Low Risk Recurrence Score Research Articles

Abstract P1-07-16: Retrospective analysis of oncotype DX recurrence score (RS) and discordance in patients with node-negative, ER+ breast cancer with recurrence

Abstract BACKGROUND: Oncotype RS is a 21-gene assay used to predict the likelihood of distant recurrence and benefit of chemotherapy in patients with node-negative, tamoxifen treated breast cancer. We developed a database to determine tumor recurrence rates and identify cases of discordance between Oncotype RS and tumor grade (TG). Our goal was to recognize patients with discordant tumors who had breast cancer recurrence and to understand the implications for patient management. METHODS/RESULTS: We analyzed patient and tumor characteristics from 704 breast cancer patients between 2006-2016. Of these patients, there were thirteen recurrences (n=13), or 1.9% recurrence rate at a median follow-up of 4.2 years. When stratified by RS, recurrence rates were 1%, 2.4% and 4.3% in low, intermediate and high-risk groups respectively. Of the 13 patients who recurred, 31% had a low RS (<18), 54% had an intermediate RS (18-30) and 15% had a high RS (>31). The median RS was 23 and median age at time of recurrence was 55 years (62% postmenopausal). Tumor characteristics at time of recurrence were notable for: 77% metastatic, 23% locally recurrent, 85% PR positive, 69% moderately-differentiated (MD) and 31% poorly-differentiated (PD). No well-differentiated (WD) tumors recurred. We defined Oncotype discordance as either 1-step or 2-step difference between Oncotype risk group (low, intermediate, high) and tumor grade (WD, MD, PD). Prior studies have demonstrated 7-19% “2-step discordance” between TG and RS (i.e. PD tumors with low-risk RS or WD tumors with high-risk RS). Of the 13 recurrences in our database, 46% were at least 1-step discordant, compared with 64.3% in our overall database. Among these recurrences, we compared discordant versus concordant tumors using two-sided T-tests. We found that fewer patients were treated with systemic chemotherapy in the discordant group (p=0.045), which was statistically significant. Among discordant patients, only one received chemotherapy, though all displayed MD or PD tumor grade. Discordant tumors tended to have lower RS (mean 17 vs. 27, p=0.34) and tended to be larger (mean 1.88cm vs. 1.33cm), however this was not statistically significant (p=0.84). Notably, the two largest tumors were both discordant. There were no significant differences in terms of age, Oncotype ER/PR score or mitotic count. CONCLUSION: Although the sample size of recurrent patients is small, our data may suggest that patients with discordant tumors of low-risk Oncotype RS but higher TG may be receiving inadequate treatment (i.e. no chemotherapy). In addition to RS, other factors such as discordance, TG and tumor size should perhaps be considered when determining treatment plans. Characteristics of Breast Cancer Recurrences in Oncotype DX DatabaseSubject #Age (years)Oncotype RSTumor GradeDiscordancePath PR%Tumor Size (cm)Chemotherapy14111MDY600.9N25811MDY1001.7N35713MDY301.0N45515MDY902.7N56122MDN301.5Y64522MDN901.8Y75323MDN00.9N83324MDN951.4Y96324PDY802.9U104129MDN801.1Y116530PDY102.1Y124933PDN01.6Y136135PDN51.0YMD=moderately-differentiated, PD=poorly-differentiated, Y=Yes, N=No, U=Unknown Citation Format: Zimmerman BS, Cascetta KP, Ru M, Eggert L, Molot MC, Nayak A, Bleiweiss I, Tiersten A. Retrospective analysis of oncotype DX recurrence score (RS) and discordance in patients with node-negative, ER+ breast cancer with recurrence [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-16.

Abstract P1-07-17: Discordant breast cancer: Genomic verse clinicopathologic

Abstract Background: Studies using the 21-gene recurrence score (RS) have shown early-stage, low-risk pathologic and genomic breast cancers do not benefit from systemic chemotherapy (CTx) whereas early stage, high-risk breast cancers have improved outcomes when treated with CTx. Data is lacking for patients with discordant risk factors and which feature, genomic or clinical, plays more of a role in determining outcomes. Methods: A retrospective analysis was conducted to identify early-stage breast cancer patients with discordant features, defined as low-risk genomic/high-risk pathologic factors (LG/HP) or high-risk genomic/low-risk pathologic factors (HG/LP), from August 2011–December 2016. LG/HP breast cancer was defined as a RS <18 with ≥2 high-risk pathologic factors: tumor size (T) ≥2cm, lymph node (N) positivity, or grade 2-3 disease. HG/LP breast cancer was defined as a RS ≥31 with all three low-risk pathologic factors: T <2cm, N negativity, and grade 1-2 disease. Results: There were 469 patients with low-risk RS identified of whom 118 (25%) met discordant high-risk pathologic criteria and 62 patients with high-risk RS of whom 14 (23%) met discordant low-risk pathologic criteria. Thirty patients in the LG/HP group received CTx despite a low RS. Of the 118 LG/HP patients, there were 22 (19%) breast cancer recurrences; 21 with locoregional and one with metastatic disease. Of the locoregional recurrences, 10 were contralateral breast whereas 11 were in-breast recurrence despite breast conservation therapy. Of the 14 HG/LP discordant patients, of whom 12 received CTx, 3 (21%) had breast cancer recurrence; one with metastatic disease to the lung and the other two with contralateral breast cancer. Majority of all recurrences occurred >5 years after initial diagnosis. Staging and management depicted below. Management (Mgt) of Discordant Risk Cancers LG/HP initial diagnosis (n=118)LG/HP recurrence (n=22)HG/LP initial diagnosis (n=14)HG/LP recurrence (n=3)Stage 004001A1411142IB14100IIA56500IIB25000IIIA2000IV0101Surgical Mgt Partial mastectomy737102Simple mastectomy431440LN Mgt Sentinel LN biopsy8510132Axillary LN dissection25310Unknown/Not Applicable6800Radiation Mgt Yes816103*No/Unknown351500Hormonal Therapy Yes9417143No/Unknown24500Systemic CTx Neoadjuvant6100Adjuvant242122No/Refused881921*metastatic pt with SBRT to lung Conclusions: Using traditional low-risk RS of 18, we observed more than expected recurrences in our LG/HP discordant patients. Thus suggesting, in patients with discordant results, clinicians must consider both pathologic and genomic factors to optimize patient-specific treatment. Further studies are needed to improve the outcomes of this unique patient population. Citation Format: Blankenship LM, Ezekwudo D, Jaiyesimi I, Stender M, Alassi O, Kresge C, Gaikazian S. Discordant breast cancer: Genomic verse clinicopathologic [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-17.

