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Introduction. The study aimed to report the efficiency of radical radiotherapy and chemoradiotherapy in patients with non-small cell lung cancer (NSCLC) treated in the Nu-Med Radiotherapy Center in Elbląg. Material and methods. Ninety-two patients diagnosed with NSCLC treated between 2013 and 2016 were included in the analysis. Overall survival (OS) was estimated by the Kaplan-Meier method. Results. The 2-year OS for all patients was 36% (median 1.5 years). Two prognostic factors had a significant impact: tre­atment method and performance status (PS). Patients who underwent concurrent radiochemotherapy and were treated sequentially had a better 2-year OS in comparison with those treated with radiotherapy alone (respectively 46% and 37% vs. 25%, p ≤ 0.05). Patients with PS 0–1 had better OS (median 1.6 years) compared with PS 2 (median 0.7 years, p = 0.04). Other prognostic factors analysed had no impact on OS in our study. Conclusions. The treatment results of our patients are comparable to those in published trials and meta-analyses.

Background: Expression of p95HER2 (p95), a truncated form of HER2 also known as p110 or M611-CTF, is a possible trastuzumab resistance mechanism and has been associated with poor prognosis in trastuzumab-treated HER2-positive metastatic breast cancer (MBC). Previously we reported on optimal clinical cutoffs for quantitative p95 (Clin Cancer Res, 16:4226, 2010) and quantitative HER2 protein expression (H2T) by HERmark® (Cancer, 116:5168, 2010) that defined patient subsets with different progression-free survival (PFS). These cutoffs were confirmed in an independent trastuzumab-treated MBC cohort (ASCO 2011, #586). Here, using individual patient data, we performed an analysis on the combined data set of 243 cases from the discovery and validation cohorts to derive optimal cutoffs for quantitative p95 and H2T. Methods: Both quantitative H2T (HERmark, Monogram Biosciences) and p95 assays employed the VeraTag® method to quantify protein expression in formalin-fixed, paraffin-embedded tumor samples from two cohorts of 101 and 142 cases of trastuzumab-treated MBC with 7.4 and 9.2 months median PFS, respectively. All analyses were stratified by hormone receptor status, tumor grade (3 vs. 1+2) and cohort. H2T measurements were compared to pre-specified cutoffs for HERmark negative (H2T17.8 RF/mm2), derived from the 95th percentile of centrally determined HER2-negatives, respectively, within a reference database of 1,090 breast cancer patient samples. Results: Patients classified as HERmark-positive had longer PFS than those classified as HERmark-negative (HR = 0.52; p = 0.0006; medians 10.0 and 5.9 months). The previously determined optimal H2T cutoff of 13.8 RF/mm2 in the center of the HERmark-equivocal zone, gave a similar result (HR = 0.54; p = 0.0005). This was close to the optimal cutoff of 12.75 RF/mm2 (HR = 0.48; p < 0.0001, unadjusted) for the combined data set. The PFS for the small group of patients in the HERmark-equivocal zone (n = 20) was more similar to the HERmark-negatives (equivocal vs. negative: HR=0.98; p = 0.9) than the HERmark-positives (positive vs. equivocal: HR=0.57; p = 0.057). The pre-specified p95 cutoff at 2.8 RF/mm2 separated the 174 HERmark-positive cases into two groups of longer (p95 Conclusions: HERmark positive and negative categories, defined by analytical comparison with centrally determined HER2 status, were confirmed to have significantly different PFS in trastuzumab-treated MBC patients. The optimal H2T clinical cutoff for this combined analysis was centered in the HERmark analytical equivocal zone. An optimal p95 clinical cutoff of 2.7 RF/mm2 derived from this combined analysis was nearly identical to the previously established cutoff of 2.8 RF/mm2. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-31.

