Table 16Clinical Validity, MammaPrint® and 70-gene signature

Study, Population characteristicsEnd points and Exclusion criteriaClinical validity and utility resultsConclusions/Comments
Buyse, 200659Exclusion criteria: Age > 61 y, TS >5cm, previous malignancy (except basal cell carcinoma), bilateral synchronous breastKM analysis stratified by MammaPrint and Adjuvant (% of patients with distant recurrence):MammaPrint is a better predictor of TTM than Age, Size, Grade, ER, Adjuvant!, NPI, St Gallen
307/403 analyzed patients, all age < 60 y, all < 5cm (ER missing: 5 patients)End points: OS, RFS, TTM Good(R>0.4), Adjuvant!Low: 52 patientsSt Gallen is a better predictor of DFS than MammaPrint
Clinical low risk/gene low risk n=52 (TS < 2cm: 67%, ER+: 100%, TG-Good: 43%, TG-Poor: 0%) OS(10years): 0.88 (0.74 to 0.95)MammaPrint is a better predictor for OS than Age, Size, Grade, ER, Adjuvant!, NPI, St Gallen
Clinical low risk/gene high risk n=28 (TS < 2cm: 59%, ER+: 100%, TG-Good: 43%, TG-Poor: 0%) Good(R>0.4), Adjuvant!High: 59 patientsThe signature remained a statistically significant prognostic factor for TTM and OS even after adjustment for various risk classifications methods based on clinicopathologic factors
Clinical high risk/gene low risk n=59 (TS < 2cm: 29%, ER+: 91%, ER-: 9%, TG-Good: 12%, TG-Poor: 18%) OS(10years): 0.89 (0.77 to 0.95)The lack of statistical significance for DFS was explained by the fact that the signature was originally developed using TTM as the endpoint
Clinical high risk/gene high risk n=163 (TS < 2cm: 25%, ER+: 48%, ER-: 52%, TG-Good: 3%, TG-Poor: 69%) Poor(R<0.4), Adjuvant!Low: 28 patientsOverall the 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for node-negative untreated patients with early breast cancer
 OS(10years): 0.69 (0.45 to 0.84)Clinical risk hazard ratios, adjusted for the gene signature were not significant, suggesting that most of their prognostic utility is subsumed by the gene signature
 Poor(R<0.4), Adjuvant!High: 163 patients
 OS(10years): 0.69 (0.61 to 0.76)
Hazard Ratios (unadjusted), MammaPrint:
 TTM=2.32 (95% CI = 1.35–4.00)
 DFS=1.50 (95% CI = 1.04–2.16)
 OS=2.79 (95% CI = 1.60–4.87)
MammaPrint adjusted by Adjuvant:
 TTM= 2.13 (95% CI = 1.19 to 3.82)
 DFS= 1.36 (95% CI = 0.91 to 2.03)
 OS= 2.63 (95% CI =1.45 to 4.79)
Development of metastases within 5 years:
 Sensitivity for Gene signature 0.90 (0.78 to 0.95)
 Sensitivity for Adjuvant! 0.87 (0.75 to 0.94)
 Specificity for Gene signature 0.42 (0.36 to 0.48)
 Specificity for Adjuvant! 0.29 (0.24 to 0.35)
ROC area under the curve:
 MammaPrint®: TTM: 0.681
 MammaPrint®: OS: 0.659
 Adjuvant: TTM: 0.648
 Adjuvant: OS: 0.576
van't Veer, 200221Exclusion criteria: Age >55 y, TS >5cm, metastases, previous malignancy, diagnosed before 1983, or after 199665/78 correct predictions:The 70-genes signatures is a better predictor of the risk of distant metastases than standard clinical predictors
Population: 78 + 19 patients, (mean age 44.9 y, TS < 2cm: 41.2%, ER+: 70.2%. PR+: 57.7%, LN-: 100%, TG-Good: 12%, TG-Poor: 49%)End point: distant metastases as first relapse event (5 years) 5 poor in the 70-gene Good group
Therapy:Outcome: 8 good in the 70-gene Poor group
Hormonal (3 patients), Chemotherapy (3 patients)No metastases within 5yrs: 51;17/19 correct predictions:
Metastases within 5yrs: 46 1 poor in the 70-gene Good group
 1 good in the 70-gene Poor group
Univariate OR=15, (95%CI=4–56, P =0.0000041)
Multivariate OR = 18, (95%CI=3.3–94, P = 0.00014)
van de Vijver, 200225Exclusion criteria: Age >52 y, TS >5cm, previous malignancy, apical axillary LN involvementThe 70-genes association with age, tumor grade, ER (P value<0.001), and tumor size (P =0.012);The authors demonstrate for the first time that microarray technology can be used as a reliable diagnostic tool
Population: 295 patients, all age < 53 y, all < 5cm, 61 in common with van't Veer 2002:21End point: distant metastases as first relapse event, OS67 LN- patients (not in van't Veer 200221) OR = 15.3, (95%CI = 1.8–127, P = 0.003)The MammaPrint assay performed similarly to the original 70-genes signature and is, therefore, an excellent tool to predict outcome of disease in breast cancer patients
Poor Prognosis n=180, (TS < 2cm: 647%, LN-: 51%, ER+: 63%);180 LN+ and LN- patients (not in van't Veer 200221): OR = 14.6, (95%CI = 4.3–50, P < 0.0001)
Hormonal (13% patients), Chemotherapy (37% patients)All patients, HR = 5.1, (95%CI = 2.9–9.0, P < 0.001)
Good Prognosis n=115, (TS < 2cm: 62%, LN-: 52%, ER+: 97%);151 LN-, HR = 5.5, (95%CI = 2.5–12.2, P < 0.001)
Hormonal (15% patients), Chemotherapy (38% patients)144 LN+, HR = 4.5, (95%CI = 2–10.2, P < 0.001)
Multivariate HR = 4.6, 95%CI = 2.3–9.2, p value < 0.001
Glas, 200658Exclusion criteria:See van't Veer, 200225 above78 patients from the van't Veer21 series:The authors demonstrate for the first time that microarray technology can be used as a reliable diagnostic tool
Population: 162 LN-, untreated patients (<55 years), from the van de Vijver and van't Veer cohortsEnd point: distant metastases as first relapse event MammaPrint OR = 13.95 (95%CI = 3.9–44);The MammaPrint assay performed similarly to the original 70-genes signature and is, therefore, an excellent tool to predict outcome of disease in breast cancer patients
All 78 patients form the van't Veer were re-analyzed 70-genes signature OR = 15, 95%CI = 2.1 to 19)
 7/78 differently classified by MammaPrint
145 LN- patients from the van de Vijver25 series:
 MammaPrint HR = 5.6 (95%CI = 2.4–7.3, P = 0.0001)
Similar results were obtained for OS

ER = estrogen receptor; TS = tumor size; TG = tumor grade; OS=overall survival; RFS=relapse free survival; TTM=time to distant metastases; ROC = Receiver operating characteristic; NPI=Nottingham prognostic index; DFS=disease free survival; OR = odds ratio; CI = confidence interval; LN = lymph node; HR=hazard ratio; KM=Kaplan-Meier.

From: 3, Results

Cover of Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes
Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes.
Evidence Reports/Technology Assessments, No. 160.
Marchionni L, Wilson RF, Marinopoulos SS, et al.

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