10-year Distant Recurrence Research Articles

Abstract P6-10-14: A new model to predict 10-year distant recurrence risk for operable endocrine-responsive breast cancer population

Abstract Background Few currently available biomarker panels can predict the risk of long-term distant recurrence (DR) in endocrine-responsive breast cancer (ERBC) patients based on lymph-node (LN) status. A new model, DGM-CM6 (Distant Genetic Model-Clinical variable Model 6), has been developed for the prediction of DR risk in our previous studies. To interrogate the prognostic value of our DGM-CM6 model for ERBC patients stratified by LN status, we retrospectively studied 752 operable breast cancer patients treated in a cancer center from 2005 to 2014. Patients and Methods Of 752 tumors, a total of 499 ERBC patients was identified from both IHC method (n=490) and PAM50 method (n=404). ERBC patients were classified by high and low-risk groups using the cutoff (<33 or 33) of DGM-CM6 score. Wilcoxon rank sum test was used for the association study between DGM-CM6 score and ERBC subtype status. Kaplan-Meyer survival curves were used to compare the prognostic difference of DRFS and OS in different ERBC risk groups stratified by LN negative (LN-) and positive (LN+) status. Multivariate Cox proportional-hazards regression was used to determine the hazard ratio (HR) of risk groups adjusted by clinical confounders such as treatment and tumor stages. Results Significant differences were observed between DGM-CM6 low- and high-risk patients with 10-year DRFS in LN- (ERBC identified by IHC: P = 0.011; by PAM50: P< 0.0001) and LN+ (ERBC identified by IHC: P = 0.015; by PAM50: P = 0.019) by log-rank test. Compared to risk prediction by intrinsic subtype, DGM-CM6 performed better in LN- patients and equally good in LN+ patients. Further multivariate analysis confirmed the independent strength of DGM-CM6 model in the prediction of high- vs. low- risk groups in DRFS (P < 0.0001, HR: 6.76; 95% CI, 1.8-25.42) and OS (P = 0.01, HR: 6.06; 95% CI:1.55-23.47), respectively. Conclusion DGM-CM6 model can be used to predict low- and high-risk of 10-year distant recurrence in both LN- and LN+ ERBC patients. This model needs a large scale of clinical trials to validate its clinical utility. Table 1. Multivariate cox regression analyses for the prognosis of predicted risk groups after adjusted for other clinical variables in the distant recurrence (DR, p=0.005) and overall survival (OS, p=0.01) respectively. Results shows that there is no interaction between chemotherapy and risk groups (DR: p=0.163; OS: p=0.195). Abbreviations: DR, distant recurrence; OS: overall survival.GroupsDROSHR [95% CI]pvHR [95% CI]pvRisk: high vs.low6.76 [1.8;25.42]0.005 ***6.06 [1.55;23.74]0.01 ***Age: <50 vs. >50yrs0.86 [0.51;1.44]0.5630.68 [0.38;1.19]0.175LN: Pos. vs. Neg.1.64 [0.88;3.05]0.1161.6 [0.79;3.22]0.189Stage: II vs. I1.35 [0.76;2.4]0.31.45 [0.76;2.77]0.264Stage: III vs. I2.08 [0.59;7.3]0.2531.59 [0.34;7.46]0.557Grade: 2 vs. 12.14 [0.77;5.97]0.1461.81 [0.63;5.25]0.272Grade: 3 vs. 11.2 [0.4;3.62]0.7481.21 [0.38;3.86]0.752PAM50: Normal vs. LumA0.6 [0.13;2.64]0.4960.7 [0.16;3.16]0.645PAM50: LumB vs. LumA1.58 [0.84;2.98]0.1591.29 [0.65;2.59]0.469PAM50: Her2 vs. LumA0.81 [0.25;2.68]0.7311.01 [0.29;3.47]0.986RT: Yes vs. No0.88 [0.47;1.66]0.7010.71 [0.36;1.41]0.326CT: Yes vs.No0.36 [0.11;1.12]0.0770.3 [0.09;1]0.05 *Interaction: CT vs. Risk0.36 [0.09;1.51]0.1630.36 [0.08;1.68]0.195 Citation Format: Lei Lei, Skye Hung-Chun Cheng, Xiao-Jia Wang, Yin-Yuan Mo, Yun-Yun Zhou. A new model to predict 10-year distant recurrence risk for operable endocrine-responsive breast cancer population [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 P6-10-14.

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.

Population-based Study of Prosigna-PAM50 and Outcome Among Postmenopausal Women With Estrogen Receptor-positive and HER2-negative Operable Invasive Lobular or Ductal Breast Cancer

PurposeThe Prosigna-PAM50 risk of recurrence (ROR) score has documented clinical utility for the prediction of 10-year distant recurrence (DR). The present study investigated the value of Prosigna-PAM50 for predicting 10-year DR and overall survival after 5 years of endocrine treatment for postmenopausal patients with invasive lobular carcinoma. Patients and MethodsUsing the Danish Breast Cancer Group database, we identified patients with a diagnosis from 2000 to 2003 of estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal (n = 1570) or lobular (n = 341) cancer > 20 mm or 1 to 3 positive lymph nodes and applied multivariate Cox models. ResultsThe median follow-up for DR was 9.3 years and for overall survival 15.2 years. Of the 341 lobular and 1570 ductal cases, 140 (41%) and 349 (22%) were classified as low ROR, with a 10-year DR rate of 7.7% (95% confidence interval [CI], 3.7%-13.6%) and 3.5% (95% CI, 1.8%-6.2%), respectively. The 10-year DR rate for the intermediate ROR group for those with lobular cancer was 18% (95% CI, 10.1%-27.9%) compared with 9.7% (95% CI, 6.7%-13.4%) for those with ductal cancer. Luminal B tumors had a significantly worse outcome than luminal A tumors in both lobular (hazard ratio, 1.89; 95% CI, 1.03%-3.45%; P = .04) and ductal (hazard ratio, 3.18; 95% CI, 2.29%-4.43%; P < .0001) cancer. ConclusionProsigna PAM-50 provides significant prognostic information beyond the clinicopathologic factors in patients with invasive lobular breast cancer. Those with lobular cancer had worse 10-year DR rates compared with those with ductal cancer in the same ROR category. Our results could have an effect on the treatment decisions regarding the addition of chemotherapy for those in the intermediate ROR group.

