High Oncotype DX Recurrence Score Research Articles

Chemotherapy benefit for ‘ER-positive’ breast cancer and contamination of Nonluminal subtypes—waiting for TAILORx and RxPONDER

BackgroundRetrospective analyses of NSABP B20 and SWOG 8814 showed a large benefit of chemotherapy in patients with ER-positive tumors and high OncotypeDX Recurrence Score (RS≥31). However, it might be possible that both studies may be contaminated by non-luminal tumors, especially in high-risk RS group. MethodsWe conducted simulations in order to obtain a better understanding of how the NSABP B20 and SWOG 8814 results would have been if non-luminal breast cancer would have been excluded. Simulations were done separately for the node-negative and node-positive cohorts. Results and conclusionThe results of the simulations suggest that the non-luminal tumors are augmenting the apparent benefit of chemotherapy, but do not appear to be responsible for the entire effect. These simulations could provide information about the potential influence of contamination by unexpected tumor subtypes on the future results of TAILORx and RxPONDER clinical trials

Abstract P2-02-12: Computer derived image features on DCE-MRI appear to distinguish estrogen receptor-positive breast cancers with low and high oncotype DX recurrence scores

Abstract The Oncotype DX (ODX) is a 21 panel gene-expression based assay for identifying which Estrogen Receptor-positive (ER+) breast cancer (BCa) patients are candidates for adjuvant chemotherapy. The objective of this research was to identify whether computerized texture features on a staging DCE-MRI can distinguish ER+ BCa with low and high ODX recurrence scores (RS) (i.e. to distinguish which ER+ BCa patients are more likely to benefit from adjuvant hormonal therapy from those who require chemotherapy). This would provide a non-invasive, imaging based, pre-therapeutic assessment tool for predicting the appropriate treatment regimen. This work, to the best of our knowledge, is the first attempt to quantitatively correlate low versus high risk stratification via computer derived MRI measurements to corresponding risk stratification via the ODX assay. 52 ER+ BCa patient studies with high (>30, N = 28) and low (<18, N = 24) ODX RS were available for this study from two sites; 16 breast MRIs from the Boston Medical Center using a Phillips 1.5T magnet with a 7-channel breast coil, and 36 MRIs from the Case Medical Center using a Siemens 1.5T magnet with a 8-channel breast coil. All datasets included T1w images obtained prior to, during, and after administration of 0.1 mmol/kg of Gd-DTPA and corresponding ODX RS. For each study a radiologist picked a representative slice showing the tumor and then manually segmented the region of interest (ROI) containing the lesion. Computerized image analysis tools developed in-house via the MATLAB© programming platform were applied to the manually segmented lesion ROI for each of the 52 MRI studies to quantitatively characterize the lesion via a set of (a) 6 shape, (b) 3 pharmacokinetic (Ktrans, ve, kep) based on Tofts model (PK), (c) 12 enhancement kinetic (EK), (d) 12 intensity kinetic (IK), (e) 312 textural kinetic (TK), (f) 6 dynamic local binary pattern (DLBP), and (g) 5 dynamic histogram of oriented gradient (DHoG) features. The computer extracted features were evaluated via a linear discriminant analysis (LDA) classifier in terms of their ability to distinguish ER+ BCa as having a low or high ODX RS via a 2-fold randomized cross validation scheme. At each iteration, half of the studies were randomly selected from the 52 cases and used for training the LDA classifier and the remaining 26 studies were used for independent testing. This process was repeated 200 times. Classification performance was evaluated by area under the ROC curve (AUC). Higher AUC values suggest a stronger relationship between risk stratification via MRI attributes and ODX. Table 1Feature classAccuracy (μ±Δ)AUC (μ±Δ)DHoG87.07%±5.66%0.89±0.04DLBP85.86%±7.82%0.83±0.07EK82.36%±8.46%0.80±0.06PK81.14%±7.55%0.78±0.07TK75.93%±6.65%0.76±0.08IK76.43%±7.23%0.75±0.12Shape71.04%±6.81%0.70±0.06 Table 1 illustrates the mean and standard deviation in accuracy and AUC values over 200 runs of randomized cross validation. DHoG, DBLP and EK features yielded the highest classification accuracy and AUC. Although lesion shape has been shown to be important for discriminating benign and malignant lesions on MRI, shape appears to be less useful in distinguishing between ER+ BCa lesions with low and high ODX RS. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-02-12.

