performance of the tests for both early and late recurrence. Citation Format: Richard Buus, Ivana Sestak, Mitch Dowsett, Ralf Kronenwett, Sean Ferree, Catherine Schnabel, Frederick L Baehner, Jack Cuzick. Correlation between and molecular drivers of oncotype DX, prosigna, EndoPredict and breast cancer index: A TransATAC study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-05.

Abstract P2-11-10: Estrogen drives the therapeutic hormonal response in ER+ breast cancers

Abstract Background: It is thought that estrogen induces proliferation in all estrogen receptor positive (ER+) breast cancer cells. However, there are paradoxical reports of a therapeutic effect of estrogen (E2) with possible E2 induced apoptosis in tumors that are chronically E2 deprived such as after the menopause. We tested whether E2 induced proliferation or apoptosis in post-menopausal women with newly diagnosed breast cancer. Method: We treated 19 women with low dose estradiol (6mg/day) in a window of opportunity trial. Changes in Ki67 and the Prosigna™ Risk of Recurrence Score (ROR) were measured. 13 patients with sufficient tissue had whole transcriptome RNA-seq analysis on pre- and post-treatment specimens to test pathway induction and to derive a gene expression profile (GEP) associated with response to E2. 13 contemporaneous untreated patients were matched for surgical ROR scores to serve as post-hoc controls. The E2-response GEP was then tested on publicly available datasets of ER+ patients as well as ER transfected cell lines. Results: Estradiol was well tolerated. 68% (13/19) and 62% (8/13) of tumors showed decreases in Ki67 and ROR respectively with the Ki67 decrease being significant (p=0.017) compared to control untreated tumors. Although the direction of change in the Ki67 and ROR indices showed good concordance (10/11, κ =0.74) the change in ROR was not statistically significant (p=0.064) because of the smaller sample size. We compared responders (ROR decrease >2 Standard Deviation beyond controls) to non-responders (ROR and Ki67 changes closest to zero) and generated 3 GEPs: (i) 69 genes differentially activated by E2 (ii) 30 genes upregulated only in the pre-treatment biopsies of responders and (iii) 45 genes downregulated only in the post-treatment specimens of responders. A Reactome (https://reactome.org/) Pathway Analysis showed 17 of the top 20 pathways differentially activated by E2 were involved in the cell cycle with no activation of apoptosis pathways. Although 3 of the 36 genes characteristic of an E2-induced apoptotic response (Ariazi et al. Proc. Natl. Acad. Sci. 2011) had a significant fold change in Responders the Chi-square test was non-significant (p= 0.24) consistent with a non-apoptotic E2 response. Responders were found to have higher pre-treatment levels of ESR1 (Pearson R=0.504, p=0.04). E2 induced increases in the p21 gene (CDKN1A) were found in both E2 responsive patients (Pearson R=0.640, P = 0.009) and ER-transfected MCF-7 cells (p<0.009), consistent with the induction of cell cycle blockade. Algorithmic combination of the biopsy and surgical GEP of the E2 responders predicted distant recurrence free survival in cohorts of patients who had been treated with Tamoxifen (Symmans et al. J Clin Oncology 2010) (p<0.001) or Aromatase Inhibitors (Miller et al. J Clin Oncology 2009) (p< 0.0001) but not in an untreated cohort (Symmans 2010). Conclusions: These findings suggest that E2 can induce cell cycle blockade in some higher ER expressing ER+ tumors without activating apoptosis. In such patients, Tamoxifen may function as an E2 agonist. These data suggest that the estrogenic testosterone metabolite 5α-androstane-3β,17β-diol, an ERα agonist increased by aromatase inhibition, (Sikora et al. Breast Cancer Res Treat 2009) may contribute to the benefit from aromatase inhibitors. This represents a conceptual change of the biological action of E2 from pro-proliferative to anti-proliferative in some ER+ patients and suggests that i) E2 treatment may be a therapeutic option for selected post-menopausal ER+ patients, and ii) a single signature can predict which patients will have an anti-proliferative response to E2, tamoxifen, and aromatase inhibitors. Citation Format: Judith Hugh, Lacey Haddon, John Maringa Githaka, Xiuying Hu, Gilbert Bigras, Brittney Loney, John Hanson, Zsolt Gabos, Fleur Huang, Mary Hitt, Kirk McManus, Kelly Dabbs, John Mackey. Estrogen drives the therapeutic hormonal response in ER+ breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-10.

Abstract P3-08-10: Characterization of oncotype DX recurrence score and chemotherapy utilization patterns in young women (≤40) with early stage ER+/HER-, lymph node negative breast cancer

Abstract Background: Meta-analyses have demonstrated that young women ≤40 (YW) derive the most benefit from chemotherapy (EBCTCG, Lancet. 1998). Oncotype DX was designed to determine the benefit of chemotherapy in women with ER+/HER2-, node-negative (LN-) breast cancer based on recurrence score (RS). TAILORx reported clinically meaningful benefits in freedom-from-distant recurrence in women <50 with the addition of chemotherapy to endocrine therapy when RS was 16-25. Recent TAILORx analyses suggest that women <40 with an intermediate (int) RS do not derive chemotherapy benefit, though YW comprised <4% of the trial population [1]. Defining the optimal adjuvant treatment strategy for this population of YW remains a clinical challenge. We sought to determine national patterns of RS utilization in association with receipt of chemotherapy and to characterize the association of RS with tumor characteristics and demographics among YW with early stage ER+, LN- breast cancer. Methods: Using the National Cancer Data Base (NCDB), we identified individuals age <75, diagnosed 2010-2015 with stage I-II, ER+/HER2-, LN- breast cancer with known RS. Cohorts were defined as low (0-10), int (11-25), and high (>25) RS. Age categories were classified as ≤40, 41-50, and >50. Chi-square tests or Fisher’s exact tests were used to compare categorical variables. Logistic regression was used to estimate the association of RS score and age group with adjuvant chemotherapy use, after adjustment for known covariates. Kaplan-Meier curves were used to visualize unadjusted overall survival (OS), and Cox proportional hazards models were used to estimate adjusted OS. Results: 120,051 women were identified, of whom 4,781 were ≤40 years, 24,846 were 41-50, and 90,424 were >50. By age group, 20% of YW had a high RS compared to 12% of women age 41-50 and 15% of women >50 (p<0.001). Among YW, black women were more likely than white women to have a high RS; 29% vs. 19% (p<0.001). RS was strongly associated with receipt of chemotherapy in YW (86% of high RS vs. 33% of int RS vs. 7% of low RS, p<0.001). Chemotherapy was omitted in 55% of YW with RS 16-25. YW in multivariate analysis with a low or int RS were more likely than women 41-50 or >50 to receive chemotherapy (p<0.001). Receipt of chemotherapy for YW with an int RS was associated with younger chronologic age (p<0.001), ductal histology (p=0.02), high grade (p<0.001), and higher pathologic T-stage (p<0.001). Among YW, the unadjusted 5-year OS (95% CI) was as follows: low RS= 100% (0.99-1), int RS= 100% (1-1), high RS= 93% (0.90-0.96). Chemotherapy did not influence 5 year OS in YW with an int RS. In univariate analysis, a high RS was associated with a worse 5-year OS in YW (log-rank p<0.001). After adjustment for race and chemotherapy receipt, high vs. low RS was associated with an increased risk of death (HR=5.86, 95% CI 1.19-28.82, p=0.03) in YW. Conclusions: High RS is more common in YW (≤40) than those age 41-50 or >50, and is associated with worse OS. YW with an int or low RS are more likely to receive chemotherapy despite unclear benefit. Chemotherapy was omitted in over half of YW with RS of 16-25, highlighting the uncertainty in clinical practice which will remain until further studies inform optimal systemic treatment specific to YW. 1. Sparano, J.A., et al., Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. New England Journal of Medicine, 2019. 380(25): p. 2395-2405. Citation Format: Sarah Sammons, Yi Ren, Jeremy Force, Oluwadamilola M. Fayanju, Laura H. Rosenberger, Jennifer K. Plichta, Gretchen Kimmick, Kelly Westbrook, Susan Dent, Carey Anders, Samantha M. Thomas, Terry Hyslop, E. S. Hwang, P. K. Marcom, Rachel A. Greenup. Characterization of oncotype DX recurrence score and chemotherapy utilization patterns in young women (≤40) with early stage ER+/HER-, lymph node negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-10.

