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MEDICAL FRONTIERS - 2011 Gastrointestinal Cancer Symposium

San Francisco, California / January 20-22, 2011

Mutations in KIT play the most important role in gastrointestinal stromal tumours (GISTs), according to Dr. Christopher Corless, Oregon Health and Science University, Portland. Much of the influence occurs on exon 11, which accounts for about two-thirds of KIT mutations. About 10% of KIT mutations involve exon 9 and exons 13 and 17 to a lesser extent. “About 75% of GISTs have KIT mutations,” stated Dr. Corless. “These mutations essentially drive the disease.”

Overall, GIST is not very common: there are about 5000 cases reported annually in the US. However, as many as 30% of adults in the general population have micro-GISTs in the stomach, Dr. Corless remarked during a symposium on translational research. Defined by size (<2 cm), micro-GISTs have KIT mutations that are similar to those found in association with GIST, have a lower mitotic index and a benign morphology. Identifying specific mutations associated with the conversion of micro-GIST to GIST has become a research priority.

Mutations involving platelet-derived growth factor receptor alpha (PDGFR-a) rank second in frequency and importance in the development of GIST. Found in about 7.5% of GISTs, PDGFR-a mutations include those involving exon 18 (5.5%), exon 12 (2%) and exon 14 (rare). “In addition to being the most common site of PDGFR-a mutations, exon 18 is significant because it harbours the D842V mutation that confers resistance to imatinib,” Dr. Corless told delegates.

Impact of Mutations on Outcome

Dr. Corless cited 2 multicentre clinical trials illustrating the impact of various types of mutations on outcome of GIST treated with imatinib. One trial conducted in Canada and the US showed that patients with exon 11 mutations had significantly better clinical outcomes compared with patients who had wild-type tumours (P=0.0002) and those with exon 9 mutations (P=0.007) (Heinrich et al. J Clin Oncol 2008;26:5360-7) (Figure 1).

Figure 1.

He noted that a multicentre European study yielded comparable results (Debiec-Rychter et al. Eur J Cancer 2006;42:1093-103). GIST associated with exon 9 mutations conferred the worst prognosis, including the risk of progression and mortality (P<0.0001 vs. exon 11 mutations) (Figure 2). Patients whose tumours were free of KIT and PDGFR-a mutations also had worse outcomes compared with GIST associated with exon 11 mutations
.028).

Figure 2.

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A pooled analysis of the data from both trials showed dose-related differences in progression-free survival (PFS) and 3-year survival among patients with mutations in exon 9 (GIST Study Group. J Clin Oncol 2010;28:1247-53). Patients who received imatinib 400 mg/day had a median PFS of 6 months and an estimated 3-year survival of 5%. In contrast, those who received 800 mg/day had a median PFS of 19 months and an estimated 3-year survival of 17% (P=0.017).

“We found that it didn’t matter whether exon 11 tumours or wild-type tumours were treated with 400 mg or 800 mg,” observed Dr. Corless. “Surprisingly, however, the dose did make a difference in patients with exon 9 mutations” (Table 1).

The PDGFR-a D842V mutation in exon 18 occurs in about 5% of all GISTs. However, the mutation has been shown to confer in vitro resistance to all currently available tyrosine kinase inhibitors (TKIs). Data from several small clinical series have shown no objective responses and only a few ca
among patients whose tumours have the D842V mutation.

Table 1.

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Secondary Resistance

Most GISTs respond to a TKI for a period of time but then start to progress, noted Dr. Corless. The observation suggested the existence of secondary, or acquired, mutations, which have subsequently been identified.

“Two hot spots have been identified for newly acquired mutations in lesions that have become fully resistant to imatinib,” confirmed Dr. Corless. “The mutations are clustered in exons 13 and 14 in the ATP drug-binding pocket. Others occur in exons 17 and 18, which encode the activation loop. The mutations lead to a more open configuration that does not favour drug binding.”

Mutations also have a key role in second-line therapy for GIST. However, the experience with imatinib does not translate directly to other TKIs. A study of sunitinib in patients with imatinib resistance showed that those who had wild-type tumours and GIST with mutations in exon 9 had the best outcomes, whereas mutations in exon 11 conferred the worst prognosis with sunitinib (Heinrich et al. J Clin Oncol 2008;26:5352-9).

More recently, sorafenib has demonstrated activity against GIST with certain secondary mutations. The evidence suggests the agent has greater activity against exon 13/14 mutations vs. exon 17/18. New data reported here at the symposium showed that a third of sunitinib-resistant tumours benefited from third-line treatment with sorafenib (Campbell et al. J Clin Oncol 2011;29 (suppl 4):Abstract 4).

Mutation Analysis and Prognosis

Dr. Corless cited a recent study from France illustrating the role of mutation analysis in prognosis as it relates to adjuvant therapy. Investigators identified 115 patients with GIST, 88% of which were localized at diagnosis (Cassier et al. Br J Cancer 2010;103:165-70). Further analysis using Armed Forces Institute of Pathology (AFIP) criteria showed that 36.5% of the tumours were low-risk, 35.6% were intermediate-risk and 27.7% were high-risk.

“This is the cohort of patients that we have to think about treating adjuvantly with imatinib,” stated Dr. Corless. “Depending on your risk threshold or your patient’s threshold, that means a substantial population of newly diagnosed patients in whom adjuvant treatment is a serious consideration.”

The current approach to risk-stratifying primary GIST for recurrence comprises 3 factors: mitotic index, tumour size and tumour location. Though somewhat crude, the system has fairly good accuracy for defining a tumour’s recurrence potential, remarked Dr. Corless. Adding information about mutation status might further improve the prognostic capability.

