IDENTIFYING THE CurrENT STaTE oF GISTclinical 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.

epidem

iolo

gy

uS INCIDENCE aND PrEvalENCE oF GIST

ClINICal PrESENTaTIoN oF GIST

32

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

4500-6000

1500neW CASeS oF GIST Per yeAr

APProxIMATely

CASeS Are MeTASTATIC

FreqUenCy oF The DISeASe In vArIoUS PrIMAry SITeS1,2

STomacHduodenum

eSopHaguS, appendix,or ouTSide THe

gi TracT

colon/recTum/anuS

JeJunum/ileum

5%

<5%

30%

60%

<1%

*estimate based on a population in Sweden.5

diag

no

SiS

DIaGNoSIS oF GIST

54

ClINICal PrESENTaTIoN oF GISTSIGnS AnD SyMPToMS1,2

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 PreSenTATIon1,2 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 population- based study suggested that the median size of GISTs is generally larger when patients are diagnosed based on disease symptoms.

loCATIon oF MeTASTASeS1

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.

diagnoSiS2 Tumor Size2 (cm)2.7Incidental findings

SymptomsAutopsy

8.93.4

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

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

hISToloGy1,2

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.

STAGInG1 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 TumorSize

regional lympHnode meTaSTaSiS

diSTanT meTaSTaSeS

HiSTologic grade

IA ≤5 cm none none

IB >5 cm none none

IIA ≤5 cm none none

IIB >5 cm none none

III >5 cm none none

noneIII Any size Present

PresentIv Any size Present/none/cannot be assessed

Any grade or cannot be assessed

1 or cannot be assessed

1 or cannot be assessed

2 or 3

2

3

Any grade or cannot be assessed

SUrvIvAl rATeS2

recurrence-free survival (rFS), based on tumor size, mitotic index, and anatomic site, may be estimated using a nomogram.

76

ProGNoSIS oF PaTIENTS wITH GIST

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.

riSK STraTificaTion of primary giST By miToTic index, Size, and SiTe2

TUMor PArAMeTerS

Mitotic rate

≤5 per 50 hPF

>5 per 50 hPF

≤2 cm

>2, ≤5 cm

>5, ≤10 cm

>10 cm

≤2 cm

>2, ≤5 cm

>5, ≤10 cm

>10 cm

none (0%)

very low (1.9%)

low (3.6%)

Moderate (10%)

none†

Moderate (16%)

high (55%)

high (86%)

none (0%)

low (4.3%)

Moderate (24%)

high (52%)

high†

high (73%)

high (85%)

high (90%)

none (0%)

low (8.3%)

Insufficient data

high (34%)

Insufficient data

high (50%)

Insufficient data

high (86%)

none (0%)

low (8.5%)

Insufficient data

high (57%)

high (54%)

high (52%)

Insufficient data

high (71%)

Size Stomach Jejunum/ileum Duodenum rectum

rISK oF ProGreSSIve DISeASe* (%), BASeD on SITe oF orIGIn

Prognosis is generally more favorable for patients with gastric GISTs than for those with GISTs of the small intestine.1

rISK STrATIFICATIon1,2

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.

• Patient example: a 2.5-cm tumor (15 points) with a mitotic index of ≥5/50 hPF (80 points) located in the colon (7 points) has a total point value of 102. A value of 102 on the “Total Points” line corresponds to a 2-year rFS of approximately 62% and a 5-year rFS of approximately 38%

POINTS

SIZE (cm)

MITOTIC INDEX

SITE

TOTAL POINTS

PROBABILITY (%) OF 2-YEAR RFS

PROBABILITY (%) OF 5-YEAR RFS

102080 304050607090

102080 304050607090

0 5 10 15 25 35 45

0 10 20 8030 40 50 60 70 90 100

0 20 40 16060 80 100 120 140 180 200

Colon/rectum

Small intestineStomach/other

<5/50 HPF

≥5/50 HPF

Nomogram for predicting probabilities of 2- and 5-year RFS. Points are assigned for size, mitotic index, and site of origin by drawing a line upward from the corresponding values to the “Points” line. The sum of these 3 points, plotted on the “Total Points” line, corresponds to predictions of 2- and 5-year RFS by drawing a vertical line down to the corresponding probability values.Adapted from Demetri GD, von Mehren M, Antonescu CR, et al. pro

gn

oSiS

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 vAlUe1,2 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.

MuTaTIoNS varY bY loCaTIoN

98

mu

TaTion

S

MuTaTIoNS IN GISTexon 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 ProlIFerATIon8,9 • Whenfunctioningnormally,KITregulatescellproliferationandsurvival

– 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 GIST1

• Approximately80%haveamutationinthegeneencodingtheKITreceptor• 5%to10%haveamutationinthegeneencodingthePDGFRα receptor• About10%to15%donothaveanydetectablemutation(wildtype);however,

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

relATIve FreqUenCy oF PrIMAry MUTATIonS In GIST10-15

pdgfrα: 5% to 7%KiT: 78% to 88%

exon 17: 1% to 2%

exon 13: 1% to 2%

exon 9: 10% to 18%

exon 11: 66% to 67%

exon 18: 2% to 6%

exon 12: 1% to 2% Juxtamembrane domain

1110

MuTaTIoNal TESTING SITES

ArUP® lABorATorIeS500 Chipeta WaySalt lake City, UT 84108-1221Tel: 800-522-2787fax: 800-522-2706e-mail: clientservices@aruplab.comweb site: www.aruplab.com

CITy oF hoPe™ MoleCUlAr DIAGnoSTIC lABorATory (MDl)1500 e. Duarte rd.Duarte, CA 91010Tel: 888-826-4362 fax: 626-301-8142 e-mail: mdl@coh.org web site: www.cityofhope.org/mdl

Fox ChASe CAnCer CenTerClinical Molecular Genetics laboratoryWest Building, room W232333 Cottman AvenuePhiladelphia, PA 19111-2497contact: Betsy Bove, PhDTel: 215-728-4785e-mail: betsy.bove@fccc.eduweb 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 nWrochester, Mn 55901Tel: 800-533-1710e-mail: mml@mayo.eduweb site: www.mayomedicallaboratories.com/ test-catalog/overview/89669

MeMorIAl SloAn-KeTTerInG CAnCer CenTer (for MSKCC patients only)1275 york Avenuenew york, ny 10065Tel: 212-639-2000web site: www.mskcc.org

oreGon heAlTh & SCIenCe UnIverSITy ohSU Department of Pathology (mailcode l471) 6036 Dillehunt hall3181 SW Sam Jackson Park roadPortland, or 97239contact: erin PopelkaTel: 503-494-6834fax: 503-494-2025 e-mail: popelka@ohsu.eduweb site: www.heinrich-corless. net/services

The following laboratories in the United States conduct GIST mutational testing16:

SAMPle ColleCTIon17-19 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.

UnIverSITy oF ColorADo DenverSChool oF MeDICIne Anschutz Medical CampusDepartment of PathologyBldg l-15, rm 22xx12631 east 17th Ave.Aurora, Co 80045Tel: (303) 724-3700e-mail: info.pathology@UCDenver.eduweb 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 nA1.075houston, Tx 77054contact: raja luthra, PhD (technical director) or Cindy lewing (laboratory manager)Tel: 713-794-4780; 713-792-2739fax: 713-794-4773e-mail: clewing@mdanderson.orgweb site: www.mdanderson.org

TeST

ing

SiT

eS

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

Pfizer oncology is committed to raising awareness of GIST.

For more information, visit www.pfizeroncology.com.

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.

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.