Abstract P3-09-05: Getting the most out of the 21-gene recurrence score assay: Increasing actionable results with a combined pathologic-genomic model

Abstract Introduction: The 21-gene recurrence score (RS) assay categorizes hormone receptor positive, node negative breast cancers (BC) into 3 risk groups for recurrence. We previously showed that the AAMC Model, using only standard pathology data, accurately does the same. This study compares the recurrence rate of the AAMC Model's risk groups to RS-based risk groups. A 2-step approach then is used, in which the AAMC model is applied first, and the RS assay is used only for AAMC intermediate risk cases. AAMC intermediate cases were reclassified by RS into low or high risk groups. Methods: From a prospective registry of newly diagnosed BC, we selected invasive, hormone receptor positive, HER2 negative, lymph node negative cases from 2005 to 2015 tested with RS assay. Five-year Kaplan-Meier distant recurrence rates were calculated for each risk category. Results: 1268 cases were included. Five-year recurrence rates were similar between the AAMC Model's low risk group and RS<18 low risk group, as well as between the AAMC Model's high risk group and the RS>30 high risk group. Applying the RS assay to the 715 cases in the AAMC Model's intermediate group resulted in re-classifying 417 (58%) as low risk and 41 (6%) as high risk. Using RS alone, 33% of cases were intermediate risk (n=424), whereas in the 2-step approach 20% were intermediate risk (n=257). For the 2-step approach, the 5-year distant recurrence rate was 3.3% for the low risk group (n=740) and 24.4% for the high risk group (n=271). Conclusions: Five-year recurrence rates in the AAMC Model's low and high risk groups were similar to those in RS-based risk groups. The 2-step approach, with RS used only for AAMC intermediate cases, resulted in larger low and high risk groups with equivalent prognostic accuracy, compared to use of the RS assay alone. The 2-step approach reliably identifies a large number of patients unlikely to benefit from 21 gene assay and provides substantial cost savings. Kaplan-Meier Calculated 5-year Distant Recurrences Rates for 4 Models: 1268 Patients Oncotype DXTAILORxAAMC Model2 Step Model with OncotypeDX for AAMC IntermediatesLow RiskRS < 18 (n=703)RS < 11 (n=250)Grade 1 and PR ≥ 1% (n=323)AAMC Low or AAMC intermediate/RS <18 (n=740) 3.4% (95% CI 1.6 – 5.1%, nf=17)4.0% (95% CI 0.8 – 7.2%, nf=8)2.7% (95% CI 0.0 – 5.4%, nf=5)3.3% (95% CI 1.4 – 5.2%, nf=16)Intermediate RiskRS 18 - 30 (n=424)RS 11 - 25 (n=787)Not meeting AAMC definition for low or high risk (n=715)AAMC Intermediate and RS 18-30 (n=257) 15.2% (95% CI 10.3 – 20.1%, nf=38)7.3% (95% CI 4.7 – 9.9%, nf=35)8.4% (95% CI 5.4 – 11.3%, nf=36)12.0% (95% CI 5.8 – 18.1%, nf=15)High RiskRS > 30 (n=141)RS > 25 (n=231)Grade 3 or ER < 20% (n=230)AAMC High or AAMC intermediate/RS > 30 (n=271) 23.0% (95% CI 14.7 – 31.3%, nf=27)22.9% (95% CI 15.9 – 29.9%, nf=39)22.8% (95% CI 16.1 – 29.5%, nf=41)24.4% (95% CI 18.0 – 30.7%, nf=51)RS= Recurrence Score, nf=number of recurrences, CI = confidence interval. Citation Format: Mylander C, Rosman M, Gage M, Fujii T, Le Du F, Raghavendra A, Sinha A, Espinosa Fernandez JR, James A, Ueno N, Tafra L, Jackson R. Getting the most out of the 21-gene recurrence score assay: Increasing actionable results with a combined pathologic-genomic model [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-09-05.

Abstract P1-06-11: Prediction of oncotype DX® results based on local gene expression measurements by MammaTyper®

Abstract Background: Oncotype DX® recurrence score (RS) has emerged as a recommended risk classifier for patients with ER+/HER2- early-stage breast cancer. While RS is one of the most rigorously studied risk scores, it is also one of the most expensive tests, thus remaining beyond reach for a many patients. The necessity for an affordable method for estimating risk of recurrence has motivated investigations on the correlation between RS and traditional parameters such as IHC for ER, PR and Ki67. However, semi-quantitative IHC lacks standardization across different laboratories especially for Ki67. In this study we therefore investigated whether the standardized assessment of HER2, ER, PR, and Ki67 on mRNA level could better serve for prediction of low risk RS cases. Methods: ERBB2, ESR1, PGR and MKI67 mRNA expression was measured by RT-qPCR in extracts from FFPE breast cancer samples using the MammaTyper® test. Complete data for RS, IHC, grading and mRNA measurement was available for 198 samples. Tumor subtypes according to St Gallen surrogate definition from 2013 were assigned based on binary mRNA marker classification (pos/neg) according to pre-defined cut-offs. Subtype results were compared to RS risk classes based on commercial and TAILORx-trial cut-offs. RS low risk classification (RS ≤25) based on four IHC markers and grading was estimated using the online tool breastrecurrenceestimator.onc.jhmi.edu and compared to observed RS classes. Finally, the prediction of continuous RS values by mRNA or semi-quantitative IHC measurement was compared by linear regression and subsequent ROC analysis of prediction models. Results: The distribution of RS risk classes in the set of samples with full data was 21% RS 0-10, 39% RS 11-17, 27% RS 18-25, 7% RS 26-30 and 7% RS >30. MammaTyper® called 38% (76) of the samples as Luminal A-like. From these samples 70% and 99% had RS values below 18 and 25 respectively. Only 1 MammaTyper® Luminal A-like sample had an RS >30. Estimation of RS according to the online tool resulted in classification of 61% (121) of the samples as low risk (RS ≤25). Of these 74% and 98% of samples had observed RS values below 18 and between 18 and 25 respectively. 2 and 1 samples called as low risk by the online tool had an RS of 26-30 and >30 and, respectively. In linear regression analysis of IHC against RS only PR and Ki67 were significant predictors (p-values <0.0001 and 0.0128) while when using mRNA values ESR1, PGR and MKI67 were found as predictors of RS in the multivariate model (all p-values <0.0001). On a training set (67% of samples) the IHC based prediction model was correlated to the observed RS with an R2 of 0.305 whereas the mRNA based model achieved an R2 of 0.489. When the models were applied to training and validation dataset (33% of samples) for prediction of an RS >25 result, the IHC based model had AUCs of 0.887 and 0.836, respectively, while the mRNA based model achieved AUCs of 0.909 and 0.899, respectively. Conclusion: mRNA based prediction of RS was considerably better than prediction based on IHC. As Ki67 IHC standardization is reaching its limits, local gene expression measurements with their high degree of standardization could serve as a safer way for prediction of Oncotype low risk results. Citation Format: Lehr H-A, Aulmann S, Laible M, Etzrodt A, Hartmann K, Gürtler C, Sahin U, Varga Z. Prediction of oncotype DX® results based on local gene expression measurements by MammaTyper® [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 P1-06-11.