Ten-year clinical outcomes in N0 ER+ breast cancer patients with Recurrence Score-guided therapy

The 21-gene Recurrence Score (RS) assay is a validated prognosticator/predictor of chemotherapy (CT) benefit in early-stage estrogen receptor (ER)-positive breast cancer (BC). Long-term data from real-life clinical practice where treatment was guided by the RS result are lacking. We performed exploratory analysis of the Clalit Health Services (CHS) registry, which included all CHS patients with node-negative ER+ HER2-negative BC who underwent RS testing between 1/2006 and 12/2009 to determine 10-year Kaplan–Meier estimates for distant recurrence/BC-specific mortality (BCSM) in this cohort. The analysis included 1365 patients. Distribution of RS results: RS 0–10, 17.8%; RS 11–25, 62.5%; RS 26–100, 19.7%. Corresponding CT use: 0, 9.4, and 69.9%. Ten-year distant recurrence rates in patients with RS 0–10, 11–25, and 26–100: 2.6% (95% confidence interval [CI], 1.1–6.2%), 6.1% (95% CI, 4.4–8.6%), and 13.1% (95% CI, 9.4–18.3%), respectively (P < 0.001); corresponding BCSM rates: 0.7% (95% CI 0.1–5.1%), 2.2% (95% CI, 1.3–3.7%), and 9.5% (95% CI, 6.0–14.9%) (P < 0.001). When the analysis included patients treated with endocrine therapy alone (95.5/87.5% of patients with RS 0–10/11–25), 10-year distant recurrence and BCSM rates for RS 0–10 patients were 2.7% (95% CI, 1.1–6.5%) and 0.8% (95% CI, 0.1–5.3%), respectively, and for RS 11–25 patients, 5.7% (95% CI, 3.9–8.3%) and 2.0% (95% CI, 1.1–3.7%), respectively. For RS 11–25 patients, no statistically significant differences were observed in 10-year distant recurrence/BCSM rates between CT-treated and untreated patients; however, this should be interpreted cautiously since the number of events was low and patients were not randomized. In conclusion, in node-negative ER+ HER2-negative BC patients, where treatment decisions in real-life clinical practice incorporated the RS, patients with RS 0–25 (~80% of patients, <10% CT use) had excellent outcomes at 10 years. Patients with RS 26–100 had high distant recurrence risk despite CT use and are candidates for new treatment approaches.

Is it possible to predict the prognostic values of Oncotype Dx using the results of web-based mathematical prognostic value models?

e12058 Background: The goal of the study was to determine whether the prognostic values for ER+ HER2- breast cancer can be calculated based on a test of gene expression profiles in tumors using Oncotype Dx or by entering clinicopathological factors into a web-based model. We evaluated the correlation between these results to shed light on whether the results from web-based models could serve as representative indices for Oncotype Dx. Patients: Two hundred two primary breast cancer patients whose prognostic value was evaluated using Oncotype Dx between May 2010 and October 2018 in St. Marianna University Hospital. Methods: The patients’ clinicopathological factors were extracted from their medical records. Then, the 5- and 10-year breast cancer-specific mortality rates were calculated using PREDICT (www.predict.nhs.uk/tool), while the 5–10 year distant recurrence rate was calculated using CTS5 (www.cts5-calculator.com/). The correlations with the Oncotype Dx prognostic values were evaluated by calculating the Spearman’s rank correlation coefficient, and JMP.ver13.0 (SAS Institute Inc., Cary, NC, USA) was employed for the analysis. Results: The patients’ median age was 49. There were 78 lymph node(LN)-negative patients and 124 LN-positive patients. For the disease stages, 51 patients were stage I, 99 patients were stage IIA, 41 patients were stage IIB, and 11 patients were stage III or above. All patients of the correlation between the Oncotype Dx recurrence score (RS) and the 10-year breast cancer-specific mortality rate was r = 0.1616. The correlation of LN-Negative patients of the 10-year distant recurrence rate between Oncotype Dx and CTS5 was r = 0.1768. The correlation of LN-Positive Cases of the 5-year distant recurrence rate between Oncotype Dx and CTS5 was r = 0.3374. The correlation of these cohort between the 5-year mortality rate from Oncotype Dx and PREDICT was r = 0.4298. Conclusions: There was no correlation between the Oncotype Dx RS and prognostic values calculated from web-based models, and there was also no correlation for prognostic values of lymph node-negative cases. However, there was a correlation for prognostic values of lymph node-positive cases, but the correlation was too weak to use the results from web-based models as representative indices for Oncotype Dx.

Breast Cancer Index and risk stratification in luminal subtypes: A trans-ATAC study.