Abstract P2-11-12: Validation of modified Magee equations for predicting the oncotype DX recurrence score: A cost-effective alternative for estimating the risk of distant recurrence in receptor positive/node negative breast cancer patients

Abstract INTRODUCTION: Oncotype DX (ODX) (Genomic Health, Redwood City, CA, USA) is a multigene quantitative reverse transcription-polymerase chain reaction-based assay used to estimate the risk of distant recurrence for ER-positive, node negative-breast cancer patients. The quoted list price for ODX is $4.175.00. ODX reports a recurrence score (RS) that is divided into low (< 18), intermediate (18-30), and high risk (≥ 30). The ODX RS has been shown to be prognostic and predict chemotherapy benefit in receptor positive breast cancer patients. The RS most highly weights genes related to proliferation (including Ki-67), HER-2, ER and PR. Klein et al. have previously shown that standard histological variables, in combination with semiquantitative ER, PR, HER-2, and Ki-67 results, can provide information similar to that found in the ODX RS using equations derived by linear regression analysis (Magee equations). In the current study, we have used a modification of these equations to validate their use in a cohort of breast cancer cases that were sent for ODX from our institution. MATERIALS AND METHODS: 233 cases (2009-present) with available ODX RS's (208 of these with Ki-67 results) were obtained from the pathology files at the University of Rochester Medical Center (URMC), and the histopathologic variables were extracted from the reports. Estimated RS's (URMC RS) were calculated by averaging results from the three published Magee equations, with a modification of the H-score for ER and PR. We estimated the H-score by multiplying the average intensity of staining by the% positive tumor cells. URMC RS's were compared with their paired ODX RS’s. RESULTS: The table shows the correlation between the ODX RS and URMC RS. 100% of cases with a high URMC RS also had a high ODX RS. There were no two step discordant results between a URMC RS and an ODX RS. A URMC RS correlated with an ODX RS of high, intermediate, and low in 7/12 (58%), 48/79 (61%) and 97/117 (83%) cases, respectively. Most of the discordant cases involved the intermediate/low groups, and the higher RS's in the discordant pairs were consistently close to the lower end cutoff point.The URMC RS and ODX RS would have resulted in similar treatment in 100% of patients. Comparison of ODX RS and URMC RS; n = number of cases (URMC median, URMC range) ODX RS ⇒URMC RS ⇓HIGHINTERMEDIATELOWHIGH7 (35,32-40)00INTERMEDIATE5 (25,22-28)48 (22,18-30)20 (20,18-27)LOW031 (15,9-18)97 (14,7-18) CONCLUSION: The modified Magee equations provide similar information as the ODX RS using information already generated by many laboratories, and may be a more cost-effective alternative than ODX in identifying breast cancer patients who might benefit from chemotherapy, or be spared its potential toxicity. If the estimated RS is clearly high or low, it is predictive of the ODX RS with a high degree of certainty. In our population a potential cost of $556,875.00 might have been avoided using the estimated RS. The estimated RS should not be dramatically different from the ODX RS. If there is a significant difference, this should be thoroughly investigated before decisions on adjuvant therapy are made. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-12.

The impact of the Oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis

The impact of the Oncotype Dx (ODX) breast cancer assay on adjuvant chemotherapy (ACT) treatment decisions has been evaluated in many previous studies. However, it can be difficult to interpret the collective findings, which were conducted in diverse settings with limited sample sizes. We conducted a systematic review and meta-analysis to synthesize the results and provide insights about ODX utility. Studies, identified from PubMed, Embase, ASCO, and SABCS, were included if patients had ER+, node -, early-stage breast cancer, reported use of ODX to inform actual ACT decisions. Information was summarized and pooled according to: (1) distribution of ODX recurrence scores (RS), (2) impact of ODX on ACT recommendations, (3) impact of ODX on ACT use, and (4) proportion of patients following the treatment suggested by the ODX RS. A total of 23 studies met inclusion criteria. The distribution of RS categories was 48.8 % low, 39.0 % intermediate, and 12.2 % high (21 studies, 4,156 patients). ODX changed the clinical-pathological ACT recommendation in 33.4 % of patients (8 studies, 1,437 patients). In patients receiving ODX, receipt of ACT were: 28.2 % overall, 5.8 % low, 37.4 % intermediate, and 83.4 % high. Low RS patients were significantly more likely to follow the treatment suggested by ODX versus high RS patients RR: 1.07 (1.01–1.14) [corrected].The pooled results are consistent with most individual studies to date. The increased proportion of intermediate scores relative to original estimates may have implications for the clinical utility and cost impacts of testing. In addition, low versus high RS patients were significantly more likely to follow the ODX results, suggesting a tendency toward less aggressive treatment, despite a high ODX RS. Finally, there was a lack of studies on the impact of ODX on ACT use versus standard approaches, suggesting that additional studies are warranted.

