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Intra-Tumoral Heterogeneity of HER2, FGFR2, cMET and ATM in Gastric Cancer: Optimizing Personalized Healthcare through Innovative Pathological and Statistical Analysis.

Author(s): Ye P, Zhang M, Fan S, Zhang T, Fu H, Su X, Gavine PR, Liu Q, Yin X

Publication: PLoS One, 2015, Vol. 10, Page e0143207

PubMed ID: 26587992 PubMed Review Paper? No

Purpose of Paper

Conclusion of Paper

Studies

1. Study Purpose

   The purpose of this study was to determine the number of biopsies necessary to compensate for gastric tumor heterogeneity in MET, ATM and HER-2 IHC staining, as well as MET, FGFR2 and HER-2 FISH staining.  A total of 1-9 biopsies were obtained from each of 166 patients with gastric tumors over an 8 year period. A threshold of >50 tumor cells was used for inclusion. MET positivity by IHC was defined as a score of 3+ and positivity by FISH was an average copy number ≥5.  FGFR2 positivity was defined as ≥6 copies. ATM IHC was defined as positive if the score was >0. HER-2 was defined as positive based on an IHC score of 3+, or an IHC score of 2+ and gene amplification by FISH.  The case was determined to be MET IHC-, MET FISH-, FGFR2 FISH-, ATM IHC- and HER2-positive if positive staining was observed in any biopsy and negative only if all biopsies were negative.  Heterogeneity was defined based on positive staining, as described above, and was considered high if it occurred  in less than 25% of biopsies, medium if present in 25-50% of biopsies, and low if present in ≥50% of biopsies.

   Summary of Findings:

   Overall, 20% had ≤2 positive biopsies, 47% of cases had 3-4 positive biopsies, 25% had 5-6 positive biopsies, and 8% had ≥7 positive biopsies. Of the 18 cases that were MET positive by IHC, 11 (61%) had low heterogeneity (present in >50% of biopsies), 6 (33%) had medium heterogeneity (present in 25-50% of biopsies) and 1 (5.5%) had high heterogeneity (present in <25% of biopsies). Similarly, for the 13 cases that were positive for MET amplification by FISH, 10 (77%) had low heterogeneity, 2 (15%) had low heterogeneity and 1 (8%) had high heterogeneity. MET IHC and MET FISH results were modestly correlated (κ=0.62, p<0.01). ATM heterogeneity was low in 36 of the 58 cases (62%) medium in 20 cases (35%), and high in 2 cases (3.8%). Of the 9 FGFR2 amplification positive cases by FISH, 5 (56%) had low heterogeneity, 3 (33%) had medium heterogeneity and 1 (11%) had high heterogeneity. Thirty-two cases were considered HER-2 positive, and 25 (78%) had low heterogeneity, and 7 (22%) had medium heterogeneity. The false negative rate for MET IHC, MET FISH, ATM IHC, FGFR2 FISH, and HER-2 (IHC and FISH) was 3.39%, 3.30%, 0.19%, 3.70% and 0.23%, respectively with 4 biopsies and 0.00%, 1.10%, 0.00%, 0.00% and 0.00%, respectively with 6 biopsies. 

   Biospecimens

   • Tissue - Stomach

   Preservative Types

   • Formalin

   Diagnoses:

   • Neoplastic - Carcinoma

   Platform:

   Analyte	Technology Platform
   DNA	FISH
   Morphology	H-and-E microscopy
   Protein	Immunohistochemistry

   Pre-analytical Factors:

   Classification	Pre-analytical Factor	Value(s)
   Biospecimen Aliquots and Components	Biospecimen heterogeneity	Intratumoral sampling (exact positions not specified)
   Immunohistochemistry Specific	Targeted peptide/protein	HER-2 MET ATM
   FISH Specific	Targeted nucleic acid	MET FGFR2 HER-2/CEP17

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