Download Case History: Dr Ross (continued)

Monday Night with Research To
Practice: An 8-Part Live CME
Webcast Series
Part VI: HER2-Positive Gastric Cancer
Monday, October 25, 2010
7:30 PM - 8:30 PM ET
Copyright © 2010, Research To Practice, All rights reserved.
Jaffer A Ajani, MD
Professor of Medicine
Department of Gastrointestinal Medical Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
Jeffrey S Ross, MD
Cyrus Strong Merrill Professor and Chair
Department of Pathology and Laboratory Medicine
Albany Medical College
Albany, New York
Neil Love, MD
Moderator
Research To Practice
Miami, Florida
Disclosures for Moderator Neil Love, MD
Dr Love is president and CEO of Research To Practice, which
receives funds in the form of educational grants to develop CME
activities from the following commercial interests: Abraxis
BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca
Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare
Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec,
Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb
Company, Celgene Corporation, Cephalon Inc, Eisai Inc,
EMD Serono Inc, Genentech BioOncology, Genomic Health Inc,
Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics
Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, SanofiAventis and Spectrum Pharmaceuticals Inc.
Disclosures for Jaffer A Ajani, MD
Consulting Agreements
Abraxis BioScience, Bayer HealthCare
Pharmaceuticals, Bristol-Myers Squibb
Company, Novartis Pharmaceuticals
Corporation, Sanofi-Aventis
Paid Research
ACT Biotech Inc, Bristol-Myers Squibb
Company, Genta Inc, ImClone Systems
Incorporated, Sanofi-Aventis, Taiho
Pharmaceutical Co Ltd
Disclosures for Jeffrey S Ross, MD
Advisory Committee
EMD Serono Inc, Genentech
BioOncology, Novartis Pharmaceuticals
Corporation
Speakers Bureau
Genentech BioOncology
Case History: Dr Ajani
• A 47 year old man with history of inflammatory bowel
disease and intrahepatic sclerosing cholangitis
• Patient presented with epigastric pain
• Endoscopy and CT scans: Mass in lower esophagus,
GE junction, proximal stomach, lung metastasis
Initial PET Evaluation
1) Would you want HER2 testing done before
deciding on a treatment plan?
Yes, in almost all
situations
57%
Yes, in some situations
23%
Yes, but it’s difficult
to get the pathologist
to do it
13%
No
7%
0%
10%
20%
30%
40%
50%
60%
2) What treatment would you generally
recommend if the patient’s tumor was
HER2-negative?
28%
DCF or DCF modification
40%
ECF or ECF modification
Irinotecan plus cisplatin
4%
Irinotecan plus fluoropyrimidine
4%
Oxaliplatin plus fluoropyrimidine
13%
Cisplatin plus fluoropyrimidine
9%
Paclitaxel-based regimen
2%
0%
Other
0%
10%
20%
30%
40%
50%
Case History: Dr Ajani (continued)
•
The patient’s tumor is HER2-positive
(IHC3+, FISH-positive)
3) Would you recommend trastuzumab-based
therapy for this patient?
95%
Yes
No
5%
0%
20%
40%
60%
80%
100%
4) If you would recommend trastuzumab, which
chemotherapy regimen would you use?
No chemotherapy –
trastuzumab alone
3%
46%
DCF or DCF modification
ECF or ECF modification
5%
Irinotecan plus cisplatin
5%
Irinotecan plus fluoropyrimidine
0%
4%
Oxaliplatin plus fluoropyrimidine
32%
Cisplatin plus fluoropyrimidine
5%
Paclitaxel-based regimen
Other
0%
0%
10%
20%
30%
40%
50%
Case History: Dr Ajani (continued)
• Patient treated with
– Docetaxel 40 mg/m2 q2wks
– Capecitabine 1,500 mg/m2 7d on/7d off
– Oxaliplatin 85 mg/m2 q2wks
– Trastuzumab 6 mg/kg q3wks
Response Evaluation in 10/2008
Patient Continues Trastuzumab as of 10/2010
Trastuzumab in Combination with
Chemotherapy versus Chemotherapy
Alone for Treatment of HER2-Positive
Advanced Gastric or GE Junction Cancer
(ToGA): A Phase 3, Open-Label,
Randomised Controlled Trial
Bang YJ et al.
Lancet 2010;376(9742):687-97.
Copyright © 2010, Research To Practice, All rights reserved.
