IDENTIFYING THE CurrENT STaTE oF GIST - PfizerPro

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IDENTIFYING THE CurrENT STaTE oF GIST - PfizerPro

IDENTIFYING

THE Current

State of GIST

clinical overview

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal

neoplasm of the GI tract. Most of these tumors are gastric or small intestinal.

Diagnosis relies on contrast-enhanced computed tomography (CT) and

histology. Prognosis varies by location and is generally more favorable for

patients with gastric tumors than for patients with GIST of the small intestine

or other less common locations. Active mutations in KIT (CD117) and PDGFRα

are involved with most of the cases of GIST and can be important diagnostic

markers with prognostic value. 1-3

KIT=stem cell factor receptor.

PDGFRα=platelet-derived growth factor receptor alpha.


US IncidencE

and Prevalence

of GIST

Clinical

PResentation

of GIST

Epidemiology

There are an estimated 4500 to 6000 new cases of GIST in the United States each year,

although incidence is difficult to determine and may vary among studies. About 1500 of these

cases are metastatic at presentation. The reported incidence has increased because of greater

awareness, improved diagnosis, and perhaps an increase in the true incidence of the disease.

Prevalence can also be difficult to determine; one study estimated that 129 per million people

are living with GIST. 2,4,5 *

PAtient Demographics

While most patients diagnosed with GIST are older than age 50, GIST may occur at any age.

African Americans and men are more likely to develop GIST. 4

Frequency of the disease in various primary sites 1,2

Esophagus, appendix,

or outside the

GI tract


Clinical

PResentation

of GIST

DIAGnosis

of gist

Imaging studies, such as CT, magnetic resonance imaging (MRI) or positron emission

tomography (PET), are used for diagnosis, initial staging, restaging, monitoring response

to therapy, and follow-up surveillance of recurrence. 1

SIGNS AND SYMPTOMS 1,2

GISTs smaller than 2 cm do not generally produce symptoms and are detected

incidentally. Larger tumors can exhibit more symptoms, such as early satiety,

abdominal discomfort from pain or swelling, intraperitoneal hemorrhage, GI

bleeding, or anemia-related fatigue. Some patients present with acute, severe

abdominal pain, which may be a sign of a medical emergency.

Median tumor size at presentation 1,2

GISTs may occur anywhere along the GI tract. The majority present as a single,

well-circumscribed nodule. GIST lesions range in size from a few millimeters to more

than 35 cm. Median size at presentation is approximately 5 cm. A recent populationbased

study suggested that the median size of GISTs is generally larger when patients

are diagnosed based on disease symptoms.

Contrast-enhanced CT is the imaging modality of choice to characterize an abdominal mass,

assess the extent of the mass, and determine if the mass has metastasized. PET scans can

facilitate differentiation of an active tumor from necrotic or inactive tissue, malignant from

benign tissue, and recurrence from benign changes. 1

Histology 1,2

Morphologic diagnosis based on microscopic examination of histologic sections is the

standard for GIST diagnosis. Immunohistochemical staining for KIT, in addition to anatomic

localization of the lesion, is essential for confirming the diagnosis. Tissue samples may be

obtained via biopsy or primary tumor resection.

Endoscopic ultrasound–guided biopsy may be considered when appropriate. A core

needle biopsy may be preferred over fine-needle aspiration biopsy because this offers the

opportunity to obtain information on mitotic rate. Supportive techniques, such as molecular

genetic testing for KIT or PDGFRα mutations, are also useful.

DIAGNOSIS

Diagnosis 2

Incidental findings

Autopsy

Symptoms

Location of METASTASES 1

Tumor Size 2 (cm)

2.7

3.4

8.9

GISTs most commonly metastasize to the liver and/or disseminate within the abdominal

cavity. Metastases beyond the abdominal cavity are observed in late-stage disease only.

Lymph node metastases are uncommon.

Staging 1

Staging can be determined using the American Joint Committee on Cancer Staging System

for Soft Tissue Sarcoma (7th ed, 2010) as adapted in the table below.

