Prevalence of HER2 Positivity and Its Clinicopatho

Authors: Pathmanathan Rajadurai Ho Kean Fatt Foo Yoke Ching

Publish Date: 2017/01/26

Volume: 49, Issue: 2, Pages: 150-157

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Abstract

Human epidermal growth factor receptor 2 Erbb2/HER2 overexpression which was previously detected in invasive breast cancer has now been implicated in advanced gastric cancer GC and gastroesophageal junction cancer GEC A study was conducted to determine the rate of HER2 positivity in patients with locally advanced or metastatic GC and GEC in Malaysia and to assess the impact of various demographic and clinical parameters on HER2 positivityA total of 228 adult patients with GC or GEC were enrolled from Subang Jaya Medical Centre Malaysia for retrospective 210 and prospective study All patients were subjected to the HER2 immunohistochemistry test using an FDAapproved standardized test kit Carcinomas scoring 2+ on immunohistochemistry were further tested with HER2 in situ hybridization ISH using an FDAapproved test kitThe overall rate of HER2 positivity in the population studied was 246 n = 56 The rate was significantly higher in men than in women 296 vs 163 p = 0024 HER2 overexpression was significantly more common in diffuse type than in intestinal type of tumors 398 vs 149 p  0001 In our study out of 56 samples 44 786 were considered for gene amplification testing out of which 40 901 samples showed gene amplification There was no statistically significant correlation between HER2 positivity and patient age race tumor location tumor differentiation and TNM stagingHER2 overexpression was evident in nearly 25 of the Malaysian patients with locally advanced or metastatic gastric cancer The overexpression correlated significantly with male gender and diffusetype tumors The majority of the IHCpositive tumors demonstrated cerb2 gene amplification and this finding reached statistical significanceThe International Agency for Research on Cancer IARC suggests that gastric cancer GC is the fifth most common cancer in the world based on its GLOBOCAN 2012 project data Gastric cancer is also the third leading cause of cancer mortality in both sexes worldwide 723000 deaths 1 The majority of patients with GC presents at an advanced stage and experiences significant morbidity and mortality 2 The agestandardized incidence rate ASR of GC is about twice as high in men as in women 1More than 70 of GC cases are diagnosed in developing countries More than 727000 cases of GC were diagnosed in Asia in 2008 accounting for 119 of all the cancers diagnosed 3 Nearly half the total global cases of GC occur in Eastern Asia mainly in China 1 The report issued by the National Cancer Registry Malaysia in 2006 showed that the total incidence of stomach cancer in the country was 39 4 However the incidence of GC varies among people of Chinese Malay and Indian origin 5 Higher rates of GC have been observed in the Chinese population compared to the Malay and Indian populations 6Human epidermal growth factor receptor 2 erb2/HER2 is a member of the HER family and is a protooncogene encoded by erb2 on chromosome 17 It plays a major role in promoting cell proliferation and suppressing apoptosis and thus facilitates excessive or uncontrolled cell growth and tumorigenesis Although HER2 expression was initially associated with breast cancer it has now been implicated in advanced gastric and gastroesophageal junction cancer GEC 7 While 15–25 of all patients with breast cancer have been found to be HER2 positive the rate of HER2 positivity varies widely among patients with GC HER2 positivity has been found to range from 68–34 on immunohistochemistry IHC and 71–426 on fluorescent in situ hybridization FISH in GC 8HER2 is a wellestablished therapeutic target in breast cancer 2 Preclinical evidence attests to the significant antitumor efficacy of antiHER2 therapies particularly monoclonal antibodies in GC 9 Trastuzumab an antiHER2 humanized monoclonal antibody 10 already in use for prolonging overall survival and progressionfree survival in patients with HER2positive breast cancer has now been shown to significantly prolong survival in patients with GC and GEC Other agents that target HER2 including lapatinib emtansine TDM1 and pertuzumab are also being developed and have demonstrated promising results in HER2positive breast cancer 7 The efficacy of lapatinib in combination with capecitabine and oxaliplatin was investigated in a randomized placebocontrolled phase III trial involving 545 patients with HER2positive advanced gastroesophageal adenocarcinoma The patients were randomly assigned to capecitabine and oxaliplatin plus lapatinib 1250 mg or placebo daily The primary endpoint of the study was overall survival There were no significant differences between the two groups in terms of overall survival although the lapatinib group demonstrated a significantly higher response rate compared to the placebo group 11 The Trastuzumab for Gastric Cancer ToGA trial a prospective phase III openlabel trial screened 3803 patients with GC/GEC for HER2 status with IHC and FISH test Patients were considered eligible for the study if their tumor samples were scored as 3+ on IHC or if they were FISH positive HER2/centromeric probe for chromosome 17 CEP17 ratio ≥ 2 In this study 810 patients were found to be HER2 positive These HER2positive patients when treated with trastuzumab in combination with ongoing chemotherapy showed significant improvement in overall survival as compared to patients who did not receive trastuzumab 138 vs 11 1 months hazard ratio 0∙74 95 CI 0∙60–0∙91 p = 00046 Post hoc analysis of two large subgroups one with high HER2 expression IHC 2+ and FISH positive or IHC 3+ n = 446 and the other with low HER2 expression IHC 0 and FISH positive or IHC 1+ and FISH positive n = 131 was performed The analysis showed that patients whose tumors had high HER2 expression had a high overall median overall survival 160 months with trastuzumab plus chemotherapy compared to chemotherapy alone 118 months 12 Thus HER2 testing has emerged as a promising prognostic marker that could benefit patients with GC/GEC if coupled with an appropriate targeted therapy 2 7 10 Studies conducted so far suggest the need for optimizing HER2 testing as appropriate interpretation of these test results could translate into delivery of optimal therapy It has been reported that only patients with high levels of HER2 expression derive maximum benefit from trastuzumab therapy 2 The European Medicines Agency has now recommended that Herceptin trastuzumab should be used only in patients with metastatic GC tumors that have HER2 overexpression defined by IHC2+ and a confirmatory ISH+ result or IHC3+ determined by an accurate and validated assay 13

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