534 Background: The Breast Cancer Index (BCI) is a gene-expression based signature that provides prognostic information for overall (0-10 years) and late (5-10 years) distant recurrence (DR) and prediction of extended endocrine benefit in hormone receptor positive (HR+) early stage breast cancer. The current analysis aims to further characterize, correlate and compare the prognostic performance of BCI in luminal subtypes based on immunohistochemical classification. Methods: 670 postmenopausal women with HR+, LN- disease from the TransATAC cohort were included in this analysis. Luminal A-like tumors (LumA) were identified as those with ER+ and/or PR+ and HER2 -, and Ki67 &lt; 20% by IHC. All other tumors were classified as Luminal B-like (LumB) for this analysis. Primary endpoint was DR. Cox regression models were used to examine BCI prognostic performance according to luminal subtype, adjusting for the clinicopathological model Clinical Treatment Score (CTS). Results: 452 (67.5%) patients were classified as LumA and 218 (32.5%) as LumB. BCI was highly prognostic in LumA cancers (adjusted HR = 1.57 (1.23-1.96), P &lt; 0.001, ΔLR-χ2= 14.09), but not in LumB tumors (adjusted HR = 1.20 (0.94-1.52, P = 0.14, ΔLR-χ2= 2.23). In LumA, 10-year DR risks in BCI intermediate and high risk groups were very similar (25.6% (16.4-38.6) and 25.3% (13.5-44.3), respectively) and significantly different from BCI low (3.9% (2.1-7.0); HR = 7.47 (3.50-15.96) and HR = 8.13 (3.27-20.23), respectively). In LumB, 10-year DR risks in BCI low and BCI intermediate risk groups (13.8% (6.8-26.9) and 14.6% (8.3-24.9), respectively) were very similar and significantly lower than for the BCI high (29.1% (20.0-41.1)). Lum subtyping was only prognostic in the BCI low risk group (LumA vs. LumB: HR = 4.27 (1.65-11.02)) but not in the other two BCI risk groups. Conclusions: BCI provided significant prognostic information in Lum A subtype. These results show that BCI intermediate and high risk had similar risk of DR in LumA tumors, while shared similarly low risk of DR as BCI-low in LumB tumors. Further evaluation is needed to elucidate the distinct mechanisms underlying each classification system.

Clinical validity of CTS5 for estimating risk of late recurrence in unselected, non-trial patients with early ER+ breast cancer.

514 Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological data to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with estrogen receptor positive (ER+) breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Methods: The validity of CTS5 was tested in a retrospective cohort of unselected, non-trial patients diagnosed with early ER+ breast cancer at the Royal Marsden Hospital from 2000-2007 who were alive and distant recurrence-free at 5 years. The primary endpoint was time to late DR (5-10 years). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated 10-year DR risks (%). Results: A total of 2428 women were included with a median follow-up of 9.34 years from diagnosis. The CTS5 was significantly prognostic for late DR in post- and premenopausal women (Table). Risk stratification by CTS5 of the postmenopausal cohort was comparable with the development cohort. 42.1% of postmenopausal women were categorised into the low risk group with a late DR risk of 4.9% and these women had significantly lower risk of late DR compared to those in the intermediate or high-risk groups (Table). Amongst the premenopausal cohort, 41% were categorised as low risk with a late DR risk of 4.9%. The prognostic effect of CTS5 was seen for chemotherapy treated (HR=2.26, 95% CI (1.68-3.03)) and untreated patients (HR=1.93, 95% (1.32-2.82)). Conclusions: CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected, non-trial patients that included premenopausal women. The low risk cohort identified by the CTS5 represents a group of women whose risk of late DR is so low as to not warrant extended endocrine therapy to ten years. [Table: see text]

Abstract P4-08-05: Prediction of distant recurrence using EndoPredict among women with ER-positive, HER2-negative breast cancer with a maximum follow-up of 16 years

Abstract Background: EndoPredict has been previously validated as a prognostic test in women with ER-positive, HER2-negative disease who received endocrine therapy only as part of the ABCSG6 and -8 trials. Here, we further evaluate the prognostic value of EndoPredict in this cohort with longer-term follow-up and compare 10-year distant recurrence (DR) and 5-15 years late recurrence according to nodal status. Methods: This analysis included 1702 patients with ER-positive, HER2-negative disease who received endocrine therapy only. Prognostic value of EPclin score and EPclin risk category (high, low) on the risk of distant recurrence adjusted for patient and disease characteristics was evaluated using multivariable Cox proportional hazard models. Kaplan-Meier estimators were used to estimate DR according EPclin class and were compared using log rank test. Analyses were performed for the overall cohort, by nodal status, and for patients who were distant recurrence free at year 5 (late recurrence). Results: The median follow-up was 9.6 years (range 0-16.6), an increase of 4.2 years over previous reports. Reanalysis with longer follow-up confirms that EPclin is a significant predictor of DR after adjusting for clinical factors, regardless of nodal status (Table 1). Overall, 62.6% of patients had low risk EPclin scores and 10-year DR was significantly improved relative to those with high risk scores (p&amp;lt;0.0001; Table 2). When nodal status was considered, 77.8% of node negative tumors and 34.9% of node positive (1-3 PLN) tumors had low risk EPclin scores. Regardless of nodal status, DR was significantly improved for those with low versus high risk EPclin scores (Table 2). Similar results were observed for the patients who were DR free at year 5 (5-15 year follow-up) (Table 2). Conclusion: This reanalysis of previous EndoPredict data with a longer follow-up confirms that EPclin can identify a large group of patients at low risk of distant recurrence after 10 years who might be sufficiently treated with 5 years adjuvant endocrine therapy only, independent of nodal status. Replication of these results for the late distant recurrence between years 5-15 also shows that EPclin scores may also be informative in selecting patients who may safely forgo extended endocrine therapy. Table 1.Multivariate analysis 0-15 year DR5-15 year DRCohortHR*p-valueHR*p-valueAll patients2.55&amp;lt;0.00012.56&amp;lt;0.0001Node negative1.680.00352.010.00881-3 positive nodes2.68&amp;lt;0.00013.430.0004*Hazard Ratio (HR) per unit score after adjusting for age, tumor grade, Ki67, ER, PR, and treatment Table 2.DR according to EPclin score Low risk EPclinHigh risk EPclin CohortHR*%0-10 year DR (95% CI)%0-10 year DR (95% CI)Log-rank p-valueAll patients N=17024.7762.60.96 (0.94, 0.97)37.40.80 (0.77, 0.84)&amp;lt;0.0001Node negative N=11653.4777.80.96 (0.94, 0.97)22.20.87 (0.83, 0.92)&amp;lt;0.00011-3 positive nodes N=4533.6534.90.96 (0.92, 0.99)65.10.81 (0.76, 0.87)0.0003CohortHR*%5-15 year DR (95% CI)%5-15 year DR (95% CI)Log-rank p-valueAll patients N=13864.5264.70.96 (0.93, 0.98)35.30.84 (0.79, 0.90)&amp;lt;0.0001Node negative N=9753.7678.30.97 (0.95, 0.99)21.70.85 (0.75, 0.96)&amp;lt;0.00011-3 positive nodes N=3623.0036.50.87 (0.72, 1.00)63.50.84 (0.77, 0.92)0.0337*HR for EPclin high risk versus low risk Citation Format: Filipits M, Dubsky P, Rudas M, Greil R, Balic M, Fitzal F, Bago-Horvath Z, Singer C, Hlauschek D, Kronenwett R, Bernhisel R, Lancaster J, Gnant M. Prediction of distant recurrence using EndoPredict among women with ER-positive, HER2-negative breast cancer with a maximum follow-up of 16 years [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 P4-08-05.