ToGA: Trial Schema
Primary Analysis: N = 584
HER2-positive
(IHC3+ or FISH+),
inoperable,
locally advanced,
recurrent or
metastatic GE
junction or gastric
adenocarcinoma
FC
Fluoropyrimidine (F) (5-FU or
capecitabine at investigator
discretion) + Cisplatin (C)
R
FC + Trastuzumab (T)
5-FU = 800 mg/m2/day continuous infusion d1-5 q3wks x 6
Capecitabine = 1,000 mg/m2 bid d1-14 q3wks x 6
Cisplatin = 80 mg/m2 q3wks x 6
Trastuzumab = 8 mg/kg loading dose followed by 6 mg/kg q3wks until PD
Bang YJ et al. Lancet 2010;376(9742):687-97.
Efficacy of Trastuzumab + Chemotherapy
versus Chemotherapy Alone in HER2-Positive
Advanced Gastric or GE Junction Tumors
FC
(n = 290)
FC + T
(n = 294)
Hazard Ratio
p-value
Overall
Survival
11.1 months
13.8 months
0.74
0.0046
PFS
5.5 months
6.7 months
0.71
0.0002
35%
47%
1.70
(Odds Ratio)
0.0017
Overall
Response
Bang YJ et al. Lancet 2010;376(9742):687-97.
ToGA: Median Overall Survival
Bang YJ et al. Lancet 2010;376(9742):687-97.
ToGA: Progression-Free Survival
Bang YJ et al. Lancet 2010;376(9742):687-97.
Cardiac Safety of Trastuzumab + Chemotherapy
versus Chemotherapy Alone in HER2-Positive
Advanced Gastric or GE Junction Tumors
FC
FC + T
Cardiac AEs
(All Grades)
6%
6%
Cardiac AEs
(Grade 3/4)
3%
1%
< 1%
< 1%
1%
5%
Cardiac Failure
Cardiac Dysfunction
(≥ 10% drop in LVEF to an
absolute value < 50%)
Bang YJ et al. Lancet 2010;376(9742):687-97.
Quality of Life Results from a
Phase III Study of Trastuzumab Plus
Chemotherapy as First-Line Therapy
in Patients with HER2-Positive
Advanced Gastric and GastroOesophageal Junction Cancer
Ohtsu A et al.
Proc 12th WCGC 2010;Abstract O-0011.
Copyright © 2010, Research To Practice, All rights reserved.
ToGA QoL Analysis: Proportion of Patients with Global
Health Status, Physical Functioning, Nausea and
Vomiting, Dysphagia and Pain Intensity Scores
Improving by at Least 10% from Baseline at Week 37
Global health status
Chemotherapy alone
Trastuzumab +
chemotherapy
Physical functioning
Nausea/vomiting
Dysphagia
Pain intensity
0%
10%
20%
30%
Ohtsu A et al. Proc 12th WCGC 2010;Abstract O-0011.
40%
50%
60%
70%
ToGA ASCO 2009 Discussion: Trastuzumab
in Gastro-Oesophageal Cancer –
Future Directions (David Cunningham, MD)
• Efficacy of trastuzumab monotherapy?
• Maintenance monotherapy after triplet regimens?
• Continuation beyond progression in association with
second-line therapy as in breast cancer
(Von Minckwitz et al, JCO 2009)?
• Role of trastuzumab in the perioperative setting?
• Other potential biomarkers to further select patients
(currently under evaluation in breast cancer)?
Ongoing Studies of Targeting HER2-Positive
Metastatic or Unresectable Gastric Cancer
Trial Name/Phase
Treatment Regimen
Accrual
Trial
Capecitabine, oxaliplatin
+/- lapatinib
410
Open
TYTAN
Phase III
Paclitaxel +/- 2nd-line lapatinib
314
Open
HERMES
Phase IV
Trastuzumab in routine clinical
practice
1,500
Open
DFCI 09-457
Phase II
Capecitabine, oxaliplatin,
bevacizumab, trastuzumab
36
Not yet
open
NCT01145404
Phase II
Lapatinib +/- capecitabine
76
Open
EORTC-40071
Phase II
Epirubicin, cisplatin, 5-FU or
capecitabine, lapatinib or placebo
192
Not yet
open
LOGiC Phase III
www.clinicaltrials.gov, October 2010
Interim Safety Analysis from
TYTAN: A Phase III Asian Study of
Lapatinib in Combination with
Paclitaxel as Second-Line Therapy
in Gastric Cancer
Satoh T et al.
Proc ASCO 2010;Abstract 4057.
Copyright © 2010, Research To Practice, All rights reserved.