Anatomic

Stage/

Prognostic

Group

Primary

Tumor

SIZE

Regional Lymph

Node Metastasis

IA ≤5 cm None None

IB >5 cm None None

Distant

Metastases

Histologic

Grade

1 or cannot

be assessed

1 or cannot

be assessed

IIA ≤5 cm None None

IIB >5 cm None None

III >5 cm None None

2 or 3

2

3

III Any size Present

IV Any size Present/none/

cannot be assessed

None

Present

Any grade or

cannot be assessed

Any grade or

cannot be assessed

4

5


prognosis

of patients

with gist

Prognosis is generally more favorable for patients with gastric GISTs than for those with

GISTs of the small intestine. 1

Risk stratification 1,2

The most important and widely used prognostic features of a primary tumor are tumor

size, location, and mitotic index. Gastric GISTs ≤2 cm with a mitotic index of ≤5 per 50

high-power fields (HPF) are considered benign; however, lesions >2 cm with the same mitotic

index have a risk of recurrence. GISTs of the small intestine are usually associated with the

greatest risk of recurrence or progression and are more aggressive than gastric GISTs of the

same size.

While tumor size and mitotic rate are useful in predicting the malignant potential of GISTs,

the likelihood of progressive disease varies among individuals.

RISK STRATIFICATION OF PRIMARY GIST BY MITOTIC INDEX, SIZE, AND SITE 2

TUMOR PARAMETERS

Mitotic rate

RISK OF PROGRESSIVE DISEASE* (%), BASED ON SITE OF ORIGIN

Size Stomach Jejunum/ileum Duodenum Rectum

survival rates 2

Recurrence-free survival (RFS), based on tumor size, mitotic index, and anatomic site, may be

estimated using a nomogram.

POINTS

SIZE (cm)

MITOTIC INDEX

SITE

TOTAL POINTS

PROBABILITY (%) OF

2-YEAR RFS

PROBABILITY (%) OF

5-YEAR RFS

0 10 20 30 40 50 60 70 80 90 100

0 5 10 15 25 35 45

2, ≤5 cm

Very low (1.9%)

Low (4.3%)

Low (8.3%)

Low (8.5%)

>5, ≤10 cm

Low (3.6%)

Moderate (24%)

Insufficient data

Insufficient data

>5 per 50 HPF

>10 cm

≤2 cm

>2, ≤5 cm

>5, ≤10 cm

>10 cm

Moderate (10%)

None †

Moderate (16%)

High (55%)

High (86%)

High (52%)

High †

High (73%)

High (85%)

High (90%)

High (34%)

Insufficient data

High (50%)

Insufficient data

High (86%)

High (57%)

High (54%)

High (52%)

Insufficient data

High (71%)

determining the specific mutational

status of patients with GIST may have

value in estimating survival. 2

Data are based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs.

* Defined as metastasis or tumor-related death.


Denotes small number of cases.

Adapted from Demetri GD, von Mehren M, Antonescu CR, et al.

6

7


mutations

in gist

Mutations Vary

by Location

Exon mutations can result in structurally and functionally abnormal receptors that can

lead to continual (“constitutive”) activation and tumor development. 6,7

Receptor mutations are known to cause

tumor cell proliferation 8,9

• When functioning normally, KIT regulates cell proliferation and survival

– Mutations can affect the normal functioning of KIT and lead to tumor growth

• PDGFRα mutations have similar biological consequences to KIT mutations and

drive the progression of GIST

Incidence of specific primary mutations

identified in GIST 1

• Approximately 80% have a mutation in the gene encoding the KIT receptor

• 5% to 10% have a mutation in the gene encoding the PDGFRα receptor

• About 10% to 15% do not have any detectable mutation (wild type); however,

the absence of such a mutation does not exclude the diagnosis of GIST

Relative frequency of primary mutations in GIST 10-15

KIT exon 11 mutations occur in various sites throughout the GI tract. KIT exon 9 mutations