Abstract P2-08-04: Prediction of distant recurrence by EndoPredict in patients with estrogen receptor-positive, HER2-negative breast cancer who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET)

Abstract Background: EndoPredict (EPclin) is a validated prognostic test combining expression of 12 cancer-related genes for breast cancer patients with estrogen receptor (ER) positive, HER2-negative disease who received 5 years of endocrine therapy (Buus et al., 2017; Dubsky et al. 2012) and for women who received chemotherapy (Martin et al., 2014). Here, we determine the EPclin and 10-year distant recurrence free interval (DRFI) rates for patients who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) using data from five large clinical trials. Methods: A total of 3746 women with ER-positive, HER2-negative disease were included in this analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET+C (GEICAM 2003-02/9906). EPclin incorporates tumor size and nodal status and accounts for different EPClin scores between ET+C and ET alone cohorts. The primary objective was to evaluate the 10-year DRFI rates as a continuous function of EPclin separately for patients in ET+C and ET. Secondary objectives included assessing the difference in the prognostic ability of EPclin between ET+C and ET overall (years 0-10) and for specific follow-up periods (years 0-5 and years 5-10). The primary endpoint was DRFI and the secondary endpoint was breast cancer free interval (BCFI). Cox proportional hazard models were used to estimate 10-year DRFI rates and to assess the prognostic information provided by EPclin. Results: All of the women on ET alone and 49% of those on ET+C were postmenopausal. Women who received ET+C had more node positive disease, more poorly differentiated tumours, and higher EPclin scores than those who received ET alone. Women who received ET+C had significantly smaller increases in 10-year DRFI rates with increasing EPclin score than those receiving ET alone (Table). EPclin was highly prognostic for DRFI in all women who received ET alone (HR=2.79 (2.49-3.13), P&amp;lt;0.0001) as well as in those who received ET+C (HR=2.27 (1.99-2.59), P&amp;lt;0.0001), both in the overall cohort and in postmenopausal women only (ET+C: HR=2.64 (2.07-3.37), P&amp;lt;0.0001). We observed a significant interaction between EPclin and treatment for DRFI at 10 years (Pinteraction=0.022). EPclin was highly prognostic in ET alone and ET+C in years 0-5 and in particular in years 5-10. Similar results were observed when BCFI was the endpoint. Conclusion: In our results from a non-randomized analysis, we observed significantly smaller increases in 10-year DRFI rates with increasing EPclin scores for women who received ET+C compared to those who received ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease. 10-year DRFI risks (%) (95% CI) according to EPclin score for patients who received ET+C versus ET alone. ET+CETEPclin10-year DR risk (%)10-year DR risk (%)11.1% (0.5-1.7)1.0% (0.6-1.4)22.5% (1.5-3.5)2.8% (2.1-3.5)35.7% (4.1-7.2)7.6% (6.4-8.8)412.4% (10.1-14.6)19.8% (17.6-22.0)525.8% (22.0-29.5)46.1% (40.2-51.4) Citation Format: Sestak I, Martin M, Dubsky P, Rojo F, Cuzick J, Filipits M, Ruiz A, Buus R, Hlauschek D, Rodriguez-Lescure A, Dowsett M, Gnant M. Prediction of distant recurrence by EndoPredict in patients with estrogen receptor-positive, HER2-negative breast cancer who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) [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 P2-08-04.

Abstract P3-08-01: Prognostic performance of EndoPredict in invasive lobular carcinoma