Impact of the 21-gene recurrence score on outcome in patients with invasive lobular carcinoma of the breast.

Invasive lobular carcinoma (ILC) of the breast has unique clinicopathologic characteristics, compared to invasive ductal carcinoma. The role of the 21-gene Recurrence Score (RS) has not been clearly defined for ILC. We sought to determine the prognostic value of RS and the impact of adjuvant chemotherapy on long-term survival in patients with ILC. Utilizing the Surveillance, Epidemiology and End Results database from 2004 to 2013, we identified records of women aged 18-74years, diagnosed with estrogen receptor (ER)-positive ILC (stage I to III) with RS available. We categorized patients into risk groups based on the traditional RS cutoffs and into those of the Trial Assigning Individualized Options for Treatment (TAILORx). Five-year breast cancer-specific survival (BCSS) was analyzed using the Kaplan-Meier method and Cox proportional hazards models. Of the 7316 women included, 21% were in the low-risk; 71%, intermediate-risk; and 8%, high-risk groups as per TAILORx RS cutoffs. The 5-year BCSS was 99% in the low-risk, 99% in the intermediate-risk, and 96% in the high-risk groups. A high-risk RS as per TAILORx cutoff was independently associated with increased mortality (hazard ratio [HR] of death 2.37, 95% confidence interval [CI] 1.14-4.95) when compared to a low-risk RS. In both the high-risk and intermediate-risk groups, adjuvant chemotherapy was not significantly associated with the HR of death (high-risk, HR 1.14, 95% CI 0.55-2.38; intermediate-risk, HR 1.08, 95% CI 0.62-1.87). For patients with ER-positive ILC, 8% were in the high-risk and 72% were in the intermediate-risk groups as per the TAILORx RS cutoffs. In the high-risk group, the RS predicted a lower 5-year BCSS. Adjuvant chemotherapy did not seem to confer a survival benefit for either the intermediate- or the high-risk cohorts.

Discordant breast cancer: Low risk genomic, high risk pathologic.

e18160 Background: Studies using the 21-gene recurrence score (RS) have shown low risk pathologic features and RS breast cancers do not benefit from systemic chemotherapy (CTx). However, data is lacking for patients with discordant risk factors and which feature, genomic or clinical, plays more of a role in determining outcomes. Methods: Retrospective analysis was conducted to identify breast cancer patients with discordant features, defined as low genomic/high pathologic factors, from 2011 to 2016. Patients were hormone-receptor positive with RS < 18 and had ³ 2 high risk factors: tumor size ³2cm, lymph node (LN) positivity, or grade 2-3 disease. Results: There were 469 patients with low risk RS were identified of whom 118 met discordant risk criteria. Patients management is depicted in Table 1. Of the 118 discordant patients, 22 had breast cancer recurrence as either metastatic (1) or locoregional (21); 11 being ipsilateral while the remainder were contralateral. Patients with ipsilateral recurrences had partial mastectomy and radiotherapy as initial management. CTx was received in 30 patients despite low RS. Recurrences occurred in 31.8% of patients who received adjuvant CTx. The majority of recurrences occurred >5 years after initial diagnosis. Conclusions: Our results show both genomic and pathologic features were important in determining the need for CTx in early stage breast cancer but neither had a greater impact. Thus, we advocate a more comprehensive and individualized approach, taking into account comorbidities, genomic, and pathologic features, for addition of CTx to standard hormonal therapy. Further studies are needed to determine the proper treatment of this unique patient population. [Table: see text]

Abstract PD7-05: How 21-gene recurrence score assay is being used to individualize adjuvant chemotherapy recommendations in ER+/HER2 -node positive breast cancer -A national cancer data base study

