The skyrocketing cost of health‐care demands that we question when to use multigene assay testing in the planning of treatment for breast cancer patients. A previously published algorithmic model gave recommendations for which cases to send out for Oncotype DX ® (ODX) testing. This study is a multi‐institutional validation of that algorithmic model in 620 additional estrogen receptor positive breast cancer cases, with outcome data on 310 cases, named in this study as the Rochester Modified Magee algorithm (RoMMa). RoMMa correctly predicted 85% (140/164) and 100% (17/17) of cases to have a low‐ or high‐risk ODX recurrence score, respectively, consistent with the original publication. Applying our own risk stratification criteria, in patients who received appropriate hormonal therapy, only one of the 45 (2.0%) patients classified as low risk by our original algorithm have been associated with a breast cancer recurrence over 5‐10 years of follow‐up. Eight of 116 (7.0%) patients classified as low risk by ODX have been associated with a breast cancer recurrence with up to 11 years of follow‐up. In addition, 524 of 537 (98%) cases from our total population (n = 903) with an average modified Magee score ≤18 had an ODX recurrence score <26. Patients with an average modified Magee score ≤18 or >30 may not need to be sent out for ODX testing. By avoiding these cases sending out for ODX testing, the potential cost savings to the health‐care system in 2018 are estimated to have been over $100,000,000.
BackgroundClinical assays for the assessment of the human epidermal growth factor receptor-2 (HER2) status in breast cancer include immunohistochemistry (IHC) and in situ hybridization (ISH), both of which have limitations. Recent studies have suggested that a more quantitative approach to the measurement of HER2 protein expression may improve specificity in selecting patients for HER-2 targeted therapy. In the current study, we have used HER2 expression in breast cancer cell lines and clinical samples as a model to explore the potential utility of a novel immunodetection technique, using streptavidin coated Phosphor Integrated Dot fluorescent nanoparticles (PID), which can be quantitatively measured using computer analysis.MethodsThe expression of HER2 protein in cell lines was evaluated with antibody-binding capacity using fluorescence-activated cell sorting (FACS) for comparison with PID measurements to test for correlations with existing quantitative protein analysis methodologies. Various other analytic validation tests were also performed, including accuracy, precision, sensitivity, robustness and reproducibility. A methods comparison study investigated correlations between PID versus IHC and ISH in clinical samples. Lastly, we measured HER2 protein expression using PID in the pretreatment biopsies from 34 HER2-positive carcinomas that had undergone neoadjuvant trastuzumab-based chemotherapy.ResultsIn the analytic validation, PID HER2 measurements showed a strong linear correlation with FACS analysis in breast cell lines, and demonstrated significant correlations with all aspects of precision, sensitivity, robustness and reproducibility. PID also showed strong correlations with conventional HER2 testing methodologies (IHC and ISH). In the neoadjuvant study, patients with a pathologic complete response (pCR) had a significantly higher PID score compared with patients who did not achieve a pCR (p = 0.011), and was significantly correlated to residual cancer burden (RCB) class (p = 0.026, R2 = 0.9975).ConclusionsAnalytic testing of PID showed that it may be a viable testing methodology that could offer advantages over other experimental or conventional biomarker diagnostic methodologies. Our data also suggests that PID quantitation of HER2 protein may offer an improvement over conventional HER2 testing in the selection of patients who will be the most likely to benefit from HER2-targeted therapy. Further studies with a larger cohort are warranted.