Abstract GS4-03: Validation of the clinical treatment score post 5 years (CTS5) in women with hormone receptor positive, HER2-negative, node-negative disease from the TAILORx study

Abstract Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological parameters (nodal status, tumor size, grade, and age) to estimate distant recurrence (DR) risk after 5 years of endocrine treatment for postmenopausal women with estrogen receptor (ER) positive breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Here, we evaluate whether the CTS5 is prognostic in women who were distant recurrence (DR) free 5 years after adjuvant treatment who participated in the TAILORx study. Methods: 10273 women with ER-positive, HER2-negative, and node-negative disease were entered into the TAILORx study and assigned or randomized to four treatment arms according to their Oncotype Recurrence Score (RS) (endocrine therapy alone (ET) or chemo-endocrine therapy (CET)). Primary endpoint of this analysis was DR and the primary objective of this analysis was to evaluate the CTS5 in the TAILORx study, stratified by chemotherapy use. Secondary objectives included validation of the CTS5 in two specific age groups (age≤50 years vs. age>50 years) and in the four separate treatment arms. Cox regression models were used to determine the prognostic value of CTS5. Kaplan-Meier curves were used to estimate conditional 9-year DR risks (%). Hazard ratios are reported for an increase of 1-standard deviation of CTS5 in the overall analysis population. Results: 7353 (71.6%) women were DR free 5 years after diagnosis with follow-up beyond 5 years, had information for all clinical parameters, and were included in this analysis. Median follow-up after 5 years was 2.9 years (1.8-3.9). Overall, mean age was 55.7 years (SD 9.0), mean tumor size 17.1mm (SD 7.8), and the vast majority had low or moderately differentiated disease (84.7%). CTS5 was significantly higher for women in arm D (RS 26-100, CET) compared to the other three arms (mean CTS5 3.09 vs. 2.82, P<0.001). Overall, CTS5 was highly prognostic for late DR stratified for assigned chemotherapy arm (HR=1.57 (1.36-1.82), P<0.0001) (Table). 5385 (72.9%) of women were categorised into the low risk group by CTS5, 1836 (25.0%) into the intermediate risk group, and 132 (2.1%) into the high risk group. Looking at each arm separately, CTS5 did not predict late DR in women with RS 0-10 and ET (arm A), but provided strong prognostic information for late DR in arms B (RS 11-25, ET), C (RS 11-25, CET), and D (RS 26-100, CET) (Table). CTS5 strongly predicted late DR in women who were older than 50 years (HR=1.78 (1.48-2.14), P<0.0001), but to a smaller extent in women aged 50 years or younger (HR=1.35 (1.01-1.82), P=0.046) (Table). Conclusions: Low risks of late DR of 3.1% (2.4-4.0) for RS scores 0-25 (ET) and 3.8% (2.9-4.8) for RS scores 11-100 (CET) were observed in this ER-positive, HER2-negative and node negative TAILORx cohort. We confirm the prognostic ability of the CTS5 for late DR in the TAILORx cohort, specifically for patients older than 50 years and/or those who were deemed intermediate or high risk by Oncotype Dx RS (11-100). Our results show that the CTS5 is less prognostic for late DR in women aged 50 years or younger who received 5 years of endocrine therapy only. Further evaluation of the CTS5 in premenopausal cohorts is needed before it can be applied to younger patients. Table: Hazard Ratios (95% CI) for prognostic value of CTS5 overall and according to sub-groups.HR (95% CI )P-valueAll (N=7353)1.57 (1.36-1.82)<0.0001Arm A (N=1323)1.34 (0.87-2.07)0.19Arm B (N=2746)1.50 (1.17-1.93)0.002Arm C (N=2655)1.56 (1.22-1.98)0.0003Arm D (N=629)1.90 (1.23-2.92)0.004Age ≤ 50 years (N=2259)1.35 (1.01-1.82)0.046Age > 50 years (N=5094)1.78 (1.48-2.14)<0.0001 Citation Format: Ivana Sestak, Michael Crager, Jack Cuzick, Mitchell Dowsett, Steven Shak, Gong Tang, Robert Gray, Joseph Sparano. Validation of the clinical treatment score post 5 years (CTS5) in women with hormone receptor positive, HER2-negative, node-negative disease from the TAILORx study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS4-03.

