INT2 AND ERBB2 AMPLIFICATION AND ERBB2 EXPRESSION IN BREAST-TUMORS FROM PATIENTS WITH DIFFERENT OUTCOMES

The relationships of INT2 and ERBB2 amplification and of ERBB2 overexp ression in primary breast tumors to prognostic factors, recurrence, an d survival have generated considerable controversy. The rationale for this study is that long-term, recurrence-free survival is a more direc t criterion for testing the validity of a tumor marker than correlatio n either with prognostic factors or with short-term recurrence and sur vival. We examined the association of recurrence with INT2 and ERBB2 a mplification and ERBB2 expression by comparing primary breast tumors f rom patients surviving without recurrence for greater than or equal to 8.5 years after diagnosis, the LTS group, to tumors from patients rec urring within two years, the RR group. The RR (N = 63) and LTS (N = 61 ) samples were coded and examined for amplification by Southern blotti ng and for expression by immunohistochemistry. Comparison between the RR and LTS groups demonstrated that INT;! amplification was associated with a significantly (P = 0.018) higher (5.6-fold) risk of recurrence , an association that remained significant after controlling for lymph node (LN), tumor size (TS), and histograde (HG) status. ERBB2 amplifi cation and expression were not associated with a higher recurrence ris k. Survival analyses within the RR group, however, demonstrated signif icantly shorter survival time among cases with than without ERBB2 ampl ification (P = 0.018, median survival 16 vs 25 months), or ERBB2 expre ssion (P = 0.019, median survival 15 vs 25 months), but not INT;! ampl ification. Univariate Cox proportional hazards regression models also demonstrated significantly shorter survival among cases with ERBB2 amp lification (P = 0.016) or expression (P = 0.049), that remained signif icant in multivariate analyses (P = 0.022) for ERBB2 amplification. Th ese results indicate a significant positive association between INT2 a mplification and risk for tumor recurrence in the RR as compared to th e LTS group. The relationship of ERBB2 amplification or overexpression to patient outcome is more complex. ERBB2 amplification and expressio n have a significant relationship with shorter survival among patients recurrent within two years, but their occurrence in tumors from women surviving without recurrence for 2 8.5 years suggests that ERBB2 stat us is not predictive of shorter survival for all breast cancers.