Amila Orucevic

Prognostic Value of Breast Cancer Subtypes, Ki‐67 Proliferation Index, Age, and Pathologic Tumor Characteristics on Breast Cancer Survival in Caucasian Women

Estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) status are well‐established prognostic markers in breast cancer management. The triple negative breast carcinoma subtype (ER‐/PR‐/HER2‐) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. We evaluated the prognostic value of breast cancer subtypes, Ki‐67 proliferation index (Ki‐67PI), and pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution, where greater than 90% of the total patient population is white. From 628 new invasive breast cancer cases in our data base (2000‐late 2004), 593 (94%) were identified in Caucasian women. ER/PR/HER2 breast cancer subtypes were classified based on St. Gallen International Expert Consensus recommendations from 2011. ER/PR/HER2 status and its effect on survival were analyzed using a Kaplan–Meier curve. ER/PR/HER2 status, grade, tumor‐node‐metastasis status (TNM)/anatomic stage, and age were analyzed in terms of survival in a multivariate fashion using a Cox regression. Ki‐67PI was analyzed between ER/PR/HER2 groups using the Kruskal–Wallis, Mann–Whitney U‐tests, and 2 × 5 ANOVA. Our results showed that patients with stage IIB through stage IV breast carcinomas were 2.1–16 times more likely to die than patients with stages IA‐B and IIA disease, respectively (95% CI 1.17–3.81 through 9.68–28.03, respectively), irrespective of ER/PR/HER2 subtype. Similar effect was seen with T2, N2/N3, or M1 tumors in comparison with T1, N0/N1, and M0 tumors. Chances of dying increase approximately 5% for every year increase in age. There was a significant main effect of Ki‐67PI between ER/PR/HER2 subtypes, p < .001, but Ki‐67PI could not predict survival. In summary, TNM status/anatomic stage of breast carcinomas and age are predictive of survival in our patient population of Caucasian women, but breast carcinoma subtypes and Ki‐67 proliferation index are not.

Is the TNM staging system for breast cancer still relevant in the era of biomarkers and emerging personalized medicine for breast cancer - an institution's 10-year experience.

We have previously demonstrated that TNM status and age were significant predictors of overall survival (OS) in our study population of Caucasian patients with invasive breast carcinoma (2000–2004 study period). However, estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) biomarker expression was not predictive of OS when using the five‐group ER/PR/HER2 subtype classification system recommended by St. Gallen International Consensus Panel in 2011. The current study reassessed the relevance of tumor biomarkers (ER/PR/HER2) in our study population using a recently proposed biologic TNM (bTNM) classification system in which the inclusion of triple negative ER/PR/HER2 phenotype (TNP) could improve the prognostic accuracy of TNM for staging, prognosis and treatment of breast cancer patients. Seven hundred eighty‐two Caucasian women diagnosed with invasive ductal carcinoma from 1998 to 2008 were grouped according to their TNM stage and TNP versus non‐TNP ER/PR/HER2 phenotype. OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis. TNM stage (Stage II = HR 1.41, 95% CI 1.01–1.97; Stage III = HR 3.96, 95% CI 2.68–5.88; Stage IV = HR 27.25, 95% CI 16.84–44.08), and age (HR 1.05, 95% CI 1.04–1.06) were significant predictors of OS. TNP significantly worsened prognosis/survival only in higher TNM stages (Stage III = HR 3.08, 95% CI 1.88–5.04, Stage IV = HR 24.36, 95% CI 13.81–42.99), but not in lower stages (I and II). Our data support the traditional TNM staging as a continued relevant predictive tool for breast cancer outcomes and show that biomarkers primarily improve the accuracy of TNM staging in advanced stages of breast cancer. We suspect that type of ER/PR/HER2 classification system(s) (St. Gallen, TNP, etc.), characteristics of populations studied (Caucasians, minorities, etc.), and the time period chosen for a study are major factors that determine impact of biomarkers on the prognostic accuracy of TNM. We propose systematic analyses of these factors before biomarkers are fully incorporated into the TNM staging system (bTNM).

Breast Cancer in Elderly Caucasian Women—An Institution-Based Study of Correlation between Breast Cancer Prognostic Markers, TNM Stage, and Overall Survival

There is still a paucity of data on how breast cancer (BC) biology influences outcomes in elderly patients. We evaluated whether ER/PR/HER2 subtype and TNM stage of invasive BC had a significant impact on overall survival (OS) in a cohort of 232 elderly Caucasian female patients (≥70 year old (y/o)) from our institution over a ten-year interval (January 1998–July 2008). Five ER/PR/HER2 BC subtypes classified per 2011 St. Gallen International Expert Consensus recommendations were further subclassified into three subtypes (traditionally considered “favorable” subtype-ER+/PR+/HER2−, and traditionally considered “unfavorable” BC subtypes: HER2+ and triple negative). OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis, when controlled for TNM stage. The majority of our patients (178/232 = 76.8%) were of the “favorable” BC subtype; 23.2% patients were with “unfavorable” subtype (HER2+ = 12% (28/232) and triple negative = 11.2% (26/232)). Although a trend for better OS was noted in HER2+ patients (68%) vs. 56% in ER+/PR+ HER2− or 58% in triple negative patients, “favorable” BC subtype was not significantly predictive of better OS (p = 0.285). TNM stage was predictive of OS (p < 0.001). These results are similar to our published studies on Caucasian BC patients of all ages in which ER/PR/HER2 status was not predictive of OS, irrespective of classification system used.