Purpose: The MET receptor is involved in the pathogenesis and progression of non-small cell lung cancer (NSCLC). Clinical trials with MET inhibitors in NSCLC are planned with patient selection based on immunohistochemistry (IHC) and/or gene copy number assessment. Therefore, a detailed understanding of relationship between these markers and prognosis is essential. Methods: This study included tumors from 189 patients with NSCLC who underwent pulmonary resection (median follow-up, 5.3 years). MET expression was evaluated by IHC on tissue microarrays and scored according to hybrid (H) score (range: 0–400) and by scoring system used in the MetMAb trial (≥50% of cells with moderate or strong staining). MET gene copy number was assessed by silver in situ hybridization ( n =140 patients). Results: Median MET IHC H score was 60 (range: 0–400; n =174). There were no associations between clinical and pathological characteristics, disease-free survival, and overall survival according to median value ( p =0.36 and p =0.38, respectively), or other cut-points. According to MetMAb scoring criteria, IHC positivity rate was 25%, again with no associations to clinicopathological features or survival. In 140 tumors evaluable for MET copy number, 3 (2.1%) showed gene amplification and 14 (10%) had tumors with average of 5 or more copies per nucleus. There were no associations of MET copy number with clinical characteristics, disease-free survival, or overall survival with any analyzed cut-points. Correlation between MET copy number and protein expression was significant (Pearson's r =0.42, p Conclusions: There is a significant correlation between MET protein expression and MET gene copy number in operable NSCLC, but neither is associated with prognosis.

Background: The ErbB2-targeting monoclonal antibody trastuzumab has remarkable efficacy in metastatic breast cancer (MBC) patients (pts) with HER2 overexpression or amplification (HER2+), either alone or in combination with chemotherapy. However, the response rate to trastuzumab is modest and not all pts derive benefit from this treatment. Predictive mechanisms of sensitivity and/or resistance are largely unknown. Recently, preclinical and limited clinical data showed that aberrant MET expression in MBC is a predictor of poor prognosis and is involved in trastuzumab resistance. Aim of the present study was to investigate whether increased gene copy number of MET or its ligand, the hepatocyte growth factor (HGF), affect trastuzumab sensitivity. Patients and Methods: This retrospective study included 130 HER2+ MBC pts treated with trastuzumab as monotherapy (N=21) or in combination with chemotherapy (N=109). Main inclusion criteria were presence of at least one measurable lesion and availability of paraffin-embedded tumor tissue from primary cancer. MET and HGF gene copy number (GCN) were assessed by fluorescence in situ hybridization (FISH). Receiver operating characteristic (ROC) analysis was used for identifying the best MET and HGF mean GCN cut-off. Results: In the whole population response rate (RR), including complete (CR) and partial response (PR) was 49.2%, disease control rate, including CR+PR+ stable disease (SD) was 76.2%, median time to progression (TTP) 9.4 months, and median survival (OS) 28.3 months. MET FISH analysis was successfully performed in all 130 cases. Median MET mean GCN was 2.96 (range 1.66−8.40), with no gene amplification. ROC curve identified a mean of 3.72 MET GCN as the optimal cut-off value for discriminating between sensitive (CR+PR+SD) and refractory pts (pts with progressive disease [PD] at the first disease assessment). MET FISH+ (N=36, mean ≥3.72) had a significantly higher PD rate (44.4% versus 16.0%; p=0.001) and a significantly shorter TTP (5.7 versus 9.9 months; HR 1.74 95% C.I. 1.16−2.62; p=0.006) than MET FISH- pts (N=94, mean Conclusions: High GCNs of MET or HGF associate with an increased risk of trastuzumab failure in HER2+ MBC. These data support a further development of combining anti-HER2 with anti-MET strategies in MBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-07.

Background. Patients with HER2−positive breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Within HER2−positive breast cancer tumors, it is possible to resolve a ∼1.5-log range of HER2 protein expression using a novel quantitative HER2 assay (HERmark®). We investigated the correlation between quantitative HER2 protein expression in primary breast cancers and the time to brain metastases (TTBM) in HER2−positive advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER2−positive metastatic breast cancer, defined as 3+ categorical staining by immunohistochemistry (IHC). HER-2/neu gene copy number was subsequently quantified as HER2/CEP17 ratio by central laboratory fluorescence in situ hybridization (FISH). HER2 protein was quantified as total HER2 protein expression (H2T) by the HERmark assay in formalin-fixed, paraffin-embedded primary tumor samples. HER2 variables were correlated with clinical features and TTBM measured from the initiation of trastuzumab-containing therapy. Results. H2T level (continuous variable) was correlated with shorter TTBM (HR=2.3; p=0.013), whereas HER2 gene amplification by FISH (p=0.28) and continuous HER2/CEP17 ratio (p=0.25) had no significant prognostic impact. The correlation between continuous H2T level and TTBM was confirmed in a multivariate analysis (HR=3.2; p=0.021). Controlling for the competing risk of death from causes other than brain metastases, continuous H2T remained a strong correlate of TTBM (HR=2.7; p=0.0009). In the subset of patients that was centrally-determined HER2 positive by FISH (117 patients), above-median H2T level was significantly associated with shorter TTBM (HR=2.4; p=0.005), whereas this was not true for median FISH/CEP17 ratio (p=0.4). In a multivariate analysis of this subset, continuous H2T (p=0.021) and a time dependent covariate capturing time to non-brain metastases (p=0.0044) were prognostic for TTBM, whereas FISH/CEP17, ER, PgR and grade were not. Conclusions. These data reveal a strong relationship between quantitative HER2 protein expression levels and the risk of brain relapse in HER2−positive advanced breast cancer patients. Consequently, quantitative assessment of HER2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-05.

