copyright © 2011 research to practice. all rights reserved. case presented by dr morganstein (prof...

Copyright © 2011 Research To Practice. All rights reserved.

Case presented by Dr Morganstein (Prof Van Cutsem)

• 78 yo woman with Stage IV GE adenocarcinoma found in 1/2010 – mets to liver, bone, nodes

– Carboplatin/irinotecan x 2 cycles progressive somnolence hemorrhagic brain mets = resected

• 4/2010: HER2-positive (IHC 3+, FISH amplified = 6.9)

– FOLFOX + trastuzumab PET/CT 4 mos later = CR and PS improved significantly

– Neurotoxicity d/c oxaliplatin on 5-FU/LV/trast

• Recent PET/CT = near CR, mild activity at GE jnx


HER2-positive (IHC3+ or FISH+), inoperable, locally advanced, recurrent or metastatic GE junction or gastric adenocarcinoma

ToGA: Trial Schema

FCFluoropyrimidine (F) (5-FU or capecitabine at investigator discretion) + Cisplatin (C)

R

FC + Trastuzumab (T)

Primary Analysis: N = 584

5-FU = 800 mg/m2/day continuous infusion d1-5 q3wks x 6Capecitabine = 1,000 mg/m2 bid d1-14 q3wks x 6Cisplatin = 80 mg/m2 q3wks x 6Trastuzumab = 8 mg/kg loading dose followed by 6 mg/kg q3wks until PD

Bang YJ et al. Lancet 2010;376(9742):687-97.


ALL Patients 584 0.74 0.60 - 0.91

IHC 0 / FISH+ 61 0.92 0.48 - 1.76

IHC 1+ / FISH+ 70 1.24 0.70 - 2.20

IHC 2+ / FISH+ 159 0.75 0.51 - 1.11

IHC 3+ / FISH+ 256 0.58 0.41 - 0.81

IHC 3+ / FISH- 15 0.83 0.20 - 3.38 0.2 0.4 0.6 1 2 3 4 5

Favors Therapy Impact Risk Ratio Favors No Therapy Impact

Number Hazard 95% ConfidenceOf Patients Ratio Limits

Relative Impact of HER2 Status by IHC or FISH in the ToGA Trial

Reprinted from The Lancet, 376(9742), Bang YJ et al, Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial, 687-697, Copyright 2011, with permission from Elsevier.


Comparison of HER2 Testing in Breast and Gastric/GEJ Cancers

Breast Cancer Gastric/GE Junction Cancer

IHC Membranous Staining Pattern

3+ requires full circumferential staining pattern

3+ score allowed for cases with loss of apical membrane staining

Required Percent of Membranous Staining

ASCO – CAP Guidelines: 30%Trastuzumab Package Insert: 10%

Biopsies: no percentage required. Any cell cluster with membranous staining is HER2+Resections: 10%

Heterogeneity of HER2 Positivity

Well-described; judged as moderate, can influence HER2 test results especially when core biopsies are assessed

More severe than for breast cancer; especially important for endoscopic biopsies


Gastric Cancer

Gastroesophageal Junction Cancer

Breast Cancer

Continuous Complete 360 Degree Membranous HER2 Staining

Incomplete Staining With Loss of Apical Membrane HER2 Expression

Marked Heterogeneity of HER2 Immunostaining

Courtesy of Jeffrey S Ross, MD

Comparison of HER2 IHC Slide Scoring in Gastric/GEJ and Breast Cancers


FISH positive/IHC 2+



FISH positive/IHC 0

FISH no result/IHC 3+

FISH positive/IHC no result

FISH negative/IHC 3+

ToGA: HER2 Status of Enrolled Patients

Bang YJ et al. Lancet 2010;376(9742):687-97.


ToGA: Pre-Planned and Post-Hoc Exploratory Analyses of Patients Stratified by HER2 Status

Reprinted from The Lancet, 376(9742), Bang YJ et al, Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial, 687-697, Copyright 2011, with permission from Elsevier.

copyright © 2011 research to practice. all rights reserved. case presented by dr morganstein (prof...

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