Abstract P3-07-17: Analysis of the National cancer data base 2010-2012 oncotype DX breast cancer assay: Lessons learned

Oncotype DX (OD) 21-gene breast cancer (BC) assay is used for testing of estrogen receptor positive (ER+) early stage BC and provides a low, intermediate or high 10-year risk recurrence score (LRS, IRS, HRS) for BC. Scores are used as guidelines to predict the probability of successfully adding adjuvant chemotherapy (AC) to endocrine therapy (ET) to reduce the risk of BC recurrence. In retrospective analysis of 2 clinical trials, patients (pts) with HRS benefited from addition of AC to ET, no benefits were shown for LRS, and benefits of AC for IRS were not clear. The OD assay has been utilized since 2004, but data on the impact of using assay results in clinical practice across the US are lacking. The TAILORx and RxPONDER prospective clinical trials which are using OD scores are ongoing (results will be available in 2017 and 2022, respectively) and may help clinicians better understand the predictive capabilities of the IRS OD score. We analyzed the current impact of IRS OD score in a retrospective observational study of the National Cancer Data Base (NCDB) (which represents 75% of the US population) from 2010-2012. This time period encompasses the beginning of required recording of molecular assays and the latest data released by NCDB in 4/2015. Demographic and clinical variables of all pts with IRS results were analyzed using frequency statistics, chi-square and logistic regression analysis. Data from 24260/27995 pts with IRS and documented AC information was analyzed. 11520=47.4% pts received AC. Age ranged from 20-90 (mean 58.4, median 59 years); 99.2% were ER+ and females, 2.7% were HER2+; 6143=25.3% had T1a, T1b or T3 tumors; 19791=81.5% were N0, 3684=15.1% N1; 17950=73.6% had ≥G2 tumors and 3389=14% had lymphvascular invasion (LVI). IRS OD result had poor PPV for the administration of AC (47.4%). AC administration was significantly associated with larger tumors, LN+, LVI, high tumor grade, higher TNM stage, younger age and black race (p 0.05). Medicare pts were less likely to receive AC than ones with private insurance (p Our data analysis reveals that additional guidelines for selection of pts for OD testing and new algorithms for AC administration in the IRS subsets are needed. The authors of this abstract solicit a call to action from interested parties on behalf of the patients affected by this conundrum. Citation Format: Orucevic A, Heidel RE, Bell JL. Analysis of the National cancer data base 2010-2012 oncotype DX breast cancer assay: Lessons learned. [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 P3-07-17.

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

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). 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.

Abstract P3-07-18: Utilization and impact of oncotype DX 21- gene breast cancer assay in clinical practice across the US: 2010-2012 National cancer data base analysis

Oncotype DX (OD), initially used for early stage estrogen receptor-positive (ER+), node-negative (LN-) invasive breast cancers (BC) and later also for ER+ and 1-3 LN+BC, provides a low, intermediate or high 10-year risk recurrence score (LRS, IRS or HRS) for BC. Based on the score, the addition of adjuvant chemotherapy (AC) to endocrine therapy is recommended for HRS; no benefit for LRS, and unclear benefits for IRS. The test has been in use since 2004. Payment for OD was approved by the Centers for MedicareM 406525 were ER+. 86409 patients with known OD results were analyzed (23.7% of ER+). Patients age range from 19-90 (mean 58.8, median 59 years); 99.1% were females. 57.9% of tests followed National Comprehensive Network (NCCN)-defined intermediate risk guidelines (ER+/LN- tumors >1cm), while 15.5% of tests included N1 disease and 25.7% included T1a, T1b and T3 tumors. LRS had 90.1% negative predictive value (NPV) for no AC administration. IRS had 47.4% positive predictive value (PPV) and HRS had 88.9% PPV for AC administration. The OD is obtained in almost ¼ of ER+BC patients across the US. Its application across geographic and racial groups is fair. Factors influencing patient selection for OD test and AC administration upon obtaining IRS results require further study. Citation Format: Orucevic A, Heidel RE, Bell JL. Utilization and impact of oncotype DX 21- gene breast cancer assay in clinical practice across the US: 2010-2012 National cancer data base analysis. [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 P3-07-18.