Abstract Introduction: The 21-gene Recurrence Score (RS) assay has been shown in retrospective studies to predict benefit of adjuvant chemotherapy (AC) in node positive (N+) breast cancer (BC) patients (pts). This study evaluates the trends and patterns of use of RS assay in N+, ER+/HER2-breast cancer and the impact of RS on decision to use AC in a real-world multi-institutional database. Methods: Pts with T1-T4c, N1mi-N3, ER+/HER2- BC diagnosed between 2010 and 2013, included in the National Cancer Data Base were analyzed. Pts who received neo-AC were excluded. Analyses included Cochrane-Armitage tests for trends and multivariable logistic regression assessing factors influencing RS testing and AC recommendations based on RS. Results: Among 73,049 pts, RS was obtained in 20.6%, increasing from 14.9% in 2010 to 24.4% in 2013 (p<0.001). RS testing was most common in N1mi (43.6%) and N1 (22.0%) and rare in N2/N3 (3.3%) BC. Of the 12,540 BC with quantitative RS results, 61.1% were low RS, 32.3% intermediate RS and 6.6% high RS. AC recommendation was less frequent in pts with RS testing compared to pts not tested (50.4% recommended AC vs 80.9%, p<0.001). In pts with N1mi/N1 BC, recommendation rates for AC were higher with higher RS (see table), however in N2/N3 BC, AC was recommended in the majority (71-88%) regardless of RS. Most pts (>85%) with RS 26-30 or high risk RS were recommended AC regardless of N stage. For pts with low risk RS, recommendation for AC increased significantly with increasing N stage (see table). On multivariable analysis, in pts with low risk RS, AC was more likely to be recommended in those with N1/N2+ stage (OR 2.3 and 9.1 vs N1mi), T2 and T3/T4 tumors (OR 1.3 and 2.2 vs T1 tumors), poorly differentiated tumors (OR 1.6) and younger age (OR 3.4 and 1.7, respectively, for <40 and 40-49 vs 50-59) (all p<0.001). Among pts with RS 18-25, AC was more likely to be recommended in those with higher tumor grade, younger age but the effect of N stage was less pronounced. Histology (IDC vs ILC) did not influence AC recommendation in any RS subset. Path N StageRS Risk GroupLow RiskIntermediate RiskHigh RiskRS<18RS 18-25RS 26-30RS>30N1mi AC No1,854 (75.9%)389 (36.9%)36 (14.6%)16 (7.0%)N1mi AC Yes590 (24.1%)666 (63.1%)210 (85.4%)212 (93.0%)N1 AC No3,000 (60.6%)699 (33.0%)75 (14.8%)33 (6.0%)N1 AC Yes1,954 (39.4%)1,422 (67.0%)431 (85.2%)518 (94.0%)N2/N3 AC No76 (29.0%)17 (16.7%)3 (12.5%)7 (14.9%)N2/N3 AC Yes186 (71.0%)85 (83.3%)21 (87.5%)40 (85.1%)p-value<0.001<0.0010.880.16 Conclusions: RS was obtained in about one fifth of pts with N+ ER+/HER2- BC, predominantly for N1mi and N1 disease. Overall, RS testing decreased frequency of recommendation of AC in N+ BC pts. The RS influenced use of AC particularly in N1mi and N1 pts, likely avoiding overtreatment of those with low risk RS and RS 18-25. Prospective data regarding RS to direct AC in N+ BC are awaited. Citation Format: Peethambaram PP, Hoskin TL, Heins CN, Habermann EB, Boughey JC. How 21-gene recurrence score assay is being used to individualize adjuvant chemotherapy recommendations in ER+/HER2 -node positive breast cancer -A national cancer data base study [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 PD7-05.

Abstract PD7-04: A novel nomogram model can predict oncotype DX results thus reducing healthcare expenditures

Abstract Oncotype DX (ODX) is a commercially available 21-gene recurrence score (RS) assay for breast cancer (BC), which has both prognostic and predictive recurrence value for estrogen receptor-positive (ER+)/HER2-negative (HER2-)/lymph node-negative (LN-) BC. ODX is currently endorsed for us by ASCO, the NCCN, and others for routine guideline application. The RS predicts benefit of adding adjuvant chemotherapy to hormonal manipulation. ODX is costly, a factor which contributes to the test being performed in only ∼1/3 of ER+BC in the USA. Disparities of its use in the US and other developed countries were recently published by us and others. The need for finding an accurate widely applicable, readily available surrogate for ODX is apparent. This study serves to develop and validate nomograms which can be used in place of ODX. National Cancer Data Base (NCDB) analysis from 2010-2012 of ODX tested ER+/HER2-/LN- patients (pts) with 6-50mm tumor size was used to create nomograms for predicting a high or low ODX RS test results. Analysis of NCDB ODX tested pts in 2013 was used for external validation. Age, tumor size, grade, progesterone receptor (PR) status, lymph-vascular invasion (LVI), and the four most frequent BC histologic types were chosen as variables for creating nomograms based on the published methods (JCO, 26(8):1364-70, 2008). Logistic regression was used to generate the scores and predicted probabilities. The predictive accuracy of the regression model was yielded using a Receiver Operator Characteristic (ROC) analysis and model fit was analyzed by plotting the predicted probabilities against the actual probabilities. Nomograms predicting a high- or low-risk ODX RS test results were created based on results from 27,719 ODX tested pts (2012-2012) and were validated on 12,763 ODX tested pts (2013) (table1). Table 1.Points assigned for original cohort nomogram (2010-2012; N=27,719)Points assigned for external validation cohort nomogram (2013; N=12,763)Clinicopathologic CharacteristicsHigh-risk ODX RSLow-risk ODX RSHigh-risk ODX RSLow-risk ODX RSAge0.1/yr0.1/yrTumor size0.8/1mm0.9/1mmGrade 101000100Grade 240403737Grade 310001000PR Positive ≥1%076075PR Negative <1%760750LVI Yes0.5020LVI No00.502Invasive ductal carcinoma036032Invasive lobular carcinoma360320Invasive ductal and lobular317302Invasive ductal mixed with other types731230Maximum points214210C-index.89.89p value<.001<.00195%CI.88-.89.88-.90Note: actual nomogram to be published in manuscript Grade and PR status were shown to be the highest predictors for a low- or high-risk ODX RS. The ROC curves for the probabilities of a low- or high-risk RS showed excellent agreement between the nomogram prediction and actual observation with high, acceptable C-indexes-.89 for both internal and external validation cohorts. We created and validated nomograms that accurately predict for a high- and low-risk ODX score based on the large, National Cancer Data Base which is comprised of >1500 Commission on Cancer accredited facilities. These nomograms may serve to select pts for which further ODX testing is not necessary and may be an excellent surrogate for BC pts for which ODX testing is not available. Citation Format: Orucevic A, Bell JL, Heidel RE. A novel nomogram model can predict oncotype DX results thus reducing healthcare expenditures [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 PD7-04.

Oncotype-DX recurrence score distribution in breast cancer patients with BRCA1/2 mutations.