Abstract P5-03-07: Distribution of the 21-gene recurrence score (RS) assay (Oncotype DX) in carriers of germline mutations associated with breast cancer predisposition syndromes

Abstract Background: BRCA1/2 carriers have higher scores in the 21-gene RS assay compared to non-carriers. Little is known about the 21-gene RS patterns in women harboring germline mutations in genes outside BRCA1/2. Methods: We utilized the Mayo Clinic Breast Cancer Study Registry to identify individuals with non-metastatic estrogen receptor positive breast cancer and clinical 21-gene RS results available. We cross-referenced this with an institutional registry of patients tested for hereditary cancer genes, either from the electronic health record or from a research study conducted using a custom QIAseq multiplex amplicon-based panel (Qiagen). The latter assay covered target regions of all coding regions for the following predisposition genes: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, ERCC2, FANCC, FANCM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, PRSS1, STK11, TP53, and XRCC2. Student’s t-test was used to compare 21-gene RS between carriers, non-carriers, and specific carrier genes (JMP v 14.0). Results: 282 patients were identified with early stage breast cancer and 21-gene RS available, including 85 known mutation carriers and 197 non-carriers (or unknown carrier status). Germline mutations were identified in CHEK2 (n=25), BRCA2 (n=18), ATM (n=10), BRCA1 (n=5), PALB2 (n=5), TP53 (n=3), FANCM (n=2), MUTYH (n=2), PMS2 (n=2), PPM1D (n=2), RECQL (n=2), BARD1 (n=1), BLM (n=1), CDH1 (n=1), ERCC2 (n=1), FANCC (n=1), MSH6 (n=1), NBN (n=1), PRSS1 (n=1), and PTEN (n=1). In the entire cohort, the mean 21-gene RS was 20.4 in carriers and 18.0 in non-carriers (p=0.11). We performed individual analyses on specific genes identified in ≥ 5 patients (table 1). Compared to the mean RS in non-carriers (18.0), higher mean RS were observed in patients harboring BRCA1 (38.8, p=0.002), PALB2 (26.6, p=0.0724), and BRCA2 (23.2, p=0.0453). The RS in CHEK2 and ATM carriers were comparable to those of non-carriers. Conclusions: We observed differences in RS score distribution based on specific mutated breast cancer predisposition genes. Further validation of the distribution and performance of the 21-gene RS in germline carriers is needed. 21-gene RS scorenMedian RSMean≤1516-25≥26n%n%n%CHEK2251616.61248728624BRCA2182123.2211.11161.1527.8ATM101716.9330550220BRCA153635.8120120360PALB253326.6120120360None1971518.09950.367343115.7 Citation Format: Karthik V Giridhar, Grace M Choong, Siddartha Yadav, Eric C Polley, Roberto A Leon-Ferre, Minetta C Liu, Matthew P Goetz, Fergus J Couch. Distribution of the 21-gene recurrence score (RS) assay (Oncotype DX) in carriers of germline mutations associated with breast cancer predisposition syndromes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-03-07.

21-Gene recurrence score influences the chemotherapy decision for patients with breast cancer of different luminal subtypes.

Luminal subtypes and the 21-gene recurrence score (RS) are important factors in the decision-making process for adjuvant chemotherapy in patients with hormonal receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, their effect on adjuvant chemotherapy decisions in the real world has not been thoroughly investigated, particularly for patients of the luminal A-like subtype with a high RS or the luminal B-like subtype with a low RS. The present study, a total of 772 HR+/HER2- patients who underwent 21-gene testing, were included in a retrospective analysis. The impact of clinicopathological factors and the 21-gene RS on chemotherapy recommendation was analyzed in the whole population and for patients of different luminal subgroups. The results revealed that chemotherapy was highly recommended for patients of younger age, with larger tumor size, node involvement, higher grade, luminal B-like subtype and higher RS. A high RS was identified to be the most important impact factor for chemotherapy recommendation among all patients [odds ratio (OR), 62.54; 95% CI, 25.58-152.92], the luminal A-like group (OR, 435.05; 95% CI, 29.90-6331.06) and the luminal B-like group (OR, 57.20; 95% CI, 22.42-145.96). For patients of the luminal A-like subtype with a high RS or patients of the luminal B-like subtype with low RS, the 21-gene RS was demonstrated to be the most important independent factor for chemotherapy recommendation, with an adjusted OR of 134.52 (95% CI, 10.39-1741.89). In conclusion, luminal subtypes and the 21-gene RS were found to be associated with chemotherapy recommendation for HR+/HER2- patients. For patients with a discordant luminal subtype and 21-gene RS risk, the 21-gene RS score was found to be the most important factor that influences chemotherapy decision, which warrants further clinical evaluation.

Abstract P2-07-07: Development of a machine learning-based classifier for Oncotype DX® category prediction in a population of lymph node positive breast carcinoma patients

Abstract INTRODUCTION: Oncotype DX® (ODX) Assay is a valuable prognostic and predictive tool in ER+, Her2- invasive breast cancer (IBC). Initially tested and validated in lymph node (LN) negative patients, the indications of this test have been expanded to include patients with limited LN-positive disease. Several prediction systems have been developed to predict the ODX Recurrence Score (RS) with substantial performance in predicting a high vs low RS score but with low performance when predicting the 3 classes that compose the standard ODX. Additionally, many of these prediction systems have not been developed and/or tested for a population of LN+ patients. OBJECTIVES: The primary objective of this study was to evaluate the performance of several previously published ODX RS predictive systems in a population of LN+ patients. Furthermore, we developed a machine-learning based classification system to accurately predict the ODX 3 category RS for this specific population. METHODS: We conducted a retrospective search of Stanford's pathology database for all patients with LN+ IBC diagnosed between January 2013 and December 2017 with an ODX RS available. A total of 119 patients were identified for inclusion in this cohort. Our multivariate pathologic feature-based discriminatory model aimed to classify each case as belonging to the low, intermediate or high ODX RS category. We performed model validation by the 10-fold cross validation (10F-CV) method. The model's performance was assessed by comparing simple accuracy, balanced accuracy, F1 score (harmonic average of the precision and recall) and several concordance classification metrics. RESULTS: Of the evaluated methods, Magee equations performed well in this population of LN+ patients with the modified Magee equation 2 displaying the best accuracy (70.9%) which was surprisingly better than originally reported (55.8%, in Klein et al. Mod Path. 2013). After an initial screen of methods and tuning of the best performing model, our model achieved an overall accuracy of 78.1% on 10F-CV with a 79.1 % balanced accuracy and no two-step discordances. This corresponded to an increase of weighted Cohen's kappa of 30% versus the best performing Magee equation in this cohort and an increase of 103% versus the modified Magee 1 equation (which uses the same features as our model except for tumor grade). DISCUSSION: Classifiers aimed at providing an alternative to Oncotype DX testing are available and perform consistently across datasets. We are currently validating our approach in a population of 1000 LN-negative patients from the MSKCC and the SEER database. Due to the substantial performance of our machine learning-based classifier based on standard reported pathologic features, our model may be considered an alternative to the ODX standard testing or a screening method for ODX testing, especially for cases with where the cost and availability of the ODX test are a concern. Citation Format: Beca F, Yang S-R, Gruber JG, Barry-Holson K, West R, Wen HY, Allison KH. Development of a machine learning-based classifier for Oncotype DX® category prediction in a population of lymph node positive breast carcinoma patients [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 P2-07-07.

