Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial

Bang, Yung‐Jue; Chung, Hyun‐Tai; Xu, Jingying; Lordick, Florian; Sawaki, Akira; Al-Sakaff, N.; Lipatov, Oleg; See, C.; Rueschoff, Josef; Cutsem, Éric Van

doi:10.1200/jco.2009.27.15_suppl.4556

Cited by 111 publications

(31 citation statements)

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“…This study reports 7/180 IHC0/1+ (4%) cases to be CISH (low-level) amplified and four of the 9 (44%) IHC 2+ cases to be CISH amplified. Our percentage of amplification in IHC 0/1+ cases is similar to that of Bilous et al (5.1%) [ 4 ] but is in contrast to the results from the ToGA trial [ 1 ] that reported a higher frequency of IHC 0/1+ samples testing FISH positive (22%) compared to that in breast cancer.…”

Section: Discussionsupporting

confidence: 85%

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Low frequency of HER2 amplification and overexpression in early onset gastric cancer

et al. 2011

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BackgroundThe recent ToGA trial results indicated that trastuzumab is a new, effective, and well-tolerated treatment for HER2-positive gastric cancer (GC). Although GC mainly affects older patients, fewer than 10% of GC patients are considered early-onset (EOGC) (presenting at the age of 45 years or younger). These EOGC show different clinicopathological and molecular profiles compared to late onset GC suggesting that they represent a separate entity within gastric carcinogenesis. In light of potential trastuzumab benefit, subpopulations of GC such as EOGC (versus late onset) should be evaluated for their frequency of amplification and overexpression using currently available techniques.MethodsTissue microarray (TMA) blocks of 108 early onset GC and 91 late onset GC were stained by immunohistochemistry (IHC, Hercep test, DAKO) and chromogenic in situ hybridization (CISH, SPoT-Light, Invitrogen).ResultsOverall, we found only 5% HER2 high level amplification and 3% HER2 3+ overexpression (6/199). In addition, 8 patients (4%) showed a low level CISH amplification and 9 patients (4.5%) showed a 2+ IHC score. IHC and CISH showed 92% concordance and CISH showed less heterogeneity than IHC. In 2/199 cases (1%), IHC showed clinically relevant heterogeneity between TMA cores, but all cases with focal IHC 3+ expression were uniformly CISH high level amplified. Early onset GCs showed a significantly lower frequency of HER2 amplification (2%) and overexpression (0%) than late onset GCs (8% and 7% respectively) (p = 0.085 and p = 0.008 respectively). Proximal GC had more HER2 amplification (9% versus 3%) and overexpression (7% versus 2%) than distal tumours although this difference was not significant (p = 0.181 and p = 0.182 respectively). HER2 CISH showed more high level amplification in the intestinal type (7%, 16% if low-level included) compared to the mixed (5%, 5% if low-level included) and diffuse type (3%, 4% if low-level included) GCs (p = 0.029). A similar association was seen for HER2 IHC and histologic type (p = 0.008). Logistic regression indicated a significant association between HER2 expression and age, which remained significant when adjusted for both location and histological type.ConclusionsEven focal HER2 overexpression in GC points to uniform HER2 amplification by CISH. We show for the first time that early onset GC has a lower frequency of HER2 amplification and overexpression than late onset GC, and confirm that intestinal type GC shows the highest rate of HER2 amplification and overexpression.