Oncotype-DX assay has never been validated for BRCA mutation carriers. This study compares the recurrence score (RS) distribution in BRCA-positive breast cancer patients with that of a general population (GP) of patients and reports their outcomes. Eligible patients were BRCA carriers who performed the Oncotype-DX assay. Two sets of databases were cross-linked: BRCA carriers at Rabin Medical Center and Sheba Medical Center with Oncotype-DX tests performed through Clalit Health Services HMO, from 2003 to 2015. Fifty-eight BRCA patients were included (20 BRCA1, 38 BRCA2). The GP included 1020 patients. Compared to the GP, BRCA1 patients were younger, had higher rate of grade three tumors, and higher Ki67. BRCA2 patients had lower PR index, higher rate of grade three tumors, and higher Ki67. Among the GP, 52.9, 37.9, and 9.1% had low, intermediate, and high risk RS, respectively. Corresponding rates were 15, 35, and 50% in BRCA1 patients, and 18.4, 52.6, and 29% in BRCA2 patients. Subgroup analysis revealed a similar RS distribution pattern regardless of the nodal status. Median follow-up was 45months. Four BRCA patients (7%) developed disease recurrence. RS of these patients were in the intermediate and low range. All recurrences occurred in chemo-naïve patients who had not undergone bilateral oophorectomy. This study revealed significantly different RS distributions between BRCA patients and the GP. RS values shifted toward high and intermediate risk categories. This pattern held regardless of the nodal status and was more pronounced in the BRCA1 group.

Abstract P5-08-06: Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage breast cancer

Abstract Background: Gene expression profiling assays estimate prognosis & predict benefit from adjuvant chemotherapy in patients (pts) with estrogen receptor positive (ER+) early stage breast cancer (ESBC). The 21-gene recurrence score (RS) and 70-gene signature (MP) are widely used assays. Pts may have both tests performed to adjudicate discordant results. We compared RS and MP in pts with both tests and evaluated their impact on adjuvant treatment decisions. Methods: This was a retrospective clinical cohort study from 5 centers from 2007-2014. Eligibility included ER+ ESBC with RS and MP results from the same tissue sample; exclusions included carcinoma in situ, primary metastatic disease, & bilateral breast cancer. Two definitions of RS risk were evaluated (Genomic Health [GH] or TAILORx [TRx]): low risk (GH:0-17) or (TRx:0-10); intermediate risk (GH:18-30) or (TRx:11-25); and high risk (GH:>31) or (TRx:>26). Demographic, clinicopathologic (CP) data, and treatment decisions were extracted from medical records. Agreement was assessed between RS and MP using weighted kappa scores. CP factors were assessed with the t-test and chi-square test. Results: 123 pts were identified from UCSF or 4 US Oncology Network practices. 60 pts had low risk RS (GH); 27 were low risk by MP (45% agreement). 15 cases had a low risk RS (TRx); 9 were low risk by MP (60%). 10 pts had high risk RS (GH); 8 were high risk by MP (80.0%). Similarly, 18 cases had high risk (TRx) RS;16 were high risk by MP (88%). Using the RS GH risk definition, there was poor agreement for low risk RS/MP and high risk RS/MP (kappa=0.169). However, using the TRx RS risk definition, there was good agreement for low risk RS/ MP and high risk RS/MP (kappa=0.509). 53 pts had intermediate risk RS by (GH); by MP 16 were low risk (30%), and 37 were high risk (70%). 90 pts had an intermediate risk RS by TRx; by MP 34 were low risk (37.8%), and 56 were high risk by MP (62.2%). Using TRx RS increased the number of pts classified as intermediate risk compared to GH RS (73.2 vs 43.1%). Complete adjuvant treatment data were available for 90 patients. Of 40 pts with low risk RS (GH), 25% received chemotherapy associated with node status but not tumor size, grade, or MP. Of 10 pts with high risk RS (GH), 70% received chemotherapy without association with CP features or MP. For the 45 pts with intermediate risk RS (GH), 53% received chemotherapy, without correlation with CP features. Receipt of chemotherapy was positively associated with MP high risk, but this was not significant (odds ratio 2.08, 95% CI 0.54-8.01); p-0.29. Conclusion: Concordance in risk prediction between RS and MP was greater using RS defined by TRx compared to GH, and RS using TRx increases those categorized as intermediate risk. There appeared to be no correlation between CP features and decisions to use chemotherapy across risk groups. Interestingly, in those with intermediate risk RS (GH or TRx), there was a non-significant trend toward use of chemotherapy in those with high risk by MP. Although gene expression tests are used frequently to aid in treatment decisions in ESBC, considerable variation exists in their application in clinical practice. Citation Format: Jiang H, Denduluri N, Majure M, Favret A, Rugo HS. Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage 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 P5-08-06.

Abstract P5-15-01: Breast cancer specific survival in 38,568 patients with node negative hormone receptor positive invasive breast cancer and oncotype DX recurrence score results in the SEER database