Abstract Background: Invasive lobular carcinomas (ILC) account for around 15% of all oestrogen receptor (ER) positive invasive breast cancers. The EndoPredict assay (EPclin) is a multigene classifier to predict the likelihood of distant recurrence in ER-positive, HER2-negative breast cancer patients treated with adjuvant endocrine therapy and has been validated in several retrospective translational studies. However, these validation studies did not include an analysis of the histological subtypes. Here, we investigate the role of EPclin for the prediction of distant recurrence in women with ILC and compare the prognostication to those with invasive ductal carcinoma (IDC) in TransATAC. Methods: Data on EPclin and histological type of tumour were available for 928 postmenopausal women with ER-positive, HER2-negative disease treated with 5 years of tamoxifen or anastrozole. The primary endpoint was distant recurrence and the primary objective was to assess the prognostic value of EPclin for the prediction of distant recurrence in women with invasive lobular carcinoma. Kaplan–Meier and Cox regression analyses were used to determine distant recurrence risk for 0-10 years of follow-up. Likelihood ratio tests were used to assess the prognostic information provided by EPclin. Hazard Ratios (HR) are for a change in 1 Standard Deviation. Results: 141 (15.2%) had ILC, 710 (76.5%) IDC, and the remaining 77 (8.3%) were of different histological type. EPclin provided highly significant prognostic value for distant recurrence in women with ILC (HR=3.33 (2.33-4.77), P&amp;lt;0.001; LR-χ2=38.4). For those with IDC, EPclin was highly prognostic for distant recurrence over 10 years of follow-up (HR=2.41 (2.04-2.84), P&amp;lt;0.001; LR-χ2=95.5). EPclin was more prognostic in IDC than ILC, and a significant interaction between EPclin and tumour type (ILC/IDC) was observed (P-interaction=0.038). 89 (63.1%) women with ILC were categorised into the low EPclin risk group and 52 (36.9%) into the high risk group. A highly significant separation between EPclin low and high risk groups was observed for ILC (10-year distant recurrence risk low: 6.2% (2.6-14.2) vs. high: 36.6% (24.2-52.1); HR=7.36 (2.71-20.01)). For women with IDC, 406 (57.2%) were categorised into the low risk group by EPclin and 304 (42.8%) were deemed high risk, with significant separation between risk groups (10-year distant recurrence risk low: 6.2% (4.1-9.3) vs. high: 28.5% (23.5-34.3); HR=5.59 (3.48-8.98)). We did not observe any differential efficacy of treatment between histological subtype and EPclin risk group. Conclusions: This is the first analysis to focus on the role of EPclin for the prognostic assessment of women with ILC. Although numbers of women with ILC in TransATAC were small, EPclin provided highly significant prognostic information and risk stratification for this subgroup of women. 10-year distant recurrence risk in the EPclin low risk groups were similar between ILC and IDC, suggesting that chemotherapy is not indicated, irrespective of tumour type. Our results show that EPclin is informative in women with ILC. Citation Format: Sestak I, Kronenwett R, Denkert C, Cuzick J, Dowsett M. Prognostic performance of EndoPredict in invasive lobular carcinoma [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 P3-08-01.

PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer.

Purpose The PAM50-based Prosigna risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR). The value of Prosigna for predicting DR was examined in a comprehensive nationwide Danish cohort consisting of postmenopausal women with hormone receptor-positive early breast cancer treated with 5 years of endocrine therapy alone. Patients and Methods Using the population-based Danish Breast Cancer Cooperative Group database, follow-up data were collected on all patients diagnosed from 2000 through 2003 who, by nationwide guidelines, were treated with endocrine therapy for 5 years. Primary tumor blocks from 2,740 patients were tested with Prosigna and, after determination of human epidermal growth factor receptor 2 (HER2) status, data from 2,558 hormone receptor-positive/HER2-negative samples were analyzed, including 1,395 node-positive patients. Fine and Gray models were applied to determine the prognostic value of ROR for DR. Results Median follow-up for recurrence was 9.2 years. Twenty-six percent of the node-positive patients were classified as low ROR (n = 359) with a DR risk of 3.5% (95% confidence interval [CI], 1.9% to 6.1%) versus a DR risk of 22.1% (95% CI, 18.6% to 25.8%) at 10 years for patients classified as high ROR (n = 648). Node-negative patients classified as low and high ROR had a risk of DR of 5.0% (95% CI, 2.9% to 8.0%) and 17.8% (95% CI, 14.0% to 22.0%), respectively. Luminal B tumors (n = 947; DR risk, 18.4% [95% CI: 15.7% to 21.3%]) had a significantly worse outcome than luminal A tumors (n = 1,474,;DR risk, 7.6% [95% CI: 6.1% to 9.2%]; P < .001). Conclusion Prosigna ROR score improved the prediction of outcome in this nationwide Danish population. In a real-world setting, Prosigna can reliably identify node-negative patients and a significant proportion of patients with one to three positive nodes who can be spared treatment with adjuvant chemotherapy.

Racial Differences in 21-Gene Recurrence Scores Among Patients With Hormone Receptor-Positive, Node-Negative Breast Cancer.

Purpose The 21-gene recurrence score (RS) breast cancer assay is clinically used to quantify risk of 10-year distant recurrence by category (low, < 18; intermediate, 18 to 30; high, ≥ 31) for treatment management among women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative, lymph node-negative breast cancer. Although non-Hispanic black (NHB) women have worse prognosis compared with non-Hispanic white (NHW) women, the equivalency of 21-gene RS across racial groups remains unknown. Patients and Methods Using the Metropolitan Detroit Cancer Surveillance System, we identified women who were diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative, lymph node-negative invasive breast cancer between 2010 and 2014. Multinomial logistic regression was used to quantify racial differences in 21-gene RS category. Results We identified 2,216 women (1,824 NHW and 392 NHB) with invasive breast cancer who met clinical guidelines for and underwent 21-gene RS testing. The mean RS was significantly higher in NHBs compared with NHWs (19.3 v 17.0, respectively; P = .0003), where NHBs were more likely to present with high-risk tumors compared with NHWs (14.8% v 8.3%, respectively; P = .0004). These differences were limited to patients younger than 65 years at diagnosis, among whom NHBs had significantly higher RS compared with NHWs (20 to 49 years: 23.6 v 17.3, respectively; P < .001 and 50 to 64 years: 19.6 v 17.4, respectively; P = .023). NHBs remained more likely to have high-risk tumors compared with NHWs after adjusting for age, clinical stage, tumor grade, and histology (odds ratio [OR], 1.75; 95% CI, 1.18 to 2.59). Conclusion NHBs who met clinical criteria for 21-gene RS testing had tumors with higher estimated risks of distant recurrence compared with NHWs. Further study is needed to elucidate whether differences in recurrence are observed for these women, which would have clinical implications for 21-gene RS calibration and treatment recommendations in NHB patients.

