Figure 6
Duration of Disease-Free Survival in Patients with Adjuvant Treatment of Breast Cancer (Study 4) Exploratory analyses of DFS as a function of HER2 overexpression or gene amplification wereconducted for patients in Studies 2 and 3, where central laboratory testing data were available. Theresults are shown in Table 10. The number of events in Study 2 was small with the exception of the IH3+/FISH+ subgroup, which constituted 81% of those with data. Definitive conclusions cannot be drawn
regarding efficacy within other subgroups due to the small number of events. The number of events in
Study 3 was adequate to demonstrate significant effects on DFS in the IHC 3+/FISH unknown and theFISH +/IHC unknown subgroups.
Table 10
Treatment Outcomes in Studies 2 and 3 as a Function of HER2 Overexpression or Amplification
Study 2 Study 3
c
HER2 Assay
Resulta
Number of Hazard Ratio DFS Number of Hazard Ratio DFS
Patients (95% CI) Patients (95% CI)
IHC 3+
FISH (+) 1170 0.42 91 0.56
 (0.27, 0.64) (0.13, 2.50)
FISH () 51 0.71 8
 (0.04, 11.79)
FISH Unknown 51 0.69 2258 0.53
 (0.09, 5.14) (0.41, 0.69)
IHC < 3+ / 174 1.01 299b 0.53
FISH (+) (0.18, 5.65) (0.20, 1.42)
IHC unknown / 724 0.59
FISH (+) (0.38, 0.93)
a IHC by HercepTest, FISH by PathVysion (HER2/CEP17 ratio ≥ 2.0) asperformed at a central laboratory.
b All cases in this category in Study 3 were IHC 2 c Median follow-up duration of 12.6 months in the one-year trastuzumabtreatment arm.
14.2 Metastatic Breast Cancer
The safety and efficacy of trastuzumab in treatment of women with metastatic breast cancer were studiedin a randomized, controlled clinical trial in combination with chemotherapy (Study 5, n = 469 patients) andan open-label single agent clinical trial (Study 6, n = 222 patients). Both trials studied patients withmetastatic breast cancer whose tumors overexpress the HER2 protein. Patients were eligible if they had 2or 3 levels of overexpression (based on a 0 to 3 scale) by immunohistochemical assessment of tumortissue performed by a central testing lab.
Previously Untreated Metastatic Breast Cancer (Study 5)
Study 5 was a multicenter, randomized, open-label clinical trial conducted in 469 women with metastaticbreast cancer who had not been previously treated with chemotherapy for metastatic disease. Tumorspecimens were tested by IHC (Clinical Trial Assay, CTA) and scored as 0, 1+, 2+, or 3+, with 3+
indicating the strongest positivity. Only patients with 2+ or 3+ positive tumors were eligible (about 33% of
those screened). Patients were randomized to receive chemotherapy alone or in combination with
trastuzumab given intravenously as a 4 mg/kg loading dose followed by weekly doses of trastuzumab at
2 mg/kg. For those who had received prior anthracycline therapy in the adjuvant setting, chemotherapy
consisted of paclitaxel (175 mg/m2
 over 3 hours every 21 days for at least six cycles