W. Douglas B. Hiller

BACKGROUND: The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor-positive tumors is poorly defined by clinical and histopathological measures. METHODS: We tested whether the results of a reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of 21 prospectively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative, tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14. The levels of expression of 16 cancer-related genes and 5 reference genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a risk group (low, intermediate, or high) for each patient. RESULTS: Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks. The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51, 22, and 27 percent, respectively. The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk, intermediate-risk, and high-risk groups were 6.8 percent (95 percent confidence interval, 4.0 to 9.6), 14.3 percent (95 percent confidence interval, 8.3 to 20.3), and 30.5 percent (95 percent confidence interval, 23.6 to 37.4). The rate in the low-risk group was significantly lower than that in the high-risk group (P<0.001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P<0.001). The recurrence score was also predictive of overall survival (P<0.001) and could be used as a continuous function to predict distant recurrence in individual patients. CONCLUSIONS: The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor-positive breast cancer.

Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC) results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide.

To determine the effects of prolonged exercise on systolic and diastolic left ventricular function, we studied 21 athletes before, at the finish (within 11 +/- 5 min), and during recovery (28 +/- 9 hr) after the Hawaii Ironman Triathlon (2.4 mile swim, 112 mile bike, 26.2 mile run). Two-dimensionally guided M mode echocardiograms were digitized for wall thickness, cavity dimension, fractional shortening, and peak rates of cavity enlargement and wall thinning. Pulsed Doppler left ventricular inflow recordings were analyzed for peak early and late velocities and their ratio. Left ventricular diastolic dimension was reduced at race finish (5.4 +/- 0.6 to 5.1 +/- 0.6 cm) and remained reduced after 1 day of recovery (5.2 +/- 0.6 cm, p less than .05). Fractional shortening fell at race finish (39 +/- 5% to 35 +/- 5%), although systolic blood pressure was unchanged, and rose to 40 +/- 4% after recovery (p less than .05). The return to prerace shortening values after recovery occurred despite continued reduction in diastolic size. Peak circumferential shortening did not change significantly. Individual reductions in fractional shortening were correlated with increases in systolic cavity size (r = -.64, p less than .01), but not with decreases in diastolic size. The stress-shortening relationship was displaced downward at race finish, but returned toward baseline after 1 day of recovery, despite a persistent reduction in cavity size. This suggests that the decrease in shortening was due to impaired contractility as well as altered preload.(ABSTRACT TRUNCATED AT 250 WORDS)