A Phase III Study of CapeOX +/Lapatinib in FISH-Positive HER2
Locally Advanced/Metastatic Upper
Gastrointestinal Adenocarcinoma:
Interim Safety Results
Hecht JR et al.
Proc ECCO-15 2009;Abstract 6584.
Copyright © 2010, Research To Practice, All rights reserved.
Phase II Multi-Center Study of Perioperative
Chemotherapy/Trastuzumab (NCT01130337)
Accrual: N = 45
Eligibility
Locally advanced,
resectable HER2+
gastric or GE
junction
adenocarcinoma
Preoperative Therapy x 3 Cycles
Capecitabine + Oxaliplatin (CAPOX)
Trastuzumab
Surgery
If complete resection, R0 or microscopic R1
Postoperative Therapy x 3 Cycles
CAPOX
Trastuzumab
Trastuzumab completion to 12 months
www.clinicaltrials.gov, October 2010
Signal Transduction by the HER Family
Promotes Proliferation, Survival, and
Invasiveness
Receptor specific
ligands
HER2
HER4
HER1, HER2,
HER3, or HER4
HER3
HER2
VEGF
HER1
(EGFR)
Plasma
membrane
P
PI3K
Tyrosine kinase
domains
Akt
P
SOS
P
RAS
MAP
K
P
RAF
MEK
Cytoplasm
Cell proliferation
Cell survival
Cell mobility and invasiveness
Nucleus
Transcription
34
Lapatinib, a Dual EGFR and HER2
Kinase Inhibitor, Selectively Inhibits
HER2-Amplified Human Gastric
Cancer Cells and is Synergistic with
Trastuzumab In Vitro and In Vivo
Wainberg ZA et al.
Clin Cancer Res 2010;16(5):1509-19.
Copyright © 2010, Research To Practice, All rights reserved.
Tumor volume (mm3)
Synergistic Antitumor Activity of Lapatinib and
Trastuzumab in Combination (N87 Xenograft)
Reprinted with permission: Wainberg ZA E et al. Clin Cancer Res 2010;16(5):1509-19.
Case History: Dr Ajani
• A 56 year old man presents with abdominal pain and
dyspepsia
• Investigations revealed a GE junction mass with liver
and adrenal masses as well
• Biopsy of GE junction mass shows HER2-positive
(by FISH) moderately differentiated adenocarcinoma
• Patient treated with:
– Docetaxel 40 mg/m2 q2wks
– Capecitabine 1,500 mg/m2/d 7d on/7d off
– Oxaliplatin 85 mg/m2 q2wks
– Trastuzumab 6 mg/kg q3wks
Initial CT Evaluation
Recent Evaluation in 8/2010
Patient continues on trastuzumab as of 10/2010 and remains free of
obvious cancer
Approximately How Many New Patients With
Gastric Cancer Do You See Per Year?
0
6%
19%
1-4
Patients
5-9
34%
10-15
>15
33%
8%
Median = 5 patients
Patterns of Care Survey of US-Based Medical Oncologists (n = 100)
How Many Patients With Gastric Cancer Have
You Treated With Trastuzumab +/- Chemo?
0
Patients
55%
1-2
≥3
38%
7%
Patterns of Care Survey of US-Based Medical Oncologists (n = 94)
Which Chemotherapy Did You Generally
Administer With Trastuzumab?
Platinum/
fluoropyrimidine
41%
Single-agent chemo
31%
Platinum/taxane
10%
Platinum/
fluoropyrimidine/
taxane
10%
fluoropyrimidine/
taxane
Other
2%
6%
Patterns of Care Survey of US-Based Medical Oncologists (n = 42)
In General, How Long Did You Continue The
Trastuzumab?
Until disease
progression
63%
Six cycles
Indefinitely
One year
31%
5%
1%
Patterns of Care Survey of US-Based Medical Oncologists (n = 42)
I’ve tested every patient with metastatic gastric
cancer whom I have cared for recently, and all
10 patients have been HER2-negative.
I don’t know whether there is a lot of
geographic variation, but I haven’t seen a lot of
HER2 positivity in gastric cancer.
— Neal Fishbach, MD
Fairfield, CT
In a patient with HER2-positive gastric cancer
who initially responds to trastuzumab plus
chemotherapy and is subsequently maintained
on trastuzumab alone, but then progresses,
does the panel feel that there is a role for
continuing the trastuzumab as is done in breast
cancer, or at least changing to another
anti-HER2-directed therapy?
— Karen Green, MD
White Plains, NY
How should we interpret the results of HER2
testing in gastric cancer? What’s considered
positive?