The ability of PAM50 risk of recurrence score to predict 10-year distant recurrence in hormone receptor-positive postmenopausal women with special histological subtypes

Introduction: The Prosigna-PAM50 risk of recurrence (ROR) score has been validated in randomized clinical trials to predict 10-year distant recurrence (DR) in hormone receptor-positive breast cancer. Here, we examine the ability of Prosigna for predicting DR at 10 years in a subgroup of postmenopausal breast cancer patients with special histological subtypes.Methods: Using the population based Danish Breast Cancer Group database, follow-up data were collected on all patients diagnosed from 2000 to 2003 with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2) normal breast cancer who by nationwide guidelines were treated with 5 year of endocrine therapy (N = 2558). Among patients with 1 to 3 positive lymph nodes or a tumor size >20 mm, we identified 1570 with invasive ductal carcinoma (IDC) and 89 with special histological subtypes (apocrine, medullary, mucinous, papillary, secretory, tubular, neuroendocrine) who were tested with Prosigna. Fine and Gray models were applied to determine the prognostic value of the Prosigna-PAM50 ROR score for DR special subtypes as compared to IDC.Results: Median follow-up for DR was 9.2 year and for OS 15.2 year. The 10-year DR rate for the special subtypes was 9.2% (95% CI: 4.0% to 17.2%) as compared to 13.7% (95% CI: 11.9% to 15.7%) for IDC. The 10-year OS was 74.2% (95% CI: 63.7% to 82.0%) for the special subtypes and 75.4% (95% CI: 73.2% to 77.4%) for IDC. Prosigna showed a statistical significant association of the continuous ROR score with risk of DR for both IDC and the special subtypes (IDC: p < .0001; special subtypes: p = .01).Conclusion: In the present study, we demonstrated that Prosigna-PAM50 continuous ROR score added significant prognostic information for 10-year DR in postmenopausal patients with special subtypes (tumor size >20 mm or 1 to 3 positive lymph nodes) and ER-positive, HER2-normal early breast cancer.

Abstract P2-08-12: Integration of tumor size and grade with the breast cancer index (BCI) for prediction of distant recurrence in hormone receptor-positive breast cancer with 1-3 positive lymph nodes

Abstract Background: BCI is a genomic signature (Molecular Grade Index (MGI) and HOXB13/IL17BR (H/I)) that significantly predicts risk of distant recurrence (DR) in hormonal receptor-positive, lymph node negative (LN-) breast cancer. As previously shown in the TransATAC and MA.14 studies, BCI was also prognostic for DR in lymph node-positive (LN+) patients. Here, a distinct BCI model that integrates tumor size and grade was evaluated for prediction of DR in women with 1-3 lymph node positive disease. Methods: 219 primary tumor samples from hormonal receptor-positive patients with 1-3 positive lymph nodes treated with 5 years of tamoxifen or anastrozole were examined. Women with four or more positive lymph nodes were excluded. BCI was combined with tumour size and grade into a comprehensive risk score, BCIN+. Kaplan-Meier (KM) estimates of 10 year DR and hazard ratios (HR) and 95% confidence intervals (CI) were estimated. Change in likelihood ratio 2 (LR-2) values were used to measure prognostic information of each variable alone or combined in new score. New cutpoints for low versus high risk groups for the new model were determined to ensure the low risk patients had minimal 10-year residual disease. Results: In 219 LN+ patients, BCI alone provided substantial additional prognostic information to tumor size (LR-2=11.83, P=0.0006) and grade (LR-2=8.33, P=0.004). Both clinical variables provided additional significant prognostic information to BCI alone (BCI alone: LR-2=9.59, P=0.0004; T: LR-2=7.09, P=0.008; G: LR-2=27.59, P&amp;lt;0.0001). Integration of tumor size and grade with BCI (BCIN+) provided additional highly significant prognostic information compared to BCI alone (Interquartile HR=3.15 [95% CI: 1.54-6.04]; LR-2=33.89, P&amp;lt;0.0001). A cut-point for a very low risk group in this LN+ population was determined, and included 55 (25%) women with no DR within 10 years. In contrast, 51 (31.1%) women developed a DR in the high risk group (N=164). 10-year DR risk for those in the high risk group was 35.4% (95% CI 28.0-44.1%). Discussion: Integration of tumor size and grade significantly enhanced the prognostic ability of BCI to predict 10 year DR risk in hormonal receptor-positive patients with 1-3 positive nodes. A significant number of patients have been identified to have a very low 10-year risk for DR, who may choose to safely forego unnecessary adjuvant chemotherapy or extended adjuvant endocrine therapy. Validation of BCIN+ in other datasets is ongoing. Citation Format: Sestak I, Zhang Y, Schroeder B, Dowsett M, Sgroi D, Cuzick J, Schnabel CA. Integration of tumor size and grade with the breast cancer index (BCI) for prediction of distant recurrence in hormone receptor-positive breast cancer with 1-3 positive lymph nodes. [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 P2-08-12.

