INT2 and ERBB2 amplification and ERBB2 expression in breast tumors from patients with different outcomes

Abstract

The relationships of INT2 and ERBB2 amplification and of ERBB2 overexpression in primary breast tumors to prognostic factors, recurrence, and survival have generated considerable controversy. The rationale for this study is that long-term, recurrence-free survival is a more direct criterion for testing the validity of a tumor marker than correlation either with prognostic factors or with short-term recurrence and survival. We examined the association of recurrence with INT2 and ERBB2 amplification and ERBB2 expression by comparing primary breast tumors from patients surviving without recurrence for > or = 8.5 years after diagnosis, the LTS group, to tumors from patients recurring within two years, the RR group. The RR (N = 63) and LTS (N = 61) samples were coded and examined for amplification by Southern blotting and for expression by immunohistochemistry. Comparison between the RR and LTS groups demonstrated that INT2 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 amplification and expression were not associated with a higher recurrence risk. Survival analyses within the RR group, however, demonstrated significantly shorter survival time among cases with than without ERBB2 amplification (P = 0.018, median survival 16 vs 25 months), or ERBB2 expression (P = 0.019, median survival 15 vs 25 months), but not INT2 amplification. Univariate Cox proportional hazards regression models also demonstrated significantly shorter survival among cases with ERBB2 amplification (P = 0.016) or expression (P = 0.049), that remained significant in multivariate analyses (P = 0.022) for ERBB2 amplification. These results indicate a significant positive association between INT2 amplification and risk for tumor recurrence in the RR as compared to the LTS group. The relationship of ERBB2 amplification or overexpression to patient outcome is more complex. ERBB2 amplification and expression have a significant relationship with shorter survival among patients recurrent within two years, but their occurrence in tumors from women surviving without recurrence for > or = 8.5 years suggests that ERBB2 status is not predictive of shorter survival for all breast cancers.

Growth factor biomarkers associated with estrogen- and radiation-induced breast cancer progression

“…Int2, located in 11q13, was found more frequently amplified in local recurrences than in primary tumors as well as in tumors of breast cancer patients with lymph node metastases (41,42). Pauley et al (41) found that those patients with Int2 and ErbB2 amplification were at a higher risk for tumor recurrence. Further support for these findings is the loss of heterozygosity (LOH) found on the chromosomal arms of 11q13 (42).…”

A human murine mammary tumour virus‐like agent is an unconvincing aetiological agent for human breast cancer

“…Interestingly, or perhaps just coincidentally, WNT10B mRNA transcripts are highly expressed in some ( 6%) human breast carcinomas [34] and, detection of FGF3 mRNA in human breast malignancies confers a 5.6 times greater risk of cancer recurrence [35,36].…”

Quantitation of c-<i>erb</i>B-2 Gene Amplification in Breast Cancer Tissue by Competitive PCR

“…A number of researchers have reported that c-erbB-2 amplifi- cation did not significantly correlate with lymph node metastasis [12,[17][18][19]. Slamon et al [16], Pauley et al [23] and Yamada et al [24] have reported that c-erbB-2 amplification is proportional to the number of lymph node metastases. There was a correlation between the degree of c-erbB-2 amplification and the stage of disease [25] in our data, but other reports have seen no correlation [17,24,26].…”