If the specimen is less than IHC3+, is it
considered HER2-negative? Or should we
use FISH?
— Richard Polkinghorn, MD
Brunswick, ME
Case History: Dr Ross
• A 67 year old woman with history of low grade ductal
carcinoma of the breast seven years ago presents
with dysphagia
• Endoscopy: polypoid mass beneath
gastroesophageal sphincter
• Punch biopsies (three): Gastric adenocarcinoma,
intestinal type. HER2-negative
Case History: Dr Ross (continued)
• Patient undergoes primary surgery, and
histopathology from surgical specimen shows
– Moderately differentiated intestinal type
adenocarcinoma
– Invasion of muscularis propria
– 1/32 regional lymph nodes+
– All margins negative
– T2N1 tumor
5) What treatment would you most likely
recommend?
Epirubicin, cisplatin,
5-FU (ECF)
15%
Docetaxel, cisplatin,
5-FU (DCF)
31%
Radiation 5-FU/leucovorin
27%
Docetaxel or paclitaxel plus
fluoropyrimidine
(5-FU or capecitabine)
2%
9%
Cisplatin, 5-FU
Oxaliplatin plus fluoropyrimidine
(5-FU or capecitabine)
14%
Irinotecan plus fluoropyrimidine
(5-FU or capecitabine)
2%
0%
5%
10%
15%
20%
25%
30%
35%
Case History: Dr Ross (continued)
HER2 testing is repeated on the surgical specimen
by both IHC and FISH, and now reported as HER2positive
 IHC3+
 FISH+
Negative HER2 Staining in Original Biopsy
versus IHC 3+ Staining in Surgical Specimen
Low Magnification of Original
Endoscopic Biopsy Showing a Negative
IHC for HER2 Protein Expression
Resection Specimen
Demonstrating 3+ IHC Staining for
HER2 in the Same Patient
6) How would you treat this patient in the
adjuvant setting?
2%
No adjuvant therapy
Adjuvant 5-FU/irinotecan
chemotherapy
0%
Adjuvant cisplatin/5-FU
chemotherapy
2%
Adjuvant cisplatin/5-FU
chemotherapy trastuzumab
(ToGA trial regimen)
51%
Another non-trastuzumab
chemotherapy regimen
2%
Another trastuzumab-based regimen
4%
Adjuvant chemo-radiation
39%
0%
10%
20%
30%
40%
50%
60%
Case History: Dr Ross (continued)
•
Patient received adjuvant platinum/5-FU plus
trastuzumab ToGA trial regimen
•
Remains alive and progression-free four months
postresection
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 Y et al.
Proc ASCO 2009;Abstract 4556.
Copyright © 2010, Research To Practice, All rights reserved.
Modified HercepTest™ HER2 Scoring
System for GC
Staining characteristics
Score/classification
No staining or membrane staining in <10% of cells
0/negative
Faint/barely perceptible membrane staining in
>10% of cells; cells are only stained in part of their
membrane
1+/negative
Weak to moderate complete or basolateral
membrane staining in >10% of tumor cells
2+/equivocal
Moderate to strong complete or basolateral
membrane staining in >10% of tumor cells
3+/positive
Biopsy (not surgery) samples with cohesive IHC
3+ and/or FISH+ clones are considered positive
irrespective of size, ie, <10% of tumor cells
Bang Y et al. Proc ASCO 2009;Abstract 4556.
HER2 Positivity Screening Results
• 3,807 tumor samples from 24 countries assessed for HER2
status in a central laboratory using the modified scoring
system
– 3,667 samples evaluable
– HER2 positivity rate: 22.1%
• Concordance rate between IHC and FISH with modified
HER2 scoring system: 87.2%
Bang Y et al. Proc ASCO 2009;Abstract 4556.
HER2 Positivity Screening Results (continued)
• HER2 positivity varied by:
– Tumor site: GEJ cancer vs stomach cancer (33.2% vs
20.9%)
– Histologic subtype: Intestinal vs diffuse/mixed (32.2% vs
6.1%/20.4%)
– Sample preparation: Biopsy vs surgery (23.1% vs 19.9%)
• Biopsy samples more likely to be HER2-positive than
surgery samples when analyzed by FISH rather than
by IHC
Bang Y et al. Proc ASCO 2009;Abstract 4556.
I see between 5-10 patients with gastric
cancer per year. To a lesser extent, we have
the same problem that we have in lung
cancer with EGFR mutations in that we often
have to talk our pathologist into looking for
HER2 status in our patients with gastric
cancer.