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 P5-10-06: Risk of recurrence estimates with IHC4 are tolerant of variations in staining and scoring

Abstract Aims 1. To determine the degree to which alterations in immunohistochemical (IHC) staining for ER, PgR, and Ki67 affect IHC4 scores and distant recurrence estimates. 2. To examine the level of scoring precision needed for accurate use of the IHC4 score. Background The IHC4+clinical (C) score combines assessment of protein expression levels of ER, PgR, HER2 and Ki67 with clinicopathological parameters to identify breast cancer patients at low, intermediate or high risk of distant disease recurrence so aiding treatment decision-making (Cuzick J, et al. JCO 2011;29:4273). The score is used in clinical decision making in our hospital (RMH). Our published studies have shown it provides information that improves decision-making on adjuvant chemotherapy in &amp;gt;65% of patients (Barton S, et al. BrJCancer 2012;106:1760; Yeo BJ, et al. AnnalsOncol 2014;25suppl_1:i2). Despite its low cost and wide availability reported use of IHC4+C in other institutions remains limited (Lakhanpal R, et al. JCO 2014;32:abstr2549); one explanation is the perception that IHC-based methods and the assessment of them lack precision, reproducibility and portability. We have examined the effect of decentralized testing and easily reproduced estimate-based scoring methods on the IHC4 score to determine its suitability for wider adoption. Methods A TMA was constructed from 30 breast cancer cases representative of those for which IHC4+C is requested at RMH. Sections were distributed to three centers that undertake diagnostic breast cancer IHC and that use reagents and platforms from Dako, Leica or Ventana who provide most IHC for oncology globally. Centers carried-out staining using their standard procedures and returned slides for central assessment. Results were compared against those obtained at RMH using standardized methods previously described (Barton S, et al. BrJCancer 2012;106:1760), and were used to calculate IHC4+C and 10-year distant recurrence probability (%DRprob) scores. In parallel the TMA slide stained at RMH for ER was scored by a variety of simplified non-counting based methods. Results were compared with those produced by counted H-Score when used to calculate IHC4+C and %DRprob. Results There was a high-degree of correlation between individual IHC results produced by all three external centers and those of RMH, and of the IHC4 and %DRprob scores derived from them (Tables 1 &amp; 2). Scoring method for ER could be adapted to require less precision without significantly affecting IHC4+C and %DRprob results (correlation coefficients range: 0.90 - 0.98). IHC4%DRprob RMHDakoLeicaRMHDakoLeicaDako0.92 0.97 Leica0.890.95 0.980.98 Ventana0.930.960.950.980.980.98 Table 1. Correlation coefficients for all pair-wise comparisons MeanMedian difference RMHDakoLeicaRMH9.9% Dako8.4%1.0% Leica8.9%0.9%0.5% Ventana9.1%0.6%0.5%0.6% Table 2. Showing for each center, the mean %DRprob score and median value obtained when the absolute difference was calculated between matched scores Conclusion The IHC4+C algorithm is tolerant of variation in staining and ER-scoring method used. Although additional comparative studies are required to confirm them, these data support the use of IHC4+C in routine clinical practice outside its institute of origin. Citation Format: Andrew Dodson, Lila Zabaglo, Belinda Yeo, Keith Miller, Ian Smith, Mitch Dowsett. Risk of recurrence estimates with IHC4 are tolerant of variations in staining and scoring [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 P5-10-06.

Abstract P1-13-02: Benefit/risk of invasive breast cancer adjuvant tamoxifen or aromatase inhibitor use by age, race/ethnicity, and co-morbidity

Abstract Background: Older age, minority race/ethnicity, and co-morbidities adversely influence early stage IBC outcome. Further, as AI compared to tamoxifen use has different effects on IBC recurrence and other health outcomes including hip fracture, endometrial cancer, stroke, pulmonary embolism and, perhaps especially, coronary heart disease (CHD), an approach to summarize relative benefit/risk of these agents is needed. Methods: Incidence rates for health outcomes by age and race/ethnicity, absent AI or tamoxifen use, were obtained from the placebo arms of the three primary Women's Health Initiative clinical prevention trials (n = 33,072). AI and tamoxifen effects on IBC distant recurrence (relative risk [PR] 0.82) were estimated from a meta-analysis of the ATAC and Big-1-98 trial results (n = 14,149) and on other health outcomes from published meta-analysis of side effects in seven AI vs tamoxifen trials (n = 30,023); RR of 1.47 for hip fracture, 0.34 for endometrial cancer, 0.84 for stroke, 0.55 for pulmonary embolism, 1.26 for CHD (Amir et al JNCI 2011;103:1299). Following the methodology of Freedman et al (JCO 2011;29:2327), mortality weights were assigned health outcomes (5 year mortality risk of 0.2 for MI, 0.8 for IBC distant recurrence, etc) to assess net all cause mortality benefit/risk for AI compared to tamoxifen by recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no) and, in separate analyses, in women with diabetes and in women with cardiovascular disease [CVD] history. Results: In these analyses, clinical outcome of women with early stage IBC was unfavorable (more deaths per 1000 women/years) with tamoxifen compared to AI adjuvant use regardless of age, race/ethnicity, diabetes or CVD history even with 10-year distant recurrence risk of only 10%. AI superiority was substantially greater in women with a uterus and, in exploratory analyses, when assuming a CVD relative risk for AI use of 1.0, rather than a CHD relative risk of 1.26 used in all other analyses, as the AI CHDrisk elevation is controversial. The net benefit of AI compared to tamoxifen influence on clinical outcomes are described in a series of tables to be presented which quantify benefit/risk in particular women groups. The example below illustrates the excess number of deaths/1000 woman years for tamoxifen vs. AI by recurrence risk, age, and hysterectomy status. Excess Number of Deaths per 1000 women/year for Tamoxifen Compared to AI Tamoxifen vs. AI (with uterus)Tamoxifen vs. AI (without uterus)10-year Distant Recurrence (%)Age GroupAge Group 50-59y60-69y70-79y50-59y60-69y70-79y1015120620010211111030326382375278287286 For a 60-69 year old woman with a uterus at 30% 10 year recurrence risk, there would be 382 more deaths per 1000 women/yr for tamoxifen vs. AI use. With prior hysterectomy, there would still be 287 more deaths for tamoxifen use. Conclusion: We developed an index to quantify the benefit risk for adjuvant AI vs. tamoxifen use. Even assessing a RR of 1.26 for CHD for AI use, tamoxifen compared to AI use had unfavorable outcome in all examined groups. This index can complement clinical evaluation in comparing use of these two adjuvant therapy approaches in women of different ages and racial/ethnic groups. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-02.