occur mostly in the small intestine, while KIT exon 17 mutations occur more frequently in

the small intestine than in the stomach. 2

PDGFRα mutations are more common in the stomach and omentum, a fatty layer in

the abdomen. 2

Identifying the specific mutation may have

prognostic value 1,2

GISTs with KIT exon 9 mutations may be more clinically aggressive than tumors with KIT

exon 11 mutations. Based on data from a large phase 3 study, the presence of KIT exon 9

mutations is strongly associated with mutational prognostic factors for the risk of progression

or death in patients with GIST, even in patients currently receiving therapy. In particular, the

presence of KIT exon 9 mutations in tumors outside the stomach appears to be associated

with an unfavorable clinical course. In randomized clinical trials, the presence of KIT exon 11

mutations was associated with better rates of response, progression-free survival, and overall

survival compared with KIT exon 9 mutations or wild type.

Patients with no detectable KIT or PDGFRα mutations are also at increased risk of progression

and death. Studies have shown that patients with KIT mutation–negative GIST have similar

time to tumor progression but inferior overall survival compared with patients with KIT

mutation–positive GIST.

In comparing KIT with PDGFRα mutations, GISTs with PDGFRα mutations may be less

aggressive than those with KIT mutations.

KIT: 78% to 88%

PDGFRα: 5% to 7%

Mutations

Exon 9: 10% to 18%

Juxtamembrane domain

Exon 11: 66% to 67%

Exon 12: 1% to 2%

Exon 13: 1% to 2%

Exon 17: 1% to 2%

Exon 18: 2% to 6%

8

9


mutational

testing sites

The following laboratories in the United States conduct GIST mutational testing 16 :

TESTING SITES

ARUP ® Laboratories

500 Chipeta Way

Salt Lake City, UT 84108-1221

Tel: 800-522-2787

Fax: 800-522-2706

E-mail: clientservices@aruplab.com

Web site: www.aruplab.com

City of Hope Molecular

Diagnostic Laboratory (MDL)

1500 E. Duarte Rd.

Duarte, CA 91010

Tel: 888-826-4362

Fax: 626-301-8142

E-mail: mdl@coh.org

Web site: www.cityofhope.org/mdl

Fox Chase Cancer Center

Clinical Molecular Genetics Laboratory

West Building, Room W232

333 Cottman Avenue

Philadelphia, PA 19111-2497

Contact: Betsy Bove, PhD

Tel: 215-728-4785

E-mail: betsy.bove@fccc.edu

Web site: www.fccc.edu/research/

facilities/clinical/cmgl/index.html

Mayo Clinic Laboratories

(For Mayo Clinic account members;

if you are not currently a member

and would like to join, please call

the number below)

3050 Superior Drive NW

Rochester, MN 55901

Tel: 800-533-1710

E-mail: mml@mayo.edu

Web site:

www.mayomedicallaboratories.com/

test-catalog/Overview/89669

Memorial Sloan-Kettering

Cancer Center

(for MSKCC patients only)

1275 York Avenue

New York, NY 10065

Tel: 212-639-2000

Web site: www.mskcc.org

Oregon Health &

Science University

OHSU Department of Pathology

(mailcode L471)

6036 Dillehunt Hall

3181 SW Sam Jackson Park Road

Portland, OR 97239

Contact: Erin Popelka

Tel: 503-494-6834

Fax: 503-494-2025

E-mail: popelka@ohsu.edu

Web site: www.heinrich-corless.

net/services

University of Colorado Denver

School of Medicine

Anschutz Medical Campus

Department of Pathology

Bldg L-15, Rm 22xx

12631 East 17th Ave.

Aurora, CO 80045

Tel: (303) 724-3700

E-mail: info.pathology@UCDenver.edu

Web site: http://www.ucdenver.edu/academics/colleges/

medicalschool/departments/Pathology/aboutus/Pages/

contactus.aspx

University of Texas

MD Anderson Cancer Center

(for MD Anderson/KIT mutation

patients only)