Abstract Introduction: The SEER Program of the National Cancer Institute (NCI) is an authoritative source of cancer incidence and survival statistics, collecting population-based data for ∼28 percent of the US. As innovations in molecular testing are validated and recommended in guidelines, new genomic research models are needed to characterize their use and impact on patient outcomes in clinical practice. To that end, Genomic Health and SEER have collaborated to electronically supplement the SEER registries with Oncotype DX results. This first report characterizes breast cancer specific survival (BCSS) in node (N)- hormone receptor (HR)+ HER2- invasive breast cancer. Methods: The prospectively-defined population-biomarker-outcomes linkage had objectives, analysis cohort, standardized biomarker, and outcome defined prior to data linkage. Patients were eligible if N-, HR+, HER2- (by RT-PCR), had no prior malignancy, were 40-85 years of age, and were diagnosed between Jan 2004 (Oncotype DX available in Jan 2004) and Dec 2011 (SEER survival analysis complete through 2012). BCSS was defined as previously described and assessed rigorously (Howlader et al, JNCI 2010). Oncotype DX Recurrence Score results were provided to SEER as mandated by their registry operations. Analysis by treatment was interpreted in the context of the lack of randomization and well known limitations of registry reporting of chemotherapy (CT) treatment (Noone et al, Medical Care 2014). Results: Among 169,158 eligible patients, 38,568 (23%) had a Recurrence Score (RS), increasing from 2% of 2004 diagnoses to 35% of 2011 diagnoses. Patients with RS had median age of 57 yr, were 99.4% female, 84% white, 29% grade 1 and 54% grade 2, 25% 1cm or less and 53% between 1 and 2cm. Median follow-up was 39 mo with 8,239 patients having >5 yrs follow-up. Among low risk RS <18 (N=21,023), intermediate risk RS 18-30 (N=14,494) and high risk RS ≥31 (N=3,051) patients, chemotherapy use was reported in 7%, 34%, and 69%, respectively. 5-year BCSS (with 95%CI) are provided in Table. Continuous RS was significantly associated with BCSS unadjusted (p<0.001), and after adjusting for age, grade, and tumor size (p<0.001), and when stratified by treatment (p<0.001). Conclusions: 5 yr BCSS outcomes are excellent (99.6%) in the over 21,000 patients with low RS disease. As expected, high RS disease is associated with lower 5 yr survival despite addition of chemotherapy. More rigorous ascertainment of treatment is planned to draw conclusions regarding chemotherapy treatment benefit. Analyses that examine test utilization as well as annual survival updates to obtain longer term event rates will be important to gain additional insights into patient subgroup outcomes that can be characterized by large population-based genomic studies. RS<18RS 18-30RS≥31 NBCSS (95%CI)NBCSS (95%CI)NBCSS (95%CI)Analysis all pts2102399.6 (99.4-99.7)1449498.6 (98.3-98.9)305195.6 (94.4-96.6)Analysis by CT reported No/Unknown CT1955499.6 (99.5-99.7)957098.6 (98.2-98.9)93694.0 (91.1-96.0)Yes CT146999.3 (98.4-99.7)492498.6 (98.0-99.0)211596.4 (95.0-97.4) Citation Format: Shak S, Petkov VI, Miller DP, Howlader N, Gliner N, Howe W, Schussler N, Cronin K, Baehner FL, Penberthy L. Breast cancer specific survival in 38,568 patients with node negative hormone receptor positive invasive breast cancer and oncotype DX recurrence score results in the SEER database. [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 P5-15-01.

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<0.001); had higher postmenopausal status (77 vs 34%, p<0.001); higher rates of breast conserving surgery (88 vs 74%, p=0.024) and sentinel node biopsy (94 vs 26%, p<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<0.001). The majority of patients received adjuvant endocrine treatment (> 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.

Abstract P2-03-15: Re-assessment of 21-gene breast cancer assay utilization as a quality indicator by the Florida Initiative for Quality Cancer Care (FIQCC) Consortium

Abstract Background: In 2006, the FIQCC conducted a comprehensive review of quality of care indicators specific to breast cancer (BC) based on QOPI/NCCN/ACOS and panel consensus, with feedback provided on indicator performance to encourage quality improvement efforts. In 2009, at re-assessment of adherence to the previous indicators, we introduced a pilot quality indicator from the NCCN treatment guidelines: discussion/recommendation of the 21-gene BC assay for treatment decisions. The current study assesses quality improvement efforts targeting specifically the 21-gene BC assay. Methods: After disclosure of results in 2012, 5 FIQCC sites agreed to participate in a re-assessment sub-study focused on the 21-gene BC assay. Following IRB approval, each site developed and implemented a site-specific quality improvement plan focused on the discussion/utilization of this assay. Following this intervention, chart reviews were conducted for ER+ BC patients first seen by a medical oncologist in 2013 and eligible for the 21-gene BC assay based on NCCN criteria (n=130). Data collected included: 1) documentation of a discussion with the patient of the 21-gene BC assay; 2) documentation of ordering/performance/results of the 21-gene BC assay; and 3) treatment decisions based on results and/or documentation of reasons for non-compliance. Statistical comparisons of the previously collected 2009 data (n=262) for these 5 FIQCC sites and new 2013 data were performed using the Pearson Chi-Square exact test based on Monte Carlo estimation. Results: Overall, the mean age of patients was 62 years (range 30-89) for the combined 2009 and 2013 years. More women had her2 negative BC in 2013 compared to 2009 (p=0.003). Since the 2009 dataset was not specific to the 21-gene BC assay eligibility, a smaller proportion of patients had tumor sizes staged as T1c/T2/T3 [80.3% vs. 92.2% for 2009 as compared to 2013, p=0.005] and less were node negative in 2009 [56.8% vs. 96.6%; p<0.001]. Based on NCCN criteria, only 60.9% of eligible patients had a documented discussion or recommendation for the 21-gene assay in 2009 with significant variability among the 5 sites (p=0.011). A significant improvement was seen in 2013 (p<0.001) with 91.4% of eligible patients having documentation of a discussion or recommendation for the 21-gene assay without significant variability amongst the practice sites. Significant improvement in the percentage of patients having the assay ordered from 2009 to 2013 was seen (p<0.001) but variability amongst the sites persisted (2009: p=0.002; 2013: p=0.018). Recurrence Score (RS) results were completely s recorded in both 2009 and 2013. All patients with high-risk RS were referred for chemotherapy. A small fraction of patients with low-risk RS was referred for chemotherapy both years (2009: 5.4%, 2013: 3.8%; p=1.00). Conclusions: Previously, the FIQCC identified quality improvement needs in multiple aspects of BC care, including recommendation and ordering of the 21-gene BC assay. A dedicated quality improvement effort can significantly increase both the discussion/recommendation and ordering of the 21-gene BC assay among eligible patients. These improvements have the potential to alter treatment recommendations. Citation Format: Christine Laronga, Weihong Sun, Erin Siegel, Ji-Hyun Lee, William J Fulp, Paul B Jacobsen, Jhanelle E Gray. Re-assessment of 21-gene breast cancer assay utilization as a quality indicator by the Florida Initiative for Quality Cancer Care (FIQCC) Consortium [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 P2-03-15.