Introduction: The recent TAILORx results suggests that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone–positive, HER2-negative, axillary node–negative breast cancer who had an Oncotype Dx recurrence score (ODXRS) between 11 and 25. These findings, along with updated results that patients with an ODXRS < 11 have a 9-year recurrence rate of only 3%, suggest that certain populations of patients with an ODXRS ≤ 25 may not benefit from additional systemic chemotherapy. Oncotype Dx is an expensive test (current list price of $4,650.00), and cost has been an impediment to its adoption in many centers throughout the United States, and internationally. The test can be performed only at a commercial specialized laboratory. Based on a modification of the new Magee equations (Klein ME, et al. Mod Pathol. 2013;26(5):658–664) we published an algorithm based on 283 patients with ODXRS's (Turner BM, et al. Mod Pathol. 28(7):921-31) that suggested our algorithm offered a less expensive alternative to Oncotype DX testing. We have validated this algorithm in a multi-institutional study on an additional 619 patients with ODXRS's (in preparation for publication). Our validation data, and our data from the original study, also suggests that the average modified Magee equation can reliably predict patients who will have an ODXRS ≤ 25. Methods: 903 cases with an available ODXRS (2006-2018) were identified from the pathology files at the University of Rochester Medical Center (n = 752) and the University of Louisville (n = 151). Information required to calculate the average modified Magee score, which includes estrogen receptor (ER) and progesterone receptor (PR) status, Her-2 status, Nottingham score, tumor size, and Ki-67 were also extracted from the medical record. 78 patients did not have an available Ki-67, leaving 825 patients for inclusion in this study. Results: 478/488 (98%) patients with an average Modified Magee score ≤ 18 had an ODXRS ≤ 25 (only 2% had an ODXRS > 25 - Table 1). 125/337 (37%) patients with an average Modified Magee score >18 had an ODXRS > 25 (Table 1) . Conclusions: The average Modified Magee Score can be helpful in predicting an ODXRS ≤ 25. Patients with an average Modified Magee score ≤ 18 may not need to be sent out for Oncotype Dx testing. The potential cost savings to the health care system would be enormous. Table 1:Average Modified Magee score and risk of an Oncotype Dx recurrence score (ODXRS) > 25Magee scorenAverage ODXRSMinimum ODXRS valueMaximum ODXRS valueCases with ODXRS > 25 [n (%)]≤ 91811.02190 (0)102110.90261 (4.8)113712.10250 (0)126012.00281 (1.7)136412.00230 (0)147012.90271 (1.4)156513.61313 (4.6)165614.12292 (3.6)175214.50272 (3.8)184514.30250 (0)195418.96379 (16.7)204319.30348 (18.6)215921.193715 (25.4)223819.32496 (15.8)232523.383811 (44)242920.83329 (31)252325.0144011 (47.8)> 25-272729.2174620 (74.1)> 27-301634.9225113 (81.3)> 302345.7317823 (100)≤ 1848812.903110 (2)> 1833723.7078125 (37) Citation Format: Turner BM, Sanders MA, Breaux A, Soukiazian A, Soukiazian N, Hicks DG. The average modified Magee score can be helpful in predicting an Oncotype DX recurrence score ≤ 25 [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 P2-08-24.
The eighth edition 1 of the American Joint Commission on Cancer Staging (AJCC) recommends that all estrogen receptor positive (ER+), HER-2 negative, lymph node-negative patients, regardless of tumor size, be placed into the same prognostic category as pT1a-T1b N0 M0 (stage 1a) breast cancers, if the Oncotype DX recurrence score (ODXRS) is <11. We have published an algorithm 2 using a modified Magee score, based on a modification of the new Magee equations 3 , showing that this algorithm provides similar risk information to the Oncotype DX test. We used a conservative algorithmic approach to stratify patients into low, intermediate, and high-risk subgroups, with the intermediate subgroup of patients being proposed for further multigene testing. Preliminary follow-up data suggested that our algorithmic approach correctly classified breast cancer patients as "low-risk", or less likely to have a recurrence compared the intermediate or high-risk subgroups. 4 Now we present additional early follow-up data on the entire population of patients from our original study. 2 Outcome data from 248 patients (257 cases) with ER+ breast cancer with a mean age of 57.4 years (range 21-84) is presented in Table 1. None of the 38 patients with an ODXRS <11 have recurred to date, supporting the new AJCC guidelines. More concerning however, are the patients in the "low-risk" Oncotype DX category from 11-17. Six patients in this category (6%) had recurrences (Table 2). This was slightly higher than the number and percentage of patients that recurred in the intermediate ODXRS category (18-30). None of these six "low-risk" patients received systemic chemotherapy. All six of these patients had a relatively high Ki-67, relatively low proges-terone receptor (PR) immunohistochemical staining, lymphovascular invasion (LVI), and/or lymph node involvement on initial presentation. Our early data support that these are important variables when considering systemic chemotherapy in hormone receptor positive patients. Oncotype DX is a 21-gene assay that has been validated for predicting systemic chemotherapy benefit in certain populations of breast cancer patients. 5,6 Although our data support the recent changes from the AJCC regarding an ODXRS <11, it brings into question the value of using an ODXRS of 11-17, still considered low-risk by Oncotype DX, as the sole criteria for making final decisions surrounding systemic chemotherapy in hormone receptor positive patients. Alternative risk stratification methods are needed to help assess the risk of recurrence in this low-risk category group. Our outcome data support the use of both the modified Magee score and histologic variables in assisting the clinician making decisions surrounding systemic chemotherapy in hormone receptor positive patients. In a recent publication, we agreed that future work should include validation of surrogate models in additional (and diverse) clinical populations. 4 We have expanded our original study population in a multi-institutional effort, validating the clinical utilit...