Background: To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). Methods: We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. Results: MET FISH-positive cases (N=36, mean ⩾3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0% P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean

Background. Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab. Methods. The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy. Results. A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024). Conclusions. These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.

International audience; Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0–81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6–13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03–2.33, = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47–1.77, = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07–2.44; = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse.

WstępWyniki badań klinicznych dotyczących sposobu frakcjonowania dawki w paliatywnym leczeniu przerzutów do kości w przebiegu nowotworów złośliwych wskazują na jednakową skuteczność jednej frakcji (najczęściej 8 Gy) w porównaniu z kilkoma frakcjami napromieniania. Pomimo tych danych, nadal powszechnie stosowana jest frakcjonowana radioterapia. Celem pracy była ocena sposobu napromieniania dużej, niewyselekcjonowanej grupy chorych leczonych z powodu przerzutów do kości w jednej instytucji.Materiał i metodyAnalizie poddano sposób napromienia 1754 przerzutów do kości u 1165 chorych leczonych w AM w Gdańsku w latach 1995–2002. Udział ognisk napromienianych z zastosowaniem jednej lub kilku frakcji był oceniany w odniesieniu do okresu leczenia i cech klinicznych.WynikiNapromienianie z wykorzystaniem jednej frakcji (8 Gy lub 10 Gy) zastosowano łącznie w 327 lokalizacjach (19%). Odsetek chorych napromienianych z zastosowaniem jednej frakcji wyniósł 28% w okresie 2001–2002 w porównaniu do 15–20% w latach 11995–2000 (p

505 Background: Brain metastases (BM) of breast cancer constitute an important part of therapeutic failures and are associated with severe morbidity and mortality. The risk of BM is particularly high in HER2+ advanced breast cancer pts. We earlier developed in this group a 13-gene signature strongly predicting for rapid development of BM (J Clin Oncol 2008; 26: 45s). Now, we validated these results in an independent group of pts and on culture model system. Methods: Discovery group included 87 samples analyzed using cDNA synthesis, annealing, selection, extension, ligation and array hybridization (DASL). Independent validation group included 75 samples analyzed using quantitative reverse-transcriptase PCR. 3D culture validation model system used immortal, non-tumorigenic human MCF10A breast epithelial cells with and without ectopic expression of HER-2 and RAD51, a DNA double strand break repair gene (one of the three genes of this group overexpressed in 13-gene signature). The number and morphology of breast acini were scored using indirect immunoflourescence and confocal microscopy. Results: Median brain metastasis-free survival (BMFS) in the discovery group for ‘high’ vs. ‘low’ expression signature tumors was 36 months and 66 months, respectively (P=0.0068), and in the validation group 54 and 86 months, respectively (P=0.032). Short BMFS was also associated with ER-negativity; BMFS in the cohort of ‘high’ 13-gene signature and ER- tumors vs. other 3 groups was 31 months and 66 months in discovery group, and 41 and 77 months in validation group (P

586 Background: Expression of p95 in HER2-positive breast cancer patients is potentially a major determinant of trastuzumab resistance because p95 lacks the trastuzumab binding site while retaining...

e21138 Background: Brain metastases of breast cancer occurs in approximately one-third of metastatic triple negative and HER2+ breast cancer patients and contributes to patient morbidity and mortality. The identification and validation of molecular pathways underlying brain metastases of breast cancer may lead to the development of effective therapeutics. Methods: We have identified 23 sets of matched primary breast tumors and resected brain metastases, and determined their gene expression profiles using the DASL platform on formalin-fixed, paraffin embedded tumor sections. Multiple independent shRNAs to L1CAM or a control shRNA were transfected into a brain metastatic derivative (231-BR) of human MDA-MB-231 breast carcinoma cells. Brain metastases were quantified one month after intracardiac injection. Results: Patient characteristics: mean age at diagnosis of brain metastases: 48 years (range 29-68 years); 10 HER2+(3+)/ER- (43.5%), 1 HER2(2+)/ER- (4.4%), 2 HER2(2+)/ER+ (8.7%), 3 HER2-/ER+ (13%), 2 HER2(...