Abstract P6-08-42: Association of metabolic syndrome, its components and multigene assays for recurrence risk

Abstract Background: There is an association of metabolic syndrome (MS) and its constituents (obesity; diabetes mellitus, DM; hypertension, HTN; hyperlipidemia, HL) with breast cancer (BC) causation and outcomes. Previously we showed an impact of obesity on tumor biology as defined by a multigene assay. Our objective was to study the association between MS, its components and tumor biology, as determined by the 70 gene signature (70-GS) and the 21-gene Recurrence Score (RS). Methods: Consecutive patients with newly diagnosed ER+, lymph node-negative BC from 2005-2012 were studied. A 70-GS was done for those pts with tumors that had either low or intermediate RS. Pearson’s Chi-square tests for univariate analyses and logistic regression for multivariate analysis were used. Results: Low or intermediate RS were found on tumors from 151 pts of which 133 had a 70-GS. The MS was present in 23/104 (22%) pts with intermediate RS and 21/46 (46%) pts with low RS (p=0.004). DM, HTN, and obesity were each inversely associated with 21-gene RS in univariate analyses (p=0.002, p=0.003, p=0.004 respectively, see Table). However, MS and its individual components were not significantly associated with the 70-GS. Upon adjustment for age and race, the association between MS and RS was not significant (OR=0.64; p=0.28); however, DM (OR=0.35; p=0.01), HTN (OR=0.44; p=0.05) and obesity (OR=0.35; p=0.01) remained significantly inversely associated with RS. Independent of age and race, patients with DM, HTN, or obesity were more likely to be in the low-risk 21-gene RS group. [Table] High Risk 70-GSLow Risk 70-GSp-valueIntermediate 21-gene RSLow 21-gene RSp-valueMetabolic Syndrome 0.30 0.004Yes14(24%)24(32%) 23(22%)21(46%) No44(76%)50(68%) 81(78%)25(54%) Diabetes 0.24 0.002Yes12(21%)22(30%) 18(17%)19(41%) No46(79%)52(70%) 86(83%)27(59%) Hypertension 0.28 0.003Yes36(62%)39(53%) 52(50%)35(76%) No22(38%)35(47%) 52(50%)11(24%) Obesity 0.27 0.004Yes35(60%)38(51%) 51(49%)34(74%) No23(40%)37(49%) 54(51%)12(26%) Conclusions and Implications: The association of MS and its components differs for the 70-GS and RS assays. There is significant association between MS (and DM, HTN, obesity) and RS, but no association with 70-GS. Patients with MS (and components) are more likely to have a biology (low RS) known to have less chemotherapy benefit. Given the reported impact of MS on BC incidence and outcomes along with the global increased MS incidence, the MS may have profound impact on BC biology and treatment outcomes in the coming years. It is also possible that multigene assays currently in use for prognosis and prediction may need refinement in the presence of MS and/or its components. Citation Format: Hanh P Mai, Stephanie Kliethermes, Shikha Jain, Shelly S Lo, Ellen R Gaynor, Kathy S Albain, Patricia Robinson. Association of metabolic syndrome, its components and multigene assays for recurrence risk [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 P6-08-42.

Prospective comparison of recurrence score and independent central pathology assessment of prognostic tools in early breast cancer (BC): Focus on HER2, ER, PR, Ki-67 results from the phase III WSG-Plan B trial.

552 Background: Use of multi-gene real-time PCR (RT-PCR) based assays e.g. Recurrence Score (RS) and single markers (grade, uPA/PAI-1, ER/PR, HER2, KI-67) is currently controversially discussed in early BC. Here, we present the final WSG-planB trial correlation analysis of risk assessment tools and first prospective comparison of independent central pathology IHC/FISH assessment and RT-PCR for single markers. Methods: Plan B trial (n=2,448 randomized for 6xTC vs. 4xEC-4xDOC in locally HER2- BC). RS has been used as selection criterion for cht omission in HR+ BC (if RS<11 in pN0 or pN1). uPA/PAI-1 was optionally obtained. Grade, ER/PR, HER2 (IHC/FISH), Ki-67 were evaluated by the independent trial pathologist in all tumors. Results: From 04/09 to 11/11, 3196 patients have been recruited and 2448 randomized. RS distribution in 2551 HR+ tumors: 0-11 (18%), 12-25 (60%), >25 (22%). In 354 pN0-1 patients, cht was omitted based on low risk RS (88% compliance). Central grade for n=3038 and IHC/FISH results are currently available in n=1476. Moderately significant correlations were only found between RS and both central grade (rs=0.313; p<0.001) as well as Ki-67 (rs=0.374; p<0.001) and a weak one for uPA/PAI-1, particularly due to poor correlations within the RS group <26. In 1476 locally HER2- cases, n=9 were found as 3+ and/or FISH+ by central analysis. In 6 HR+/HER2+ cases, RS revealed 2 positive, 2 equivocal and 2 negative results. In 7 cases positive for HER2 by RT-PCR central pathology revealed 4 negative results. 24 locally HR+ cases are assessed as HR- in central pathology (2%). Among these, 6 were ER positive by RT-PCR. Final correlation analyses will be presented at the meeting. Conclusions: These first prospective data demonstrate that high-risk status according to RS is predictive of high risk by other factors, but the converse is not true. Regarding controversial HER2 and HR status by RT-PCR and IHC/FISH, we found few cases with false-negative or positive RT-PCR results in HER2- BC by local pathology. However, these discrepancies could potentially have a substantial impact on clinical patient management.

Concordance between the 21-gene recurrence score (RS) and the 70-gene profile (MP) in breast cancer (BC) patients (pts).

