Abstract C49: A population-based study from Royal Marsden Hospital (RMH) of mutational analysis and response to therapy in primary resected and locally advanced or metastatic gastrointestinal stromal tumor (GIST).
Authors: Vitfell-Pedersen Joanna , Olmos David , Gonzalez-De-Castro David , Thway Khin , Watkins Rebecca , Al-Muderis Omar , Krarup-Hansen Anders , Scurr Michelle , Benson Charlotte , Judson Ian 
Published: June 2012

Abstract
Background: Preliminary analysis of a population based study of progression free survival (PFS) and time to treatment failure (TTF) after surgery and / or imatinib (IM) according to mutational analysis in patients (pts) with GIST. Secondary mutations during treatment were also investigated.
Materials and methods: A retrospective analysis was performed on all pts with GIST referred to the Sarcoma unit at RMH between 1987 and 2011. Data collected included gender, performance status, site of primary tumor, mutational analysis, surgery, IM and IM dose and response by RECIST.
Results: Out of 585 pts, 109 (18%) pts had mutational analysis performed, 21 (19%) had metastatic disease at baseline. The most common primary site was the stomach 49 (45%). Primary mutations were KIT exon 11: 72 (66%); wild-type: 16 (15%); KIT exon 9: 8 (7%); PDGFRA 18: 7 (6%); KIT exon 13: 3 (3%); KIT exon 11 +17: 2 (2%) and PDGFRA 12: 1 (1%).
73 pts underwent curative surgery of who 13 received adjuvant IM. In pts receiving curative surgery a trend to better survival was seen in pts with a PDGFRA mutation.
57 pts with locally advanced or metastatic disease received IM 400 mg/day. The median TTF was 58 months (m) for exon 9/13 (95%CI 11–106), 33 m for exon 11 (95%CI 18–48) and 16 m for wild-type (95%CI 0–37). Median PFS was 58 m for exon 9/13 (95%CI 0–124), 22 m for exon 11 (95%CI 5–37) and 16 m for wild-type (95%CI 15–17). Responses were complete remission in 4 pts (9.5%) with exon 11; partial response in 13 pts (31%) with exon 11; 5 (46%) with wild-type and 2 (40%) with exon 9.
24 pts received high dose IM 800 mg/day. The median TTF was 8 m for exon 9/13, 7 m for exon 11 and 3 m for wild-type. It was not possible to calculate PFS in these pts due to lack of events.
One patient experienced an interesting mutational change during treatment. The patient initially had a KIT exon 11 mutation which subsequently became wild-type after treatment with IM.
Conclusions: Our results indicate that pts with a PDGFRA mutation have more indolent disease and better survival compared to other mutations after primary curative surgery. Not all pts with wild-type were routinely tested for all mutations in KIT and PDGFRA which could explain the high number of partial responses observed in this group of pts.
In contrast to published data KIT exon 9 and exon 13 mutations when combined into the same group had a trend to a higher median TTF and PFS when treated with IM 400 mg/day and 800 mg/day, however none of these results were statistical significant. The differences observed probably relate to the small number and heterogeneous population.
A larger study in collaboration with Denmark including mutational analysis on approximately 675 pts is currently underway. While loss of KIT expression has been reported as a mechanism of resistance, reversion to wild-type is at least unusual and warrants further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C49.