Immunohistochemical analysis of RTKs expression identified HER3 as a prognostic indicator of gastric cancer

Abstract

Standard treatment in Japan for the 13th Japanese Gastric Cancer Association stage II/III advanced gastric cancer is postoperative adjuvant S-1 administration after curative surgery. High expression of receptor type tyrosine kinases (RTKs) has repeatedly represented poor prognosis for cancers. However it has not been demonstrated whether RTKs have prognostic relevance for stage II/III gastric cancer with standard treatment. Tumor tissues were obtained from 167 stage II/III advanced gastric cancer patients who underwent curative surgery and received postoperative S-1 chemotherapy from 2000 to 2010. Expression of the RTKs including EGFR, HER2, HER3, IGF-1R, and EphA2 was analyzed using immunohistochemistry (IHC). Analysis using a multivariate proportional hazard model identified the most significant RTKs that represented independent prognostic relevance. When tumor HER3 expression was classified into IHC 1+/2+ (n = 98) and IHC 0 (n = 69), the cumulative 5-year Relapse Free Survival (5y-RFS) was 56.5 and 82.9%, respectively (P = 0.0034). Significant prognostic relevance was similarly confirmed for IGF-1R (P = 0.014), and EGFR (P = 0.030), but not for EphA2 or HER2 expression. Intriguingly, HER3 expression was closely correlated with IGF-1R (P < 0.0001, R = 0.41), and EphA2 (P < 0.0001, R = 0.34) expression. Multivariate proportional hazard model analysis identified HER3 (IHC 1+/2+) (HR; 1.53, 95% CI, 1.11–2.16, P = 0.0078) as the sole RTK that was a poor prognostic factor independent of stage. Of the 53 patients who recurred, 40 patients (75.5%) were HER3-positive. Thus, of the RTKs studied, HER3 was the only RTK identified as an independent prognostic indicator of stage II/III advanced gastric cancer with standard treatment.

Prognostic relevance of FGFR2 expression in stage�II/III gastric cancer with curative resection and S‑1 chemotherapy

“…Of the 172 patients, informed consent to use specimens was obtained from 167 patients, for whom the median follow up term was 75 months (inter quartile range, 61-90 months). These patients were identical to the patients whom we had analyzed previously (22).…”

“…We have previously analyzed various RTK expressions and reported that HER3 and EGFR were significant and marginally significant independent prognostic factors, respectively, in patients with stage II/III gastric cancer who underwent curative gastrectomy followed by adjuvant chemotherapy with S-1 (22). However, we have not included this critical RTK of FGFR2 in the study.…”

Expression of the ERBB Family of Ligands and Receptors in Gastric Cancer

“…In contrast, previous studies reported a poor survival in GC with a high ERBB3 expression [30,31] . Since the cytoplasmic ERBB3 expression was regarded as a positive expression in those reports, a consensus guideline for ERBB3 expression is needed to resolve the contradictory results [32] .…”

Macroscopic appearance of Type IV and giant Type III is a high risk for a poor prognosis in pathological stage II/III advanced gastric cancer with postoperative adjuvant chemotherapy

“…HER2 immunostaining (defined as +3 immunostaining) is the well-established molecular target in far advanced gastric cancer using trastuzumab[20], but HER2-positive cases are infrequently found in recurrent gastric cancer[12]. Even in high-risk advanced gastric cancer, HER2-positive cases were infrequently seen (Table 4), while HER3-positive cases were frequently found.…”