A mitotically active, cellular tumor stroma and/or inflammatory cells associated with tumor cells may contribute to intermediate or high Oncotype DX Recurrence Scores in low-grade invasive breast carcinomas

Oncotype DX is an RT-PCR-based 21-gene assay validated to provide prognostic and predictive information in the form of a Recurrence Score in patients with estrogen receptor-positive, lymph node-negative breast cancer. Although the Recurrence Score was shown to correlate with several histopathological tumor features, there is a significant proportion of cases showing an apparent discrepancy between Recurrence Score and risk estimates based on the traditional clinicopathological tumor features. In this study, we tested whether a proliferating, cellular stroma and/or admixed inflammatory cells may result in an artificially increased Recurrence Score in low-grade invasive breast cancers. We analyzed the histopathological features in 141 low-grade invasive breast carcinomas, including 41 special type (tubular, cribriform and mucinous) carcinomas, with available Recurrence Score. The tumor stroma was evaluated for increased cellularity and presence of inflammatory cells. Double immunohistochemical stains for pancytokeratin and Ki-67 was performed to assess the cell proliferation in tumor vs stromal/inflammatory cells. The clinicopathological features of tumors with Recurrence Score <18 (low risk) were compared with those with Recurrence Score ≥18 (intermediate/high risk). Carcinomas associated with Recurrence Score ≥18 showed lower progesterone receptor immunoreactivity, increased stromal cellularity and presence of inflammatory cells associated with the tumor. Double immunohistochemical stains showed significantly increased proliferation in stromal/inflammatory cells compared with carcinoma cells in cases associated with Recurrence Score ≥18. A Ki-67-positive stromal/tumor cells ratio of >1 predicted Recurrence Score ≥18 with an area under the curve of 0.8967 on receiver operator curve analysis (P<0.0001). Our results suggest that the presence of increased stromal cellularity and/or associated inflammatory cells in low-grade invasive breast carcinomas may contribute to an apparently increased risk of recurrence according to Oncotype DX Recurrence Score. Careful assessment and correlation with histopathological features in such cases may help in determining the appropriate patient management.

Can Features Evaluated in the Routine Pathologic Assessment of Lymph Node–Negative Estrogen Receptor–Positive Stage I or II Invasive Breast Cancer Be Used to Predict the Oncotype DX Recurrence Score?

Oncotype DX is a multigene reverse transcription-polymerase chain reaction assay used to quantify recurrence risk in patients with stage I or II estrogen receptor-positive, lymph node-negative invasive breast cancer. The results are reported as a Recurrence Score (RS). The 16 cancer genes evaluated include a proliferation set, hormone receptor set, and HER2 set. The activity of these genes is addressed by pathologic assessment of breast cancers. To determine if factors evaluated in pathologic evaluation of breast cancer could be used to predict Oncotype DX results. We studied 138 cases of invasive breast cancer for which Oncotype DX results and pathology data were available. Grading was performed by using Nottingham grading system. For hormone receptor immunostaining, 10% nuclear staining was considered a positive result. Oncotype DX RS was low in 81 cases, intermediate in 44 cases, and high in 13 cases. All 6 cases with both a negative progesterone receptor (PR) and a mitotic count score of 3 had a high RS. All 12 cases with both a negative PR and a mitotic count score greater than 1 had either an intermediate or high RS. Although Nottingham grade, PR status, mitotic count score, tumor size, and nuclear grade were each significantly associated with RS, in bivariate analyses the only variables that remained independently predictive of an intermediate or high RS score in a multivariate logistic regression model were negative PR and mitotic count score greater than 1. Our study suggests that a mitotic count score greater than 1 combined with a negative PR result, as determined by pathologic assessment, could serve as a marker for an intermediate or high Oncotype DX RS.