13 Background: Genomic assays are increasingly incorporated into treatment planning for pts with early stage BC to provide prognostic and/or predictive information. MP is a validated predictor of recurrence risk (RR) in pts without any treatment and RS is a validated predictor of RR in pts treated with 5 years of hormonal therapy (HT). Because concordance between RS and MP is largely unknown, we analyzed concordance in untreated pts that had both tests performed. Methods: Data are from 50 early stage BC pts treated at 4 US Oncology practices and the University of California, San Francisco. We used linear regression to test whether clinical features were related to discordance, measured as part of the gamma statistic. Results: Median age was 52.5 years, 16% (8 pts) had micro or macroscopic nodal involvement, and 66%, 30%, and 4% of pts had stage I, II, and III disease, respectively. All pts had estrogen receptor positive disease and 2 pts had HER2 overexpression by IHC or FISH. Concordance of MP and RS is shown below. Clinical features, including tumor size, grade, and HER2 were not significantly related to discordance. Gamma concordance was 0.64 (95% CI 0.28 to 0.98, p=0.0013). Conclusions: Concordance is high, mostly due to agreement in low risk scores. Five cases are truly discordant (MP low/RS intermediate or high) based on predicted outcomes. The 11 cases with high-risk MP with low risk RS may reflect endocrine sensitivity to 5 years of HT, or true discordance. Our identification of discordance should stimulate research to further clarify biology and elucidate the drivers of different types of risk. Large studies are underway to refine risk definition and treatment recommendations. [Table: see text]

The influence of the 21-gene recurrence score assay on decision making about adjuvant chemotherapy in stage I-II estrogen receptor-positive breast cancer: Experience at a single center with a uniform treatment policy.

660 Background: The 21-gene assay (OncotypeDx) recurrence score (RS) has been validated in retrospective studies as prognostic of distant disease recurrence and predictive of benefit of chemotherapy in estrogen receptor (ER)-positive breast cancer. Published data on the impact of the assay on clinical practice is limited. We analyze the influence of the RS on decision making in 135 patients seen in a single practice with a unified treatment policy. Methods: Patients with stage I and II breast cancer, ER-positive, Her2-negative who had no contraindications to chemotherapy were eligible. Clinical and pathologic data were recorded, as was the recommendation on adjuvant chemotherapy both before and after obtaining the RS. The test was performed by Genomic Health (Redwood City, CA, USA) on paraffin imbedded tissue from surgical specimens or biopsies. Our treatment policy was to give adjuvant chemotherapy for high risk RS (> 30), endocrine therapy alone for low risk RS (< 18), and for intermediate risk RS (18-30) to decide based on classical clinicopathologic features. Results: From 2/2006 to 6/2009 RS was obtained on 135 patients, including 3 males. Median age 58 (range 33-75). Histologic grade: low 36 (26.7%), intermediate 82 (60.7%), high 7 (5.2%), undetermined 10 (7.4%). Node-negative: 115 (85.2%). RS results: median 19 (range 1-57). RS risk: low 70 (51.9%), intermediate 50 (37%), high 15 (11.1%). Prior to RS result, 64 (47.4%) were recommended for chemotherapy, while after RS result 50 (37.0%) were recommended for chemotherapy. Of the 34 (25.2% [95%CI 17.9-32.5]) patients for whom recommendation was changed, 10 (7.4%) were changed to chemotherapy, and 24 (17.8%) were changed to endocrine therapy. Recommendation was unchanged in 101 (74.8% [95%CI 67.4-82.1%]). RS was independent of T stage, Ki67, and ethnic group. There were insufficient cases of high grade to evaluate correlation with grade. Conclusions: The 21-gene RS, when applied in a consistent manner in early stage breast cancer, changes the treatment plans in one quarter of patients tested. No significant financial relationships to disclose.

Complementary Value of the Ki-67 Proliferation Index to the Oncotype DX Recurrence Score

Oncotype DX is a 21-gene assay that quantifies the recurrence risk in estrogen receptor-positive breast cancer, which is expressed as the recurrence score (RS). Studies have shown that patients with a high-risk RS will most likely benefit from adjuvant chemotherapy, but there is no proven advantage for patients with a low-risk RS who still face an average recurrence risk of 7%. In this study, the relationship between the RS and the cell cycle-related antigen Ki-67 was assessed in 32 breast carcinomas and evaluated for a potential association. Comparison of the RS with tumor type, grade, and the Ki-67 proliferation index (PI) revealed an overall concordance. However, some tumors with a low RS revealed a surprisingly high Ki-67 PI. These cases may correspond to the 7% of low-risk RS carcinomas that recur. Therefore, the authors propose a combined evaluation of the RS and Ki-67 PI to identify tumors with high recurrence potential from the low-risk and intermediate-risk RS groups.

A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients

IntroductionThe Oncotype DX assay was recently reported to predict risk for distant recurrence among a clinical trial population of tamoxifen-treated patients with lymph node-negative, estrogen receptor (ER)-positive breast cancer. To confirm and extend these findings, we evaluated the performance of this 21-gene assay among node-negative patients from a community hospital setting.MethodsA case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with node-negative invasive breast cancer from 1985 to 1994 and not treated with adjuvant chemotherapy. Cases (n = 220) were patients who died from breast cancer. Controls (n = 570) were breast cancer patients who were individually matched to cases with respect to age, race, adjuvant tamoxifen, medical facility and diagnosis year, and were alive at the date of death of their matched case. Using an RT-PCR assay, archived tumor tissues were analyzed for expression levels of 16 cancer-related and five reference genes, and a summary risk score (the Recurrence Score) was calculated for each patient. Conditional logistic regression methods were used to estimate the association between risk of breast cancer death and Recurrence Score.ResultsAfter adjusting for tumor size and grade, the Recurrence Score was associated with risk of breast cancer death in ER-positive, tamoxifen-treated and -untreated patients (P = 0.003 and P = 0.03, respectively). At 10 years, the risks for breast cancer death in ER-positive, tamoxifen-treated patients were 2.8% (95% confidence interval [CI] 1.7–3.9%), 10.7% (95% CI 6.3–14.9%), and 15.5% (95% CI 7.6–22.8%) for those in the low, intermediate and high risk Recurrence Score groups, respectively. They were 6.2% (95% CI 4.5–7.9%), 17.8% (95% CI 11.8–23.3%), and 19.9% (95% CI 14.2–25.2%) for ER-positive patients not treated with tamoxifen. In both the tamoxifen-treated and -untreated groups, approximately 50% of patients had low risk Recurrence Score values.ConclusionIn this large, population-based study of lymph node-negative patients not treated with chemotherapy, the Recurrence Score was strongly associated with risk of breast cancer death among ER-positive, tamoxifen-treated and -untreated patients.