Examination of the Biomark assay as an alternative to Oncotype DX for defining chemotherapy benefit.

Currently the 21-gene recurrence score (RS) assay called Oncotype DX is recommended by the National Comprehensive Cancer Network guideline for defining the benefit of chemotherapy. To overcome the cost disadvantages of the Oncotype DX assay and the turnaround time, a multigene assay was examined to compare the correlation of the RS and the predicted score (PS) of the present study. Paraffin-embedded tissues of 50 cases with early-stage estrogen receptor (ER)-positive breast cancer, who underwent the Oncotype DX test were used. A total of 149 candidate genes with high correlation to the RS were identified, in another project (Lee et al, unpublished data). Reverse transcription-quantitative polymerase chain reaction biomark assays were conducted using the dynamic array integrated fluidic circuit and the correlation analysis was performed with BRB ArrayTools. A predictive model was developed by the coefficient and gene expression, and 41 genes were identified. If the cut-off was ≥18, the predicted model was 18/50 cases, and the RS was 19, indicating that the differential rate of predicted response against RS was 2%. If the cutoff was ≥11, the predicted model was 38/50 cases and the RS was 34, indicating a difference of 8%. Genes common to the Oncotype DX and the Biomark assay include marker of proliferation Ki-67, aurora kinase A, Erb-B2 receptor tyrosine kinase 2, glutathione S-transferase Mu 1, estrogen receptor 1, progesterone receptor, B-cell lymphoma 2, signal peptide CUB domain EGF-like 2 and 5 reference genes. The remaining 28 genes are involved in various pathways and functions. This result indicates that there is a significant correlation between PS and RS scores, although validation of results is required to accurately determine the risk of distant recurrence. The Biomark assay is an easy and inexpensive way to measure mRNA expression. The present study demonstrates the possibility of the Biomark assay as an alternative for defining chemotherapy benefit in individual patients with ER-positive early-stage breast cancer.

Abstract P1-06-05: Clinical practice and mortality in patients with oncotype DX intermediate score: What do we know about the gray zone?

Abstract BACKGROUND: The 21 gene expression signature Oncotype DX (ODX) is a powerful predictor of disease outcome in early stage hormone receptor positive breast cancer. ODX can be used for better risk stratification of patients who may benefit from chemotherapy. ODX testing increases confidence in treatment decisions especially when ODX recurrence score (RS) is low or high. However, for the intermediate RS, decisions on receiving chemotherapy or not is a joint decision made by the physician and patient, in part because results from the TAILORx and RxPONDER randomized clinical trials addressing this very important clinical question has yet to be published. OBJECTIVE: To examine “real world” oncology practice and survival outcome for breast cancer patients with ODX RS score in the intermediate range. METHODS: A retrospective cohort of women diagnosed with early stage, hormone receptor positive breast cancer whose ODX score was in the intermediate range was established using the National Cancer Data Base (NCDB), 2009-2013. We assessed the relationship of overall survival with chemotherapy receipt and RS score using Cox proportional hazards models adjusted for patient characteristics, including age, race/ethnicity, grade, year of diagnosis, Charlson Co-morbidity Index, lymphovascular invasion, nodal involvement, tumor size, and histology. Intermediate RS score was analyzed as both continuous variable and categorical variables (18-20, 21-23, 24-26, and 27-30). RESULTS: Of 24,945 females reported to have intermediate ODX score, 10,179 (41.4%) received chemotherapy. Receipt of chemotherapy depended on ODX score monotonically, ranging from 19.1% in patients with RS = 19 to 76.1% in patients with RS = 30. In total, 426 patients have died from all causes. Overall, chemotherapy receipt was associated with a statistically significant reduction in the risk of death (hazard ratio=0.77; 95% confidence interval [CI]: 0.62-0.96, p=0.02) in multivariable Cox model. RS score was statistically positively associated with increased risk of death, with one unit increment in RS corresponding to 6.2% increased mortality risk (95% CI 3.2%- 9.2%, p<0.0001). Using a categorical scale, we found patients with intermediate ODX scores in RS 27-30 range had 1.64-fold increased risk of death (95% CI: 1.13-2.37) compared to patients with ODX scores in RS 18-20 range.. The association between ODX score and overall survival was more pronounced in women younger than 50 (hazard ratio per 1 unit increment = 1.28, 95% CI: 1.17-1.40) than in women 50 years or older (hazard ratio per 1 unit increment = 1.04, 95% CI: 1.01-1.07). CONCLUSION: Our analysis revealed the ODX score in the intermediate range still has prognostic value for overall survival especially for young-onset breast cancer patients, which is independent of other clinopathologic factors. As we eagerly await results from randomized clinical trials, young women with intermediate RS should be counseled to consider more aggressive treatment including chemotherapy, ovarian function suppression or participation in ongoing clinical trials of CDK inhibitors to improve overall survival outcomes. Citation Format: Ibraheem AF, Press D, Dezheng H, Olopade F. Clinical practice and mortality in patients with oncotype DX intermediate score: What do we know about the gray zone? [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 P1-06-05.