— Erik Rupard, MD
Fort Gordon, GA
Pathological Complete Response
After Neoadjuvant Chemotherapy
With Trastuzumab-Containing
Regimen in Gastric Cancer: A Case
Report
Wang J et al.
J Hematol & Oncol 2010;3.
Copyright © 2010, Research To Practice, All rights reserved.
Case History
• A 49-year-old male with a 2-cm gastric ulcer
• Biopsy: moderately differentiated adenocarcinoma
– HER2-positive by IHC and FISH
• Ultrasound, CT, PET: T3N1M0
• Received capecitabine, oxaliplatin, docetaxel and
trastuzumab x 3 cycles
• Gastrectomy with extended D2 lymph node dissections
– Pathologic complete response
• Postoperative chemotherapy x 3 cycles
Wang J et al. J Hematol & Oncol 2010;3.
Case History: Dr Ross
• A 58 year old man with history of GERD and biopsy
proven Barrett’s esophagus presents with anorexia,
weight-loss, fatigue and anemia
• Multiple endoscopic biopsies of GE junction reveal
adenocarcinoma of GE junction with sub-mucosal
invasion
• HER2 testing showed
– Rare microfoci of incomplete staining by IHC,
limited to areas of in situ adenocarcinoma
– FISH-negative for HER2 gene amplification
Illustration of IHC 3+ HER2 Immunostaining
Limited to the In Situ Component of Invasive
Gastric Adenocarcinoma
Hofmann M et al. Histopathology 2008;52:797-805.
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
More severe than for breast
HER2 test results
cancer; especially important for
especially when core
endoscopic biopsies
biopsies are assessed
Comparison of HER2 Testing in Breast and
Gastric/GEJ Cancers (continued)
Breast Cancer
Gastric/GE Junction Cancer
In Situ Component
Not scored
Is scored. If in situ component is
positive and invasive component is
negative, the tumor is still classified
as HER2+
IHC – FISH
Concordance
High (85-95%)
Moderate (83% in the ToGA trial)
HER2 testing in gastric/GEJ tumors
approved in Europe, but not in US.
Regulatory issues
IHC and FISH tests
approved by US FDA
Approval in US likely to be identical
to that in Europe (Dako HercepTest
for IHC and Dako pharmDxTM for
FISH)
Comparison of HER2 IHC Slide Scoring in
Gastric/GEJ and Breast Cancers
Marked Heterogenity of HER2
Immunostaining
Incomplete Staining With Loss of
Apical Membrane HER2 Expression
Gastroesophageal
Junction Cancer
Gastric
Cancer
Breast
Cancer
Continuous Complete 360 Degree
Membranous HER2 Staining
NSABP B-47: A Phase III Trial of Adjuvant
Chemotherapy +/- Trastuzumab in HER2 Normal
Breast Cancer
Target Accrual: N = 3,260
• Node-positive or
high-risk nodenegative breast
cancer
• IHC 0, 1+, 2+ and
FISH-negative
Protocol undergoing revisions
Docetaxel/cyclophosphamide (TC)
or
AC  weekly paclitaxel (WP)
R
NSABP Protocol Summaries, April 2010
TC + Trastuzumab (H)  H x 1 yr
Or
AC  WP + H  H x 1 yr
Case History: Dr Ross
• A 53 year old woman with history of breast cancer for
15 years presents with symptoms of gastric
obstruction with marked gastric distension
• Endoscopic biopsy
– Infiltrating adenocarcinoma on H&E stain
– Cords and columns of cells through the submucosa
– No mucosal site of origin is seen
– Primary diffuse adenocarcinoma of the stomach is
diagnosed
Case History: Dr Ross (continued)
• Review of pathology from primary breast cancer
revealed infiltrating lobular carcinoma
• Surgical specimen contained a multifocal intramural
obstructing mass, and the tumor closely resembled
the histology of the primary breast carcinoma
– Strongly ER/PR+
– HER2-negative
– E-cadherin-negative
• A final diagnosis of recurrent lobular breast cancer in
the gastric outlet was made
Case History: Dr Ross (continued)
• Patient treated with tamoxifen alone
• Continued symptoms of abdominal pain but no
recurrence of gastric outlet obstruction in the last 6
months
Metastatic Lobular Breast Cancer with Gastric
Outlet Obstruction Simulating Primary Gastric
Adenocarcinoma
Gastric Outlet Obstruction Caused
by Metastatic Breast Cancer
Lobular Breast Cancer with Cords and
Columns of Infiltrating Malignant Cells