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11558Background: We already reported (Cancer 2012;118:5857) the correlation of Choi criteria (Choi) and RECIST with outcome of pts affected by high-risk STS entering a multicentric Italian/Spanish ...

Purpose To explore the prognostic value of mutations in c-KIT and PDGFR-α genes with respect to relapse-free survival (RFS) in patients with gastrointestinal stromal tumors (GIST). We have investigated the prognostic relevance of the type and position of the mutations, in addition to other clinicopathologic factors, in a large series of patients with GIST. Methods For this study, 162 patients were selected according to the following criteria: completely resected tumors with negative margins attended between 1994 and 2001; no metastasis at diagnosis; tumor larger than 2 cm, c-KIT–positive immunostaining; and no other primary tumors. Results The median follow-up was 42 months for patients free of recurrence. Mutations were detected in 96 tumors (60%): 82 cases involving c-KIT and 14 cases involving PDFGR-α. Univariate analysis demonstrated the following as poor prognostic factors for RFS: tumors larger than 10 cm (P < .0001); mitotic count higher than 10 mitoses per 50 high-power fields (P < .0001); high risk index (P < .0001); intestinal GIST location (P = .0041); high cellularity (P < .0001); tumor necrosis (P < .0001); deletions affecting exon 11 (P = .0007); and deletions affecting codons 557 to 558 (P < .0001). After the multivariate analysis, only the high risk index (relative risk [RR], 12.36), high cellularity (RR, 3.97), and deletions affecting codons 557 to 558 of c-KIT (RR, 2.57) corresponded to independent prognostic factors for RFS in GIST patients. Conclusion Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.

11016 Background: Patients with extremity and trunk wall STS with high malignancy grade and size larger than 5cm are considered at high risk of death, but in fact this risk varies broadly depending on histologic subtype and size. The Sarculator, a nomogram for STS, can improve prognostic assessment of these patients. This tool was evaluated for stratifying risk of distant metastasis (DM) and overall survival (OS) in a RCT investigating perioperative chemotherapy. Methods: High-risk STS patients were randomly assigned to receive either three cycles of preoperative chemotherapy with epirubicin (120 mg/m2) and ifosfamide (9 g/m2) or the same three preoperative cycles followed by two further postoperative cycles. The Sarculator was used to stratify patient risk according to predicted 10-year cumulative incidence of DM and OS rates. Results: The Sarculator identified three different prognostic groups of patients at low (N = 101), intermediate (N = 102), and high (N = 107) risk. Cumulative incidence of DM was 0.26 (SE: 0.04), 0.31 (SE: 0.05), and 0.48 (SE: 0.05) for low, intermediate, and high risk patients, respectively. Similarly, OS rates were 0.78 (95%CI 0.68-0.85), 0.63 (95%CI 0.53-0.72), and 0.42 (95%CI 0.32-0.52), respectively. Patients in the low risk group were at significantly lower risk of death compared to those in the intermediate (HR 0.51, 95%CI 0.34-0.78, P = 0.002) and high (HR 0.28, 95%CI 0.17-0.46, P < 0.001) risk groups. Subgroup analysis performed by jointly considering these three groups and the two study arms did not identify statistically significant survival differences between the treatment arms within each risk category. Conclusions: Patients with high-risk STS included in this RCT were not a homogeneous population. The Sarculator identified different risk groups for DM and OS even in patients included in a RCT investigating perioperative treatments. This tool should be considered for redefining high-risk STS and stratifying patient risk in future RCT investigating perioperative chemotherapy. Clinical trial information: 2004-003979-36.

11044Background: We already reported (Cancer 2012;118:5857) on better correlation of Choi criteria (Choi) than RECIST with the outcome of pts affected by high-risk STS entering a multicentric Itali...