Molecular Diagnostic Laboratory

8515 Fannin Street

Room NA1.075

Houston, TX 77054

Contact: Raja Luthra, PhD (technical director)

or Cindy Lewing (laboratory manager)

Tel: 713-794-4780; 713-792-2739

Fax: 713-794-4773

E-mail: clewing@mdanderson.org

Web site: www.mdanderson.org

Sample Collection 17-19

Stained or unstained slides or formalin-fixed, paraffin-embedded blocks containing histologically

confirmed GIST tissue are generally accepted. Larger amounts of sample tissue are preferred. It’s

important to discuss specific requirements with the local pathologist or to contact the lab conducting

the mutational testing directly to verify the appropriate specimen-collection techniques.

10

11


Pfizer Oncology is committed

to raising awareness of GIST.

For more information, visit www.pfizeroncology.com.

References to NCCN are made with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft

Tissue Sarcoma V.1.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines may

not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and

complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK ® , NCCN ® , NCCN

GUIDELINES, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

References: 1. National Comprehensive Cancer Network ® . NCCN Clinical Practice Guidelines in Oncology. Soft tissue sarcoma. V.1.2011.

http://www.nccn.org. Accessed February 1, 2011. 2. Demetri GD, von Mehren M, Antonescu CR, et al. NCCN Task Force report: update on the

management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010;8(suppl 2):S1-S41. 3. Okuno SH. The use of

tyrosine kinase inhibitors for gastrointestinal stromal tumors (GIST). Contemp Oncol. 2011;3(1):28. 4. American Cancer Society ® Web site.

http://www.cancer.org/Cancer/GastrointestinalStromalTumorGIST/DetailedGuide/gastrointestinal-stromal-tumor-key-statistics. Updated August

24, 2010. Accessed May 5, 2011. 5. Nilsson B, Bümming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors: the incidence, prevalence,

clinical course, and prognostication in the preimatinib mesylate era—a population-based study in western Sweden. Cancer. 2005;103(4):821-

829. 6. U.S. National Library of Medicine ® Web site. Genetics home reference: your guide to understanding genetic conditions. http://ghr.

nlm.nih.gov/glossary. Accessed June 30, 2011. 7. Demetri GD. Gastrointestinal stromal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA,

eds. Cancer: Principles & Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2004:1050-1060. 8. Hirota S, Isozaki

K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577-580.

9. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708-

710. 10. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813-3825. 11. Heinrich

MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.

J Clin Oncol. 2003;21(23):4342-4349. 12. Debiec-Rychter M, Sciot R, Le Cesne A, et al.; on behalf of the EORTC Soft Tissue and Bone Sarcoma

Group, the Italian Sarcoma Group, and the Australasian Gastrointestinal Trials Group. KIT mutations and dose selection for imatinib in patients with

advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42(8):1093-1103. 13. Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in

gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005;23(23):5357-5364. 14. De Giorgi U, Verweij

J. Imatinib and gastrointestinal stromal tumors: where do we go from here? Mol Cancer Ther. 2005;4(3):495-501. 15. Braconi C, Bracci R, Bearzi I,

et al. KIT and PDGFRα mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study. Ann Oncol. 2008;19(4):706-

710. 16. Gist Support International Web site. http://www.gistsupport.org/for-new-gist-patients/mutation-testing.php. Accessed May 3, 2011.

17. Arup ® Laboratories Web site. http://www.aruplab.com/guides/ug/tests/2002674.jsp. Accessed May 3, 2011. 18. Mayo Clinic Medical Laboratories

Web site. http://www.mayomedicallaboratories.com/test-catalog/Specimen/88955. Accessed May 3, 2011. 19. MolecularMD Web site. http://www.

molecularmd.com/testMenu/kit.php. Accessed May 3, 2011.

SUU01170/286050 © 2011 Pfizer Inc. All rights reserved. Printed in USA/July 2011

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