INTRODUCTION: The recent TAILORx results suggest that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-positive, HER2-negative, node-negative invasive breast carcinomas with an Oncotype Dx® recurrence score < 26. Oncotype Dx® is an expensive test (current list price of $4,620.00). Although the Oncotype Dx® test has gained widespread acceptance, cost may be an impediment to its adoption in certain areas of the world, and it may not be the most cost-effective or cost-efficient option in certain subsets of breast cancer patients. Based on a modification of the new Magee equations, we published an algorithmic approach in 283 ER+ cases using an average modified Magee equation (Turner BM, et al. Mod Pathol. 2015;28(7):921-31), and subsequently published a validation of this algorithmic approach in an additional 620 ER+ cases (Cancer Med. 2019 Jun 14. doi: 10.1002/cam4.2323. [Epub ahead of print]), supporting only reflex Oncotype Dx® testing for certain subsets of breast cancer patients. We now have recurrence data and at least five years of outcome data on 310 cases. METHODS: A total of 310 cases with ER+ invasive breast cancer, all with Oncotype Dx® recurrence scores, were included in this study from the University of Rochester and the University of Louisville. The outcome analysis included all patients who had at least five years of follow-up data, and all patients who had a breast cancer recurrence. In order to calculate the average modified Magee score, information on the Nottingham score, ER, PR, Ki-67, HER-2, and tumor size was extracted from the pathology report. RESULTS: 255/310 cases had an Oncotype Dx® < 26, and 4% (10/255) of these cases were associated with a breast cancer recurrence. 187/310 cases had an average modified Magee score ≤ 18, and 184 of these 187 cases (98%) had an Oncotype Dx® recurrence score < 26. Only 2% (n = 4) of these 184 cases were associated with a breast cancer recurrence. On average, the Nottingham score and Ki-67 were lower for cases with an average modified Magee score ≤ 18 compared to cases with an Oncotype Dx® recurrence score < 26 (Table 1). On average, the modified ER and PR H-scores were higher for cases with an average modified Magee score ≤ 18 compared to cases with an Oncotype Dx® recurrence score < 26 (Table 1). CONCLUSION: If the average modified Magee score is ≤ 18, the patient has a low likelihood of recurrence, and the Oncotype Dx® recurrence score will likely be < 26. Given the recent TAILORx findings, we suggest that patients with an average modified Magee score ≤ 18 not be sent out for Oncotype Dx® testing if an Oncotype Dx® recurrence score < 26 is the basis on which the clinician will use to decide whether or not to give chemotherapy. The information needed to use the average modified Magee equation is already generated by many pathology laboratories during the initial assessment of breast cancer, and the Magee equations are free of charge (https://path.upmc.edu/onlineTools/mageeequations.html). Based on the Genomic Health 2017 Annual Report, our data suggests that not sending out cases with an average modified Magee score ≤ 18 would have resulted in a potential cost savings to the health-care system in 2018 of almost 300 million dollars. Table 1: Average Nottingham score, modified ER H-score, modified PR H-score, and Ki-67, with number and percent recurrence for cases with an average modified Magee score ≤ 18 and cases with an Oncotype Dx® recurrence score < 26AVERAGERecurrence Sore typeNNS**ER***PR***Ki-67Recurrence N (%)Average modified Magee score ≤ 18*1875.2262.3235.410.34 (2)Oncotype Dx® recurrence score < 262555.5253.2192.613.610 (4)*98% (184/187) of patients with an average modified Magee score ≤ 18 had an Oncotype Dx® recurrence score < 26**Nottingham score***modified H-score (Turner BM, et al. Mod Pathol. 2015;28(7):921-31) Citation Format: Hasan Khatib, Mary Ann G Sanders, Andrea Breaux, Armen Soukiazian, Nyrie Soukiazian, David Hicks, Bradley M Turner. ER+ patients with an average modified Magee score ≤ 18 have a low likelihood of breast cancer recurrence and a high likelihood of an Oncotype Dx® recurrence score < 26 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-06.