Abstract P4-04-05: Primary endocrine therapy (PETx) induces PAM50 intrinsic subtype migration with prognostic implications

Abstract Backgorund: ER activation is a major ruler of cell biology in ER+ve breast cancer. Hence, ER dependent gene expression at diagnosis, may unveil most of the oncogenic mechanisms responsible of potential tumour relapse and metastasis. Thus, we hypothesized that oestrogen deprivation through PETx may unveil underlying tumour biology with deeper prognostic implications. To explore this, we studied changes in PAM50 intrinsic subtyping and Risk of Recurrence score throughout PETx and their correlation with known prognostic factors. Methods: Clinical-pathological data were evaluated in a series of patients with stage I-III ER-positive/HER2-negative breast cancer treated in 6 centers in Spain with PETx during more than two months with available baseline and surgical samples. The expressions of 50 genes were measured in baseline samples and surgical specimens using the nCounter platform. Intrinsic subtypes and Risk of Recurrence score (ROR) were determined by the research-based PAM50 predictor. Response by ultrasonography (US) and magnetic resonance (RMI) between diagnosis and before surgery and PEPI score in surgical samples were used as the endpoints. Association between two variables was evaluated using χ2 test or Pearson correlation. All statistical tests were two-sided and considered significant when P≤0.05. Results: Gene expression profile was feasible in 58 pre/post sample pairs with a median of 7.8 months (range 2.5-40.6) of PETx with AIs (98.3%) or tamoxifen (1.7%). At baseline, 68.9%(n=40) were classified as Luminal A, followed by Luminal B (24.1%; n=14), HER2 enriched (HER2-E) (5.2%; n=3) and Normal-like (1.8%; n=1). Radiologic response did not change significantly according to intrinsic subtype either by MRI or US (P>0.05). Instead, PEPI score varied according to intrinsic subtype (P=0.024).Thirteen (32%) of LumA, while neither of LumB or HER2-E tumours showed a PEPI score Group 1. PETx resulted in changes in the intrinsic subtype in 29 (50%) of tumours Table 1 Her2-E postLumA postLumB postNormal postHer2 pre2 (66.7%)1 (33.33%)00LumA pre1 (2.5%)21 (52.5%)3 (7.5%)15 (37.5%)LumB pre06 (42.86%)5 (35.71%)3 (21.43%)Normal pre0001 (100%) . Of note, 2 of 3 (66.7%) HER2 tumors, and 5 of 14 (35.7%) LumB tumors did not change their profile. Forty-eight (83%) tumours showed a decrease in ROR score after PETx (P<0.001). ROR was over 30 in 29 tumours (49.1%) at baseline and 16 (27%) at surgery. Change in ROR was moderately correlated with percentage of change in Ki-67 [correlation: 0.417 (P<0.01)]. Correlation of surgical tumour subtype with IHC markers of cell-viability/apoptosis will be presented. Conclusion: Oestrogen deprivation of luminal tumours through PETx results in profound changes in tumour biology including a migration in intrinsic subtype in 50% of tumours. Correlation of the largely decreased ROR with changes in Ki67 reveals the potential prognostic additional information generated by profiling tumours after PETx. ER-blockade may unveil underlying tumour oncogenic capabilities for relapse, survival and metastasis. Hence, the post-PETx gene expression profile, molecular subtype and ROR may bear incremental prognostic and predictive information generating a novel scenario for optimal clinical decision making. Citation Format: Larburu L, Paré L, Rezola R, Carrera M, Buch E, Gimenez J, Quiroga V, Fernandez M, Aragón S, Pascual T, Prat A, Urruticoechea A. Primary endocrine therapy (PETx) induces PAM50 intrinsic subtype migration with prognostic implications [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 P4-04-05.

Abstract P1-06-02: Comparative survival analysis of multiparametric tests in the TEAM pathology study: What to do when molecular tests disagree?

Abstract Multiparametric assays for risk are increasingly used in the management of node-negative and node-positive hormone receptor-positive invasive breast cancer. Data from multiple sources suggests different tests may provide different risk estimates at the individual patient level1. Analysis from the TEAM pathology study (Bayani and Yao et al npjBreast Cancer, 2017) allows direct comparison of prognostic information from gene signatures in a clinical trial cohort of postmenopausal patients. Risk classifications using genes comprising the following multi-parametric tests: OncotypeDx® (Genomic Health Inc.)2,3, Prosigna™(NanoString Technologies, Inc.)4-6, Mammaprint® (Agendia Inc.)7,8 were performed. For the OncotypeDX-Like Recurrence Score (RS), RNA abundance was processed to fit the measurement range as described2,3, with classification into high, intermediate or low risk groups based the derived RS and modeled for DRFS. For the Prosigna-Like Risk of Recurrence Score (ROR), samples were processed as previously outlined9, then modelled against DRFS. For the MammaPrint-Like Risk Score, samples were processed by published methods8 and modelled for DRFS. Comparing OncotypeDx-Like with Prosigna-Like showed that 45% of cases were classified identically by both (3.3% low risk, 20.9% intermediate, 20.7% high). Of 3370 cases, 353 (10.5%) had scores differing by more than 1 classification (i.e. hi/low or low/high). Almost all (343) of these were cases classified high risk by OncotypeDX-Like RS/low risk by Prosigna-Like ROR (Table 1). Univariate Cox regression analysis, using low/low cases as a reference (relative risk of distant metastasis =1.0), suggested that cases called low risk by Prosigna-Like ROR/High risk by OncotypeDx-Like RS did not perform differently from cases called low risk by both tests (Table 2). However, all cases called intermediate by one test and high risk by another appeared to be high risk (Table 2). Comparisons between Prosigna-Like ROR and MammaPrint-Like scores showed similar concordance between low/low and high/high (52.5% of cases with concordant results). In Prosigna-Like ROR intermediate risk cases, MammaPrint-Like results divided cases between low and high risk, as predicted. Comparisons between these tests is challenging, and evidence on their discordance in risk stratification presents further dilemmas. Preliminary analysis of TEAM suggests a complex inter-relationship between test results in the same patient cohorts requiring careful evaluation. Table 1OncotypeDX-Like RSLowInt.HighTotalLow1126163431071Prosigna-Like RORInt.1677046151486High10106697813Total289142616553370 Table 2OncotypeDX-Like RSLowInt.HighLowRef1.26 (0.57-2.79)1.13 (0.49-2.62)Prosigna-Like RORInt.1.2 (0.47-3.05)2.22 (1.03-4.78)4.27 (2.01-9.08)High6.10 (1.58-23.6)4.15 (1.79-9.59)4.92 (2.32-10.42) Citation Format: Bartlett JMS, Bayani J, Kornaga E, Piper T, Mallon E, Yao CQ, Boutros PC, Hasenburg A, Kieback DG, Markopoulos C, Dirix L, Seynaeve C, Can de Velde CJH, Rea DW. Comparative survival analysis of multiparametric tests in the TEAM pathology study: What to do when molecular tests disagree? [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 P1-06-02.