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Section: Discussionsupporting

confidence: 85%

“…As reported in previous studies [ 1 , 39 ], there was an association between HER2 amplification/overexpression, tumour location (proximal vs . distal) and tumour type (intestinal vs .…”

Section: Discussionsupporting

confidence: 78%

Low frequency of HER2 amplification and overexpression in early onset gastric cancer

et al. 2011

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“…The ToGA study presented at 2009 annual meeting of American Society of Clinical Oncology has screened about 3,800 patients with advanced gastric cancer from 24 countries [ 14 ]. HER2 overexpression was detected in 22%, and the concordance rate between IHC and FISH was high at all levels of HER2 positivity [ 15 ]. There was a specific pattern of disease which correlated with HER2 overexpression.…”

Section: Discussionmentioning

confidence: 99%

Pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen in gastric cancer: a case report

et al. 2010

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We report a 49-year-old Chinese male with locally advanced gastric adenocarcinoma achieving pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen. He underwent esophagogastroduodenoscopy in September 2009, which revealed a 2-cm gastric ulcer on the lesser curvature proximal to angularis. Biopsy of gastric ulcer showed moderately differentiated adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and fluorescence in situ hybridization. Further workups with endoscopic ultrasound, computed tomography and positron emission tomography staged his cancer as T3N1M0. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, docetaxel and capecitabine without severe toxicities except grade 2 diarrhea near the completion of cycle 3 requiring discontinuation of capecitabine. Afterwards, he received total gastrectomy with extended D2 lymph node dissections showing pathological complete response. He went on to receive 3 more cycles of chemotherapy postoperatively. The role of trastuzumab as a part of perioperative therapy in gastric cancer overexpressing HER2 is worth further investigation.

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“…In esophageal and gastric cancer, concordance percentages between amplification and overexpression reported in literature range between 86.9 and 96.4% [ 60 ], as illustrated in Figure 1 . Nevertheless, primary results from a very recent phase III trial (ToGA) containing >3,800 advanced esophageal and gastric cancer samples showed that the frequency of samples with amplification but without corresponding overexpression was high (23%) compared to that in breast cancer suggesting that FISH testing may be the more relevant procedure to conduct on these tumor specimens [ 61 ]. However, preliminary data from this same trial reported that patients with amplified tumors without overexpression (IHC 0 or 1+) did not show a substantial overall survival benefit from trastuzumab (HR 1.07, median overall survival 10.0 months versus 8.7 months) in contrast to patients with IHC 2+/FISH positive or IHC 3+ tumors (HR 0.65, median overall survival 16.0 months versus 11.8 months) [ 57 ], suggesting that measuring HER2 at the protein level should be the primary screening method for selecting gastroesophageal cancer patients for trastuzumab therapy.…”

Section: Human Epidermal Growth Factor Receptormentioning

confidence: 99%

HER-2/neuTesting and Therapy in Gastroesophageal Adenocarcinoma

Moelans

Diest

Milne

et al. 2011

Pathology Research International

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Despite ongoing advances in the treatment of gastroesophageal cancer, prognosis remains poor. The best promise to improve this poor survival is provided by new targeted agents. Of these, human epidermal growth factor receptor 2 (HER2) is currently in the spotlight. In this review, we provide an overview of recent developments in HER2 testing and results of clinical trials targeting HER2 in gastroesophageal adenocarcinoma. Based on the encouraging ToGA trial findings it is now expected that routine HER2 testing will be included in the diagnostic work-up of patients with advanced gastric cancer. With regard to this testing, overexpression of the HER2 protein seems to possess the best predictive properties. However, HER2 immunohistochemistry (IHC) is subject to assay and interobserver variability, so standardization and internal and external proficiency testing is an absolute prerequisite, especially as the IHC scoring system in gastric cancer is different from that of breast cancer. Further study is needed to investigate the clinical meaning of the significant heterogeneity observed in both gene amplification and protein overexpression in gastroesophageal cancer. Highly effective therapies for gastroesophageal cancer can only be accomplished by a multi-targeted approach, considering crosstalk between pathways and continuing to optimize chemotherapy.

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Pathological features of advanced gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) positivity in the global screening programme of the ToGA trial

Cited by 111 publications

References 0 publications

Low frequency of HER2 amplification and overexpression in early onset gastric cancer

Low frequency of HER2 amplification and overexpression in early onset gastric cancer

Pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen in gastric cancer: a case report

HER-2/neuTesting and Therapy in Gastroesophageal Adenocarcinoma

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