15038 Background: EGFR expression, usually determined on primary tumour specimens, may be altered by confounding factors including chemotherapy (CT) administration. We have evaluated the impact of CT on the EGFR expression of CTCs in comparison to the primary tumor EGFR status. Methods: 7.5 ml of peripheral blood were prospectively collected from chemo-naive patients with metastatic colorectal cancer (mCRC) initiating first-line CT at baseline, before the second cycle, and after four CT cycles.CTCs were detected by using immuno-magnetic separation and immuno-fluorescent identification (Cell Search System, Veridex). The EGFR status in CTCs was determined by immuno-fluorescent labelling. A retrospective evaluation of EGFR expression in the corresponding primary paraffin- embedded tumors was performed with immuno-histochemistry using the Dako Pharm Dx Kit. Results: 22 patients were evaluated: 13 patients received 5-fluorouracil (5-FU), folinic acid (FA), oxaliplatin (FOLFOX), 4 patients FOLFOX + panitumumab; and 5 patients 5- FU+FA+irinotecan. Nine patients (41%) experienced partial response, 7 (32%) stable disease and 6 (27%) progression a progressive disease after 4 cycles of CT. The median storage time of the primitive tumor was 6 weeks (range: 4–8). Fourteen (64%) patients had positive EGFR CTCs at baseline (median 9, range 1–36). On an individual basis, no correlation was found between the EGFR status of the primitive tumour and baseline CTCs (Spearman's correlation: r 0.122; p=0.599). The EGFR status modifications during CT and the predictive value of baseline CTCs EGFR expression in CTCs are reported here. Conclusions: CT administration induces changes in the EGFR status of CTCs. EGFR negative tumours should be retested for EGFR after CT, before initiating anti-EGFR treatment. The EGFR expression of CTCs in mCRC could be useful in predicting outcome under CT and deserves further evaluation. EGFR status modific Baseline CTCs EGFR -ations during CT and predictive value of baseline CTCs EGFR expression Baseline CTCs EGFR + Baseline CTCs EGFR - Patients (N) 14 8 CTCs EGFR+ after 1 cycle CT 14 6 CTCs EGFR + after 4 cycles CT 13 7 Median time to progression (months) 6.6 (confidence interval : 4–8.2) 8.5 (confidence interval : 7.5–9.5) Log rank test p = 0.04 No significant financial relationships to disclose.
3637 Background: Induction chemotherapy has been suggested to impact on preoperative chemoradiation efficacy in LARC. To evaluate the feasibility and efficacy of a short-intense course of induction chemotherapy in LARC patients treated with standard preoperative radiochemotherapy (RCT). Methods: Patients with T2-T4/N+ rectal adenocarcinoma were randomized to Arm A (A): concomitant RCT (45 Gy/25 fr/5weeks + 5-FU in continuous infusion, 250 mg/m2/day) or Arm B (B): two courses of mFOLFOX6 (oxaliplatin: 100 mg/m2; folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2 followed by 2,000 mg/m2 continuous infusion, d1 = d15) followed by RCT (idem A). Surgery was planned 6 to 8 weeks after the end of RCT. Primary endpoint was ypT0-1 stage rate and secondary endpoints were tolerance, toxicity, sphincter preservation rate and tumor regression grade rate. Results: 57 patients from 6 Belgian centers were randomized between 04/2007 and 08/2009 (Arm A/B: 29/28) and evaluated for interim analysis. Patients characteristics (age, sex, performance status, clinical TNM stage, tumor location and size) were well balanced at baseline. Completion of full sequence was similar in both groups: 27/29 (96%, A) vs. 25/28 (88%, B) pts (p = ns). About surgery, there was no significant difference in terms of type, R0 resection, number of lymph nodes resected or invaded, longitudinal and circumferential margin. ypT0-1 stage were reported in 10/29 (34%, A) vs. 8/28 pts (29%, B) (p = ns). T and N downstaging occurred in 14/29 (58%, A), 13/28 (65%, B) and 16/29 (55%, A), 12/28 (43%, B) pts, respectively (p = ns). pCR was observed in 8/29 (27%, A) vs. 7/28 (25%, B) pts (p = ns) and the tumor regression grades (Dworak) distribution was similar. Sphincter preservation was obtained in 67% (A) vs 100% (B) (p = 0.058). Overall grade 3/4 toxicity was significantly higher in chemotherapy induction group: 8% (A) vs. 35% (B) (p = 0.017). Conclusions: Oxaliplatin-based chemotherapy induction is feasible for patients with LARC without compromising the preoperative RCT completion although preliminary results do not indicate increased locoregional impact on standard therapy. No significant financial relationships to disclose.
Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 are the major transporters responsible for 2',2'-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen.We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1 and hCNT3 expression using immunohistochemistry.When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1(high)/hCNT3(high) expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor.Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabine-based adjuvant therapy.
e22022 Background: The chemoreceptors CXCR4, CXCR7 and the hypoxia inductible factor-1 alpha (HIF-1α) are implicated in PA growth, dissemination and angiogenesis. These protagonists are expected to play a key role in radiotherapy and chemotherapy resistance in PA. Methods: We conducted a retrospective study of patients undergoing curative surgery (R0 resection) for PA between 2001 and 2006 in our institution. All were treated with adjuvant RCT (treatment group). The treatment group was case-matched with resected PA patients who did not receive any adjuvant therapy (control group). FFPE specimens were subjected to immunohistochemical analysis using tissue microarray and monoclonal antibodies against human CXCR4, CXCR7, and HIF-1α. Based on the intensity (I) and the extend (E) of staining, cases were stratified into those with high (E x I>3) or low (E x I ≤ 3) expression of CXCR4, CXCR7 and HIF-1α and results were correlated with disease-free survival (DFS) and overall survival (OS). Results: 31 PA patients (median age: 57years, range: 39–76) were analysed in the treatment group and 30 (median age: 59 years, range: 38–81) in the control group. The two groups were well-matched in terms of age, sex, tumor stage (T1-T2 vs T3-T4), tumor differentiation (poor vs well-moderate), lymph node (LN) status (N0 vs N+), lymphatic and vascular embols. In univariate analysis, CXCR4 expression and LN status were associated with DFS and OS (OS, CXCR4 low/high : HR, 5.43, 95%CI: 2.03–14.49, p=0.001; N0/N+: HR: 4.62, 95% CI, 1.33–13.12, p=0.016; DFS: CXCR4 low / CXCR4 high : HR, 3.01, 95%CI: 1.21–7.46, p=0.018; N0/N+: HR: 3.30, 95% CI, 1.09–9.90, p=0.034) in the treatment group while in the control group LN status was the only variable significantly correlated with DFS and OS. CXCR4 appeared to be the only independant predictor for DFS (CXCR4 low/high : HR, 4.95, 95%CI: 1.68–14.71, p=0.007) and OS (CXCR4 low/high : HR, 4.76, 95%CI: 2.03–14.49, p=0.004) in the treatment group but not in the control group. Conclusions: CXCR4 was an independant predictor for DFS and OS after adjuvant RCT in resected PA patients. This chemoreceptor could be implicated in the resistance of pancreatic cancer cells to RCT and its targeted inhibition deserves clinical evaluation. No significant financial relationships to disclose.
Chemokines and their receptors are involved in tumourigenicity and clinicopathological significance of chemokines receptor expression in pancreatic adenocarcinoma (PA) is not fully understood. This study was conducted to determine patients' outcome according to the expressions of CXCR4, CXCR7 and HIF-1α after resection of PA. Immunohistochemistry for CXCR4, CXCR7 and HIF-1α expressions as well as cell proliferative index (Ki-67) was conducted in 71 resected (R0) PA and their 48 related lymph nodes (LN) using tissue microarray. CXCR4 and CXCR7 expressions were positively correlated to HIF-1α suggesting a potential role of HIF-1α in CXCR4 and CXCR7 transcription activation. Patients with CXCR4high tumour expression had shorter OS than those with low expression (median survival: 9.7 vs 43.2 months, P=0.0006), a higher risk of LN metastases and liver recurrence. In multivariate analysis, high CXCR4 expression, LN metastases and poorly differentiated tumour are independent negative prognosis factors. In a combining analysis, patients with CXCR4low/CXCR7low tumour had a significantly shorter DFS and OS than patients with a CXCR7high/CXCR4high tumour. CXCR4 in resected PA may represent a valuable prognostic factor as well as an attractive target for therapeutic purpose.