KIT mutations in exon 11 can occur as deletions, point mutations or insertions. Deletions are by far the most common type of mutation, and they are harbingers of worse prognosis, according to Dr. Corless.

A recent analysis of a randomized trial of adjuvant therapy in GIST illustrated the potential value of including mutation status in determining prognosis (DeMatteo et al. Lancet 2009;373:1097-104). Investigators had genotype results for 513 patients. Dr. Corless and colleagues examined the impact of genotype in patients randomized to placebo after surgical resection.

The analysis showed that exon 11 deletion mutations conferred the highest risk of recurrence. The difference held up in comparison to exon 11 insertions, PDGFR-a mutations, exon 11 point mutations, exon 9 mutations and wild-type tumours. Dr. Corless remarked, “How can we take advantage of this information? We’re working on that, trying to develop a nomogram that incorporates genotype information on top of pathologic information.”

Recent Developments in GIST Therapy

Genotyping does have potential to help clinicians build on the benefits of adjuvant therapy demonstrated in the American College of Surgeons Oncology Group (ACOSOG) Z9001 trial, stated Dr. Ronald P. DeMatteo, Memorial Sloan-Kettering Cancer Center, New York, during an education session at the symposium. However, the optimal method to incorporate the information has yet to be determined.

The ACOSOG Z9001 trial demonstrated a significant improvement in recurrence-free survival in patients with GIST who underwent surgical resection of the primary tumour and then were randomized to imatinib or placebo. The trial ended prematurely when an interim analysis showed a 65% reduction in the recurrence risk among patients treated with imatinib (HR 0.35, P<0.0001). A preliminary analysis of overall survival (OS) suggested a benefit from imatinib. The difference did not achieve statistical significance (HR 0.66, P=0.47); however, “the trial was underpowered to examine OS,” Dr. DeMatteo reported.
ued that recurrence should be the primary end point for clinical trials of this disease” (Table 2).

Table 2.

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Dr. DeMatteo and colleagues developed a nomogram to predict recurrence risk in GIST, derived from 127 patients treated at the centre. The nomogram comprises tumour size, tumour location and mitotic index and compared its performance in 2 cohorts comprising a total of 360 patients. The results suggested the system has better calibration for prediction of recurrence-free survival compared with the AFIP criteria. In contrast to the analysis by Dr. Corless and colleagues of the ACOSOG Z9001 data, adding TK mutation status did not improve the predictive accuracy of the nomogram (Gold et al. Lancet Oncol 2009;10:1045-52).

Despite the differing results, Dr. DeMatteo agreed that awareness of exon 11 mutations could improve decision-making regarding the use of imatinib and other treatment decisions. Wild-type tumour status appears to have little or no prognostic value. The prognostic potential of exon 9 and PDGFR-a mutations remains unclear.

The clinical science surrounding metastatic GIST continues to evolve. Dr. DeMatteo noted how the available evidence would suggest that patients with metastatic disease benefit from treatment with imatinib. A multicentre study involving 746 patients with advanced GIST showed a median PFS of 18 and 20 months with the 400- and 800-mg doses of imatinib, respectively, and median OS of 55 and 51 months, respectively (Blanke et al. J Clin Oncol 2008;26(4):626-32). Neither difference was statistically significant, added Dr. DeMatteo. Among patients randomized to high-dose imatinib after progression, one-third had objective responses or stable disease.

In contrast, an earlier study showed that both doses of imatinib achieved similar response rates in patients with advanced GIST. However, the higher dose was associated with modest improvement in PFS (Verweij et al. Lancet 2004;364:1127-34).

Clinicians have yet to reach a consensus about the value of surgery to remove liver metastases. “There might be a rationale for surgery in patients with TKI-stable GIST,” suggested Dr. DeMatteo. “Removal of the metastases might delay the development of resistance to imatinib.”

Dr. DeMatteo and colleagues examined the issue in 40 patients treated with TKIs followed by surgery (DeMatteo et al. Ann Surg 2007;245:347-52). Prior to surgery, patients were classified as having TKI-responsive disease, focal resistance (1 tumour growing) or multifocal resistance (more than 1 tumour growing).

Initially, all but 1 patient achieved stable disease or better in response to TKI therapy. Of 20 patients considered to have responsive disease, 2-year PFS was 61% and 2-year OS was 100%. The 13 patients with focal resistance progressed after a median of 12 months and had a 2-year OS of 36%. The 7 patients with multifocal disease progressed within a median of 3 months and had a 1-year survival of 36%.

Investigators in another study examined outcomes in 69 patients with GIST who underwent surgery while receiving TKI therapy (Raut et al. J Clin Oncol 2006;24:2325-31). After surgery, no evidence of disease was found in 78% of patients who achieved stable disease with TKI therapy, 25% of those who had limited progression and 7% of patients with generalized progression. Bulky residual disease remained in 4%, 16% and 43% of patients, respectively.

The 12-month PFS was 80%, 33% and 0% for patients with stable disease, limited progression and generalized progression, respectively. The 12-month OS was 95%, 86% and 0%.

Summary

In summarizing the current status of therapy for GIST, Dr. DeMatteo remarked, “One year of imatinib prolongs relapse-free survival. The risk of recurrence depends on the mitotic rate. Patients with low-risk tumours do not need imatinib. Adjuvant therapy with a TKI is beneficial for patients with exon 11 mutations, but more data are needed regarding exon 9, wild-type tumours and PDGFR-a mutations. Surgery for responsive metastatic GIST appears to be beneficial.”