Abstract P6-09-31: Study of oncotype DX® recurrent score in bilateral synchronous primary invasive breast cancer

Abstract Background: The 21-gene Oncotype Dx® Recurrence Score (RS) is routinely used to assess the risk of distant recurrence and benefit for adding chemotherapy in the treatment of ER positive HER2 negative early stage breast cancer. Among patients diagnosed with bilateral primary breast cancer there is limited information on the utilization of RS for each primary cancer. In this study, we evaluate the concordance of RS in bilateral breast cancer, and the value of testing both primary cancers in patients diagnosed with synchronous bilateral breast cancer Materials & Methods: This is an IRB approved retrospective study. From 2007 to present, we identified 158 patients with synchronous (within 6 months) bilateral primary breast cancer in our Institutional databases. In this dataset, there were 36 patients who had early stage ER positive, and Her-2 negative bilateral invasive cancer, and for whom the 21-gene Oncotype Dx® RS test was ordered. We excluded patients with bilateral invasive cancer who did not have Oncotype Dx® RS test performed (n=20), patients with bilateral in-situ cancers (n=15), patients with unilateral invasive with contralateral in-situ cancer (n= 64), and patients with locally advanced stage of one or both primary invasive cancers (n=23). In this study, RS score was scored low risk < 18, intermediate 18-30, and high risk >31. The RS for bilateral primary cancers was noted as concordant if the 2 values were in the same risk category and discordant when 2 values represented different risk category. Results: Among the 36 patients, 19 patients had Oncotype Dx® RS tested for one primary cancer, and 17 patients had testing from bilateral primary cancers. Patients median age is 55 years (range: 44 years to 75 years), and invasive duct cell was the most common histology. The RS distribution of low risk, intermediate risk and high risk was 60 %, 30% and 10%, respectively. Further, evaluation of the 17 patients in whom the RS score from bilateral invasive breast cancers was obtained, we noted that the RS was concordant in 11 patients (64.7%), and discordant in 6 patients (35.3%). In 4/6 patients the discordance was between low and intermediate risk, and in 2/6 patients it was between low and high risk. Clinical variables including age, histology, receptor positivity, and grade were not predictive of the rate of RS concordance between the 2 primary cancers. Conclusion: The significant rate of discordance observed in our study suggests that the 21-gene RS for each invasive primary breast cancer should be routinely obtained in patients presenting with bilateral breast cancers. Albeit synchronous events, the individual risk assessment of each primary cancer would help guide risk-tailored personalized cancer treatment. Citation Format: Chadha J, Goel A, Wallach J, Shao T, Klein P, Malamud S. Study of oncotype DX® recurrent score in bilateral synchronous primary invasive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-31.

Abstract OT3-04-03: The impact of the 21 gene recurrence score (RS) on chemotherapy prescribing in estrogen receptor (ER) positive, lymph node positive early stage breast cancer in Ireland

Abstract BACKGROUND For Estrogen Receptor (ER) positive, early stage breast cancer, the 21 gene Recurrence Score (RS) has clinical use both as a prognostic tool and to predict chemotherapy benefit. The availability of this tool in Ireland has led to a reduction in the use of adjuvant chemotherapy for women with lymph node (LN) negative disease. However, the RS is not routinely funded for patients with LN positive (LN+) breast cancer in Ireland. In addition, there are limited international data on the use of this tool in the preoperative setting. In this prospective observational study, we are investigating whether access to the 21 gene RS leads to a reduction in the receipt of chemotherapy for patients with ER+, LN+ breast cancer, and to correlate the 21 gene RS with response to preoperative systemic therapy. TRIAL DESIGN This is a national, multi-site, prospective, observational study that will examine the impact of the 21 gene RS on chemotherapy recommendations in both the neoadjuvant and adjuvant setting. Prior to and following tumor testing with the 21 gene RS, Physicians will complete a questionnaire which details type and strength of systemic therapy recommendations. ELIGIBILITY Cohort 1 (postoperative) will include patients with ER+ tumors of any size with involvement of 1-3 lymph nodes (N1 including micrometastases). Cohort 2 (preoperative) will include patients with ER+, T2-T4 tumors with biopsy proven nodal metastases. Both cohorts will have ECOG PS 0 or 1 and be fit for consideration of chemotherapy as determined by the Investigator. SPECIFIC AIMS The primary endpoint is the percentage reduction in the number of patients for whom treating physicians recommend chemotherapy after testing with 21 gene RS. Secondary endpoints include the correlation between the 21 gene RS and residual cancer burden score, as well as pathological, clinical and radiological response rates. The economic impact of the 21 gene RS in ER+, LN+ will also be assessed. STATISTICAL METHODS The sample size is based on similar decision impact studies conducted in other countries. Physician recommendations for chemotherapy pre 21-gene RS and recommendations post 21-gene RS testing will be compared and percentage change estimated with 95% confidence intervals. For secondary endpoints, the Pearson correlation coefficient (rho) will be used to examine the strength of the correlation between the 21 gene RS category and response. A budget impact model will be used to estimate the cost reduction in adjuvant chemotherapy as a result of 21-gene RS testing. PRESENT ACCRUAL AND TARGET ACCRUAL Target accrual is 75 in each of the neoadjuvant and adjuvant cohorts to total 150 patients. Supported by Genomic Health. Citation Format: Keegan NM, Milewski M, Kelly CM, Murphy V, Chao C, Walsh J, Kennedy MJ, O'Connor M, Murphy C, O'Reilly S, Keane M, Duffy K, Hennessy B, Morris PG. The impact of the 21 gene recurrence score (RS) on chemotherapy prescribing in estrogen receptor (ER) positive, lymph node positive early stage breast cancer in Ireland [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-04-03.

Association Between Phosphorylated Histone H3 and Oncotype DX Recurrence Scores in Breast Cancer.

We investigate the association between phosphorylated histone H3 (PhH3) and Oncotype DX recurrence score (RS). All invasive breast carcinoma with RS results from our city between 2007 and 2010 (n=47) were reviewed. Whole-tumor sections were stained for PhH3. Mitotic and PhH3 counts were performed and clinical charts reviewed. PhH3 correlated well with RS (r=0.69, P<0.001). Other correlations were: PhH3 versus mitotic count (r=0.87, P<0.001), PhH3 versus mitotic score (r=0.71, P<0.001), PhH3 versus modified Bloom-Richardson-Elston (MBR) grade (r=0.65, P<0.001), RS versus mitotic count (r=0.62, P<0.001), RS versus mitotic score (r=0.44, P=0.002), and RS versus MBR grade (r=0.49, P=0.001). Significant correlation between PhH3 and RS remained after controlling for mitotic count (r=0.39, P=0.007), mitotic score (r=0.60, P<0.001), MBR grade (r=0.56, P<0.001), and all 3 (r=0.37, P=0.014) by partial correlation. Two patients died of metastasis at 12 and 38 months after diagnosis. One had intermediate RS, and 1 high RS; both were in the top-third of PhH3 count. All other patients are alive and recurrence free. Correlation between PhH3 and RS was statistically significant in our cohort, and remained significant after controlling for traditional measures of proliferation. Given that RS has an established strong relationship with prognosis and therapy responsiveness, PhH3 may thus also be an important prognostic/predictive marker in breast cancer.