10051 Background: Approximately 60 to 85% of GISTs harbour activating mutations of the KIT or PDGFRA tyrosine kinase genes. Deletions affecting codons 557–558 of KIT are relevant to prognosis of resected GIST (Martin J, et al. J Clin Oncol. 2005, 23:6190). Methods: GIST of high or intermediate malignant risk according to Fletcher classification (Hum Pathol. 2002;33; 459) with a complete (R0) or microscopic residual (R1) resection were prospectively evaluated. Central pathology review was carried out. The mutational analysis of exons 9, 11, 13 and 17 of KIT and exons 12 and 18 of PDGFRA was undertaken from DNA extracted from paraffin-embedded tissue. The purpose of this study was to explore the correlation between deletion mutation involving 557–558 codons within KIT gene and known prognostic factors in GIST: mitotic count and size. Results: Of the 33 GIST, 19 were gastric, 13 of small bowell and one of other location. Median tumor size was 10.4 cm (1.9–22 cm), and median mitotic count was 2 (1–32). All cases showed an immunostaining with diffuse cytoplasmic pattern of c-kit (CD117). An 82% (27) presented either a KIT (23) or a PDGFRA (4) mutation. Eleven deletions affecting codons 557–558 of KIT were observed. KIT mutations were associated to spindle type histology and PDGFRA mutations to epithelioid histology. No statistical association between tumor size and KIT mutations, including patients with deletions 557–558, was found. Tumors carrying a deletion of codons 557–558 of KIT presented a different median of mitotic count (8 mit × 50 hpf) than the rest (2 mit × 50 hpf), this difference was statistically significant (p = 0,029) in the Mann-Whitney U test. Conclusions: Deletions affecting codons 557–558 of KIT define a group of cases with a high proliferative potential. The prognostic and predictive significance of these findings are waiting for a longer follow-up. No significant financial relationships to disclose.

602 Background: Aromatase (CYP19A1) is the main enzyme implicated in estrogen biosynthesis. Polymorphisms in CYP19A1 can affect both aromatase expression and activity leading to changes in the estrogen levels. These changes have been previously associated with pathogenesis of estrogen-dependent diseases, including breast cancer. The purpose of this study is to evaluate whether the genotype of CYP19A1 can have an effect on the response to endocrine therapy with the aromatase inhibitor letrozole (L). Methods: We retrospectively analyzed a series of 58 postmenopausal women with stage II-III ER/PgR[+] breast cancer treated with L as neoadjuvant therapy. Response was evaluated by radiology (mammogram or ultrasound) at four months L (OMS) and data was available in 56 cases. A total of ten single nucleotide polymorphisms (SNPs) spanning the gene, a TCT insertion/deletion and a (TTTA)n repeat were evaluated. The (TTTA)n repeat was analyzed by using GeneScan to detect polymorphism length, TCT Ins/Del by direct sequencing and SNPs by allelic discrimination using TaqMan SNP Genotyping Assays (Applied Biosystems). Logistic regression analysis was used to estimate the most accurate predictive model for response to therapy. Results: Median age of our series was 77 years (range: 68 to 90). Twenty women (36%) responded to 4 months L, while 38 (67%) did not (2 PD and 36 EE). Allelic frequencies were determined for each polymorphism and the global genotype data was evaluated in a logistic regression analysis. In a first step, the analysis with the genetic information for the 12 polymorphisms resulted in a model that predicted radiological response to L with an accuracy of 80% (85% specifity, 69% sensibility). However, a reduction to 4 informative polymorphisms generated a simpler predictive model with an accuracy of 76% (76.5% specifity, 75% sensibility). Conclusions: Polymorphism analysis of CYP19A1 could predict for response to neoadjuvant therapy with L. A validation of this predictive model in an independent series is ongoing. No significant financial relationships to disclose.

10531 Background: Letrozole (L) is more active than tamoxifen in early stage ER[+] breast cancer both as adjuvant (BIG-98 trial) or neoadjuvant (LET-024) therapy. However, complete pathological remissions to neoadjuvant endocrine therapy are anecdotal ( [Table: see text] No significant financial relationships to disclose.

9029 Background: Several studies of prognostic factors have been published in mesenchymal tumors of the gastrointestinal tract. Most of them, however, have not considered the current definition of GIST. In patients with complete surgical resection the size of primary tumor and the mitotic count seems to be the most predictive of disease-specific survival. The analysis of kit-mutation (level or type) has emerged as a potential prognostic significance in GIST patients, although, to date, the results remains controversials requiring a larger patient numbers or a more extensive mutational analysis of all exons known to be implicated in the KIT and PDGFRα gens. Methods: Three hundred and fifty patients with eventual GIST diagnosis included between 1994–2001 in our Registry and admitted in 29/53 hospitals members of GEIS were evaluated. The clinical collected data has been updated and a independent pathologic review of paraffin-embedded blocks including inmunohistochemistry with kit, s-100 protein, smooth muscl...