Ethnic differences in tumor proliferation in women with early-stage breast cancer.

560 Background: Hispanic women have a higher mortality rate and lower incidence of breast cancer (BC) compared to Caucasian women. Studies report higher tumor proliferation in African American (AA) women compared to Caucasian women. The 21-gene assay (OncotypeDX) Recurrence Score (Score) is based on the expression of 16 cancer related genes, including 5 proliferation genes that are grouped to provide the proliferation axis score (PAS). We evaluated the differences in the Score and PAS between Hispanic and Caucasian women with early-stage BC in a matched cohort analysis. Methods: Women with early-stage BC who had a Score obtained from 2005- 2011 were identified. Hispanic women were matched to Caucasians in a 1:2 ratio, based on age (+/- 10 years), stage, and nodal status. Lymphovascular invasion (LVI) and grade were collected. The Score result, 10-year distant recurrence, ER/PR/HER2 expression, and PAS were obtained from the OncotypeDX assay. Assuming equal variances, we expected &gt; 90% power to detect a difference in the mean PAS between Hispanic and Caucasian women Results: We identified 219 women who had OncotypeDX testing (74 Hispanic: 145 Caucasian). Of the 74 Hispanic women, 84% were from the Dominican Republic or Puerto Rico. Mean age was similar between groups (56.3 and 56.8). All but 8 patients were node(-). Mean PAS was higher in Hispanic (5.53, range: 3.9-7.8) vs Caucasian women (5.26, 3.7-7.3) (p=0.03, 95% CI: 0.03-0.51). The mean Score was 18.3 (0-54) and 16.3 (1-50) for Hispanic vs Caucasian women. There was no statistical difference in Score (p= 0.17) or 10-year distant recurrence (p=0.13) between groups. No differences were observed in median ER (9.8% vs 9.9%: Hispanic vs Caucasian), PR (7.3% vs 7.6%), or HER2 (9.1% vs 9.0%) by RT-PCR. Rates of LVI and grade 3 tumors were also not statistically different. Conclusions: Similar to higher PAS in AA women, Hispanic women with ER/PR(+), HER2(-) early-stage BC have higher tumor proliferation markers, measured by RT-PCR in the Oncotype DX assay, than Caucasian women. This may contribute to ethnic differences in BC mortality. We plan to evaluate ethnic differences in the 5 single PAS genes (CCNB1, MKI17, MYBL2, BIRC5, AURKA) to determine which are driving proliferation differences.

Identifying clinically relevant prognostic subgroups in node-positive postmenopausal HR+ early breast cancer patients treated with endocrine therapy: A combined analysis of 2,485 patients from ABCSG-8 and ATAC using the PAM50 risk of recurrence (ROR) score and intrinsic subtype.

506 Background: Most postmenopausal women with node positive HR+ EBC receive adjuvant chemotherapy. We hypothesized that a molecular-based characterization of residual risk after endocrine therapy using the ROR score and IS may identify node-positive patient subgroups with limited long-term recurrence risk after endocrine therapy better than clinical-pathological risk assessment by clinical treatment score (CTS) alone. Methods: Long-term follow-up and tissue samples were obtained from 2,485 postmenopausal HR+ patients from the ABCSG-8 (N=1,478) and transATAC (N=1,007) trials. The PAM50 test was conducted on RNA extracted from paraffin blocks using the NanoString nCounter Analysis system. The ability of ROR, IS and ROR-defined risk groups (ROR-RG) to add prognostic information to CTS was assessed by the likelihood ratio test in a prospectively defined analysis plan. Results: Patients in the combined data set were grouped by the number of positive nodes into 1 (N1), 2 (N2), or 2 or 3 (N2-3),Baseline hazards for these subgroups were similar in the two trials. ROR score, IS and ROR-RG added statistically significant prognostic information (10-year distant recurrence risk) beyond CTS in all groups. In patients with one positive node, the absolute 10-year risk of distant recurrence was 6.6% [95% CI: 3.3%-12.8%] in the PAM-50-low risk group (40% of patients) and 8.4 % [5.3%-13.3%] in the Luminal A subgroup (69% of patients). Conclusions: The results of this combined analysis demonstrate that a significant proportion of N1 EBC patients have very limited long term recurrence risk and suggest the same for some N2 patients. The PAM50 ROR score, IS and ROR-RG reliably provide additional prognostic information beyond CTS and may be useful in deciding which women with node-positive HR+ EBC can be spared adjuvant chemotherapy. [Table: see text]

Overview of the use of Oncotype DX® as an additional treatment decision tool in early breast cancer

Oncotype DX® is a multigene assay that provides prognostic information in terms of 10-year distant recurrence and predicts the likelihood of adjuvant chemotherapy benefit in estrogen receptor positive breast cancer patients, based on the expression of a panel of 21 genes (16 cancer-related and five reference genes) from a tumor specimen (core biopsy or surgical resection). It has been validated using multiple prospectively designed studies of archived tumor specimens from well-controlled clinical studies. In different countries with varying therapeutic approaches, using Oncotype DX has consistently resulted in a significant reduction in the number of patients who are prescribed chemotherapy, and in addition, it can identify a smaller subset of patients who would benefit from chemotherapy among patients who would otherwise receive endocrine therapy alone.