21-Gene recurrence score decreases receipt of chemotherapy in ER+ early-stage breast cancer: an analysis of the NCDB 2010-2013.

The purpose of this study was to determine if receipt of chemotherapy was associated with utilization of the 21-gene recurrence score assay (RS assay) or with recurrence score (RS) in eligible patients. Using the National Cancer Data Base (NCDB), we identified female patients eligible for RS assay based on National Comprehensive Cancer Network (NCCN) guidelines: age 18–70, ER-positive and HER2-negative early-stage breast cancer diagnosed during 2010–2013. We excluded patients not meeting testing guidelines. Inclusion required result of RS in patients who underwent RS assay and status for receipt of chemotherapy. Multivariable logistic regression models and propensity matched analysis were used to determine associations between RS assay and RS with receipt of chemotherapy. Among 129,765 patients who were eligible, 74,778 underwent RS assay and had results available. Of these, 59.5 % (44,505) had low-risk, 32.0 % (23,920) had intermediate-risk, and 8.5 % (6353) had high-risk RS. Patients with intermediate- and high-risk RS were more likely to receive chemotherapy [OR 12.9 (CI 12.2–13.6), p <0.001 and OR 87.2 (CI 79.6–95.6), p <0.0001], respectively. In both low- and intermediate-risk groups, increasing RS score was significantly associated with increasing odds of receiving chemotherapy [OR 1.10 (CI 1.09–1.12), p <0.0001 and OR 1.26 (CI 1.25–1.27), p <0.0001, respectively, for each point increase in RS]. Receipt of chemotherapy was more likely in patients who did not undergo RS assay compared to those who did, OR 1.21 (CI 1.175–1.249) p <0.0001. The utilization of RS assay and the RS were both strongly associated with chemotherapy receipt. Patients eligible for chemotherapy, based on NCCN criteria, were more likely to receive chemotherapy if they did not undergo RS assay or they had a high RS.

Retrospective analysis of molecular scores for the prediction of distant recurrence according to baseline risk factors.

Clinical variables and several gene signature profiles have been investigated for the prediction of (distant) recurrence in several trials. These molecular markers are significantly correlated with overall and late distant recurrences. Here, we retrospectively explore whether age and body mass index (BMI) affect the prediction of these molecular scores for distant recurrence in postmenopausal women with hormone receptor-positive breast cancer in the transATAC trial. 940 postmenopausal women for whom the Clinical Treatment Score (CTS), immunohistochemical markers (IHC4), Oncotype Recurrence Score (RS), and the Prosigna Risk of Recurrence Score (ROR) were available were included in this retrospective analysis. Conventional BMI groups were used (N = 865), and age was split into equal tertiles (N = 940). Cox proportional hazard models were used to determine the effect of a molecular score for the prediction of distant recurrence according to BMI and age groups. In both the univariate and bivariate analyses, the effect size of the IHC4 and RS was strongest in women aged 59.8 years or younger. Trends tests for age were significant for the IHC4 and RS, but not for the CTS and ROR, for which most prognostic information was added in women aged 60 years or older. The CTS and ROR scores added significant prognostic information in all three BMI groups. In both the univariate and bivariate analyses, the IHC4 provided the most prognostic information in women with a BMI lower than 25 kg/m2, whereas the RS did not add prognostic information for distant recurrence in women with a BMI of 30 kg/m2 or above. Molecular scores are increasingly used in women with breast cancer to assess recurrence risk. We have shown that the effect size of the molecular scores is significantly different across age groups, but not across BMI groups. The results from this retrospective analysis may be incorporated in the identification of women who may benefit most from the use of these molecular scores, but our findings need further evaluation before these scores can be used in clinical decision making.

Abstract P5-08-09: Differential patient stratification by the breast cancer index HoxB13/IL17BR ratio vs recurrence score (RS) plus quantitative ER expression in hormone receptor positive, node negative breast cancer

Abstract Background: Second generation genomic biomarkers for patients with early stage breast cancer are based on integration of proliferative and estrogen signaling-related gene expression, which has led to data applicable in the extended (post-5 year) endocrine therapy setting. The Breast Cancer Index (BCI) assay interrogates these two signaling pathways, significantly stratified patients into high (13.4%) or low (3.5%) risk of late (5-10y) distant recurrence in TransATAC , and includes a gene expression signature (HoxB13/IL17BR, H/I) that predicted benefit from extended endocrine therapy in MA.17. The 21-gene assay has recently been investigated in combination with quantitative estrogen receptor (qER) expression, wherein a subset of approximately 20% of patients with a high recurrence score (RS) and qER above 9.1 had a higher prognostic risk for late distant recurrence (12.6%) than those with Low RS (4.7%) or intermediate RS (4.1%) (Wolmark, ASCO 2014). The objective of this study was to compare patient stratification with H/I and RS+qER. Methods: Consecutive cases submitted for BCI clinical testing from lymph node-negative breast cancer patients with available RS scores and qER &amp;gt;9.1 abstracted from pathology reports (N=115) were analyzed. Cohen's kappa statistic was used to test agreement between H/I and RS+qER for patient stratification. Results: No statistically significant agreement was observed between H/I stratification and RS+qER prognostic risk stratification with respect to identifying patients for extended endocrine therapy (Cohen's kappa = -0.002, p = 0.51). H/I identified 36 cases (34%) as High likelihood to benefit from extended endocrine therapy compared to 3 cases (3%) classified as by RS+qER as having high risk of late recurrence (Table). Of the 69 cases (66%) classified as RS+qER Low risk, 19 were identified as High likelihood to benefit from extended endocrine therapy by H/I. Table Low H/I PredictiveHigh H/I PredictiveTotalRS+qER Low Risk50 (48%)19 (18%)69 (66%)RS+qER Inter Risk17 (16%)16 (15%)33 (31%)RS+qER High Risk2 (2%)1 (1%)3 (3%)Total69 (66%)36 (34%) Conclusions: This retrospective analysis of clinical cases shows that H/I and RS+qER identify distinct subsets of patients, and highlights that the underlying biology of risk stratification differs from that of endocrine responsiveness. Comparatively, findings indicate that the H/I identifies additional patients that may be considered for extended endocrine therapy. Citation Format: Naughton MJ, Schroeder BE, Operana TN, Zhang Y, Schnabel CA. Differential patient stratification by the breast cancer index HoxB13/IL17BR ratio vs recurrence score (RS) plus quantitative ER expression in hormone receptor positive, node negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-09.

