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Randomized Controlled Trial
. 2016 Apr 29;108(9):djw050.
doi: 10.1093/jnci/djw050. Print 2016 Sep.

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others

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Randomized Controlled Trial

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others

John M S Bartlett et al. J Natl Cancer Inst. .
Free PMC article


Background: Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population.

Methods: Three hundred thirteen women with early breast cancer were randomized to standard (chemotherapy and endocrine therapy) or test-directed (chemotherapy if Oncotype DX recurrence score >25) treatment. Risk stratification was also determined with Prosigna (PAM50), MammaPrint, MammaTyper, NexCourse Breast (IHC4-AQUA), and conventional IHC4 (IHC4). Subtype classification was provided by Blueprint, MammaTyper, and Prosigna.

Results: Oncotype DX predicted a higher proportion of tumors as low risk (82.1%, 95% confidence interval [CI] = 77.8% to 86.4%) than were predicted low/intermediate risk using Prosigna (65.5%, 95% CI = 60.1% to 70.9%), IHC4 (72.0%, 95% CI = 66.5% to 77.5%), MammaPrint (61.4%, 95% CI = 55.9% to 66.9%), or NexCourse Breast (61.6%, 95% CI = 55.8% to 67.4%). Strikingly, the five tests showed only modest agreement when dichotomizing results between high vs low/intermediate risk. Only 119 (39.4%) tumors were classified uniformly as either low/intermediate risk or high risk, and 183 (60.6%) were assigned to different risk categories by different tests, although 94 (31.1%) showed agreement between four of five tests. All three subtype tests assigned 59.5% to 62.4% of tumors to luminal A subtype, but only 121 (40.1%) were classified as luminal A by all three tests and only 58 (19.2%) were uniformly assigned as nonluminal A. Discordant subtyping was observed in 123 (40.7%) tumors.

Conclusions: Existing evidence on the comparative prognostic information provided by different tests suggests that current multiparameter tests provide broadly equivalent risk information for the population of women with estrogen receptor (ER)-positive breast cancers. However, for the individual patient, tests may provide differing risk categorization and subtype information.


Figure 1.
Figure 1.
Agreement charts for two-by-two comparison of tests according to risk groups. A) Prosigna against Oncotype DX. B) IHC4 against Oncotype DX. C) IHC4-AQUA against Oncotype DX. D) IHC4 against Prosigna. E) IHC4-AQUA against Prosigna. F) IHC4 against IHC4-AQUA. Only tests that provide three risk categories are included in this analysis. The Oncotype DX intermediate-risk group is defined as RS 18-25. The IHC4-AQUA mid-risk group was combined with the high-risk group. Rectangles are drawn for each level of the test outcomes, ie, low, intermediate, and high risk, based on the row and column cumulative totals. Thus, for the low-risk rectangle of the test 1 vs test 2 comparison, all tumors categorized as low risk by either test are included. The boundaries of the rectangles along both axes represent the number of tumors that were categorized as that outcome for each test. Black squares within the rectangles represent exact agreement between the levels of the two tests, eg, both low scores, and are of size based on the cell frequencies and located according to the cumulative totals of the previous levels. Gray rectangles represent partial agreement, where the scores from one test are within one level of those from the other test, ie, a low score on one test but intermediate on the other test. White areas within the rectangle reflect disagreement by more than level, ie, low scores on one test and high scores on the other test.

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