Introduction: The recent TAILORx results suggest that additional systemic chemotherapy may not be necessary in certain hormone +, HER2 -, node negative breast cancer patients with an Oncotype Dx recurrence score (ODXRS) ≤ 25. ODX is an expensive test (current list price of $4,650.00), and cost has been an impediment to its adoption in many centers throughout the world. Based on a modification of the new Magee equations (Klein ME, et al. Mod Pathol. 26[5]) we published data based on 283 patients with ODXRS's (Turner BM, et al. Mod Pathol. 28[7]), suggesting that the modified Magee equation (MME) offered a less expensive alternative to ODX testing in certain breast cancer patients. We now have outcome data suggesting that the MME along with progesterone receptor (PR), Ki-67, lymph node (LN) status, and lymphovascular invasion (LVI) status can be helpful in predicting which patients with an ODXRS ≤ 25 are more likely to recur. Methods: 248 patients with information on estrogen receptor (ER), PR, Ki-67, Her-2 status, Nottingham score, tumor size, LN status, LVI status, and an available ODXRS (2008-2018) were identified from the pathology files at the University of Rochester Medical Center. Results: All of the patients that recurred had an average modified Magee score (MMS) ≥ 14 (Table 1). Patients with LN involvement (5/43,12% ) or with LVI (5/27,19%) had a higher percentage of recurrence than patients without LN involvement (8/197, 4%) or without LVI (8/216, 4%). Patients that recurred had a significantly (p < 0.05) lower PR and higher Ki-67 than patients in the same risk class that did not recur (Table 2). Neither grade nor ER status was significantly different between patients that recurred and did not recur (Table 2). All of the patients that recurred had at least a lowered PR, higher Ki-67, LN involvement, or LVI, and most had some combination of these variables (Table 1). 8 of the 13 patients that recurred in our population (61.5%) had an ODXRS of ≤ 25. Conclusions: Risk stratification is still important in patients with an ODX score ≤ 25. The MMS along with PR, Ki-67, LN, and LVI status can be helpful in predicting patients with a higher risk of recurrence. Table 1:Recurrence dataODXRSMMSType of therapy*Nodal and LVI status**Nottingham scoreER-H score***PR-H score***Ki-671119.1NONENONE6240180271319.7HNONE530015201521.6HN51209051514HNONE5270210UNKNOWN1615HLVI527018051727.2HB62701601916.3HNONE428545UNKNOWN2424.5CLVI8240105352723.9BNONE7210100352821HN527021252823.4HB528530353128.7HB82701454432.3HNONE9210607021.4****21.4****--5.9****250.7****93.4****31.4*****H = Hormone only;C = Chemo only;B = Both; ** N = Nodal involvement;L = LVI;B = Both; ***modified (Turner BM, et al. Mod Pathol. 2015;28(7):921-31); **** average Table 2:Recurrence data in specific populationsPopulation typeNGradeER*PR*Ki-67≤ 25 no recurrence2165.4249.7185.712.8**≤ 25 recurrence85.5249.4103.325.3***> 25 no recurrence267.3211.776.834.1****> 25 recurrence56.8249.042.542.0* modified (Turner BM, et al. Mod Pathol. 2015;28(7):921-31); ** n = 181; *** n = 6; **** n = 23 Citation Format: Turner BM, Sanders MAG, Soukiazian A, Soukiazian N, Hicks DG. Reconsidering “at risk” criteria for breast cancer recurrence in hormone positive patients: Risk stratification is still important in patients with an Oncotype Dx recurrence score ≤ 25! [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 P2-08-40.
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