Abstract OT2-01-01: Endocrine therapy alone as primary treatment for elderly patients with clinical stage I to III estrogen receptor positive breast cancer with low recurrence score

Abstract Background: Approximately 20% of breast cancers are diagnosed in women 75 years of age or older. Elderly patients with breast cancer are at a higher risk for over- or under-treatment. In general, older patients are more likely to die from comorbidities than from their breast cancer. The 21-gene Recurrence Score (RS) predicts 10-year distant recurrence rate in the adjuvant setting in women with early stage ER+ breast cancer. In elderly patients, a large percentage of the cancers diagnosed are ER+. It is likely that a subpopulation of elderly women with good prognosis ER+ tumors can be identified who may benefit from endocrine therapy alone, without surgery, to treat their cancer without compromising clinical outcome. We hypothesize that endocrine therapy alone will provide adequate local and systemic control of breast cancer in the subpopulation of women 75 or older with ER+ breast cancer and low RS. Trial Design: This is a single arm phase II trial in pts with newly diagnosed early stage ER+ breast cancer, age 75 or greater. RS will be obtained on core biopsies collected at the time of diagnosis. Patients whose scores are &amp;lt; 18 will be enrolled into the trial and receive endocrine therapy only. Patients whose scores are ≥ 18 will receive standard of care (SOC) treatment. Tumor assessment will occur every 6 months. Patient can continue on endocrine therapy for up to 10 years. If there is progression of disease, then an alternative endocrine agent may be prescribed or the patient can opt for SOC treatment. Objectives: Primary: To determine the rate of loco-regional progression in women with early-stage ER+ breast cancer, 75 years or older with low RS who are treated with endocrine therapy alone. Secondary: To determine the breast cancer-specific survival and overall survival of women with early-stage ER+ breast cancer who are 75 years or older treated with endocrine therapy alone. To correlate response to treatment with RS. Eligibility: Newly diagnosed invasive breast cancer defined as cT1 or T2, N0-1, M0, age 75 years of age or older and ECOG performance status ≤ 2. Disease must be ER+ (Allred score ≥ 5) and HER2- and measurable defined as lesions that can be accurately measured in at least one dimension by ultrasound or mammogram. Statistical Methods: A Kaplan-Meier model will be used to estimate the 5-year local or systemic progression rate with a Brookmeyer-Crowley confidence interval. If the true 5-year progression rate is 10%, a sample size of 50 will provide power = .90 at a one-sided .05 significance level to demonstrate that the rate is less than 25.5%. A point estimate of the cumulative incidence of local progression at 5 years will be calculated using a Kaplan-Meier model or, if covariate adjustment is desired, a Cox proportional hazards model. The upper bound of a 95% confidence interval will be used to determine whether the rate may plausibly fall above 25.5%. Accrual: Target 50 patients with an RS score &amp;lt; 18 will be enrolled. Anticipated opening is July 2015. Citation Format: Aft R, Trinkaus K, Ma C. Endocrine therapy alone as primary treatment for elderly patients with clinical stage I to III estrogen receptor positive breast cancer with low recurrence score. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-01.

Abstract P3-09-08: Patterns of oncotype DX testing and adjuvant chemotherapy use in a tertiary care centre

Abstract Introduction: The Oncotype DX Recurrence Score (RS) is a 21-gene signature, retrospectively validated prognostic marker and predictor of response to adjuvant chemotherapy (ACT) in estrogen receptor (ER) positive breast cancer (BC). In 2010 RS became publicly funded in Ontario for patients with estrogen-positive, HER2 negative and node negative breast cancer. The aim of our study was to explore the pattern of RS testing and use of adjuvant chemotherapy at the Cancer Centre of Southeastern Ontario (CCSEO) since the introduction of RS testing. Additionally we compared the RS tested patients with a matched cohort treated for early BC prior to 2010. Methods: A retrospective paper and electronic chart review was undertaken of patients with early BC (stage 1 and 2) with the following pathologic features: T1-T2, N0/N1mic, ER positive and Her-2neu negative. We collected patient demographics, co-morbidities, surgical data, tumour characteristics, ACT use, Adjuvant! mortality estimates and breast cancer outcomes. Cohort A included patients who underwent RS testing (2010 – 2013) and cohort B patients treated prior to 2010. The two cohorts were compared using chi-square tests for categorical data, and independent samples t-tests and the Mann-Whitney U for continuous data. Results: 160 patients were included in our analysis of which 83 underwent RS testing. Compared to cohort B, cohort A was older (median age 60 versus (vs) 48, p&amp;lt;0.001); had higher postmenopausal status (77 vs 34%, p&amp;lt;0.001); higher rates of breast conserving surgery (88 vs 74%, p=0.024) and sentinel node biopsy (94 vs 26%, p&amp;lt;0.001). Cohort A also had larger tumors (T2 23 vs 5%, p=0.010), higher stage (stage 2 - 24 vs 6%, p=0.002) and higher Adjuvant! mortality estimates above 15% (18 vs 8%, p=0.054). Despite this the use of ACT decreased significantly (20 vs 98%, p&amp;lt;0.001). The majority of patients received adjuvant endocrine treatment (&amp;gt; 90% in both cohorts). Of the 83 patients in cohort A 55 (66%) had low risk RS (0-17), 18 (22%) intermediate risk (18-30) and 10 (12%) high risk RS. ACT was received by 2 of 55 patients with low RS; 6 of 18 patients with intermediate RS and 9 of 10 with high RS. Median follow-up was only 16 months in cohort A vs 74 months in cohort B. 92% of patients in cohort B remain recurrence free. To date only 2 patients in cohort A have recurred, both of which had high RS scores and received ACT. Conclusion: In patients with early BC undergoing RS testing at CCSEO we observed a higher proportion of low risk RS as compared to the literature. Additionally, despite larger tumors, higher stage disease and higher Adjuvant! mortality estimates above 15%, the proportion of patients undergoing ACT has significantly decreased since the introduction of RS testing. So far this has not translated into a negative long-term disease outcome although longer follow-up is needed for real-world validation. Citation Format: Gautam Sudan, Mihaela Mates, Hopman Wilma. Patterns of oncotype DX testing and adjuvant chemotherapy use in a tertiary care centre [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-08.