1030 Background: Breast cancer is estimated to be the second most frequent cause of BM; however biological basis of this phenomenon is not well established. Pts with HER2-overexpressing breast cancer are at greater risk for BM. This study sought to investigate the correlation between quantitative HER2 expression in primary breast cancers using a novel HER2 quantitative assay (the HERmark assay; Joensuu H. et al, 2008 SABCS, abstract 2071) and the risk of BM in a consecutive series of pts with MBC treated with trastuzumab-containing therapy. Methods: HER2/neu gene was quantified as HER2/CEP17 ratio by central lab fluorescence in situ hybridization (FISH) and HER2 protein was quantified as total HER2 expression (H2T) by the HERmark assay in 126 formalin-fixed, paraffin-embedded (FFPE) tumor samples. HER2 results were correlated with tumor histologic grade and BM. Mann-Whitney and Kruskal-Wallis tests were performed to compare HER2 results (as continuous variables) with tumor grade and BM. Results: HER mark ...

e21063 Background: Studies suggest that high TS expression associates with poor prognosis and confers resistance to antifolates, particularly pemetrexed. TS is essential for de novo production of d...

Background: c-Met is a receptor capable of activating downstream proliferative, survival and invasive pathways. Numerous human malignancies, including NSCLC, show over-expressed and amplified c-Met. Elevated expression of c-Met and its ligand, HGF, have been associated with inferior prognosis. The aim of this study was to evaluate the prognostic relationship of c-Met gene copy number in surgically-treated NSCLC patients (pts) using dual-color silver in situ hybridization. SISH is advantageous because bright field microscopy allows visualization of intact malignant and non-malignant cell morphology. Methods: Experimental SISH probes, Ventana Medical Systems, Inc. (Tucson, AZ), were used to evaluate c-MET and CH 7 copy numbers on a tissue microarray containing triplicate samples from 189 pts (median follow-up 5.3 yrs and 5-yr survival probability 38%). Evaluable results, at least one core with valid c-Met and CH 7 counts, were obtained for 140 pts. There were 109 males; 80 squamous cell carcinomas; and 37 adenocarcinomas. The pathological stages were I: 50, II: 33 and III: 46, IV: 8 and unknown: 3. A certified pathologist counted signals (1 for individual signal, 6 for small cluster and 12 for big cluster) in 50 nuclei for each core and the mean number of c-Met and CH 7 copies/nucleus/core were determined, along with the ratio. The triplicate cores were averaged and compared to the core with the highest score. Results: There was very high correlation between the highest core and the average of the triplicate cores: c-Met (r=0.98), CH 7 (r=0.96), and ratio (r=0.98). The highest core value was used for further analysis. The median copy numbers were: c-Met 3.1 (1.7–11.8), CH7 2.4 (1.5–2.4), and ratio 1.3 (0.6–6.3). There were 14 pts with greater than or equal to five c-Met genes/nucleus and 3 pts with clusters. Using the median as a cut-off there was no statistical difference related to age, gender, pathological stage, histology, grade or smoking. Kaplan-Meier analysis revealed no significant differences in PFS or OS using the median scores, however there was a trend for increased PFS and OS in patients with high copy numbers. Cox regression analysis examining copy number as a continuous variable, and accounting for other variables, showed a similar trend of protection but statistical significance was not achieved: c-Met (PFS- HR 0.88 (0.72–1.07, p=0.19, OS- HR 0.90 (0.73–1.10), p=0.29); CH7 (PFS- HR 0.88 (0.57–1.34, p=0.54, OS- HR 1.02 (0.66–1.57), p=0.95): ratio (PFS- HR 0.84 (0.54–1.30, p=0.43, OS- HR 0.79 (0.49–1.28), p=0.33). Analysis of the data using a cut-off of 5 for c-Met gave similar results. Conclusions: This study shows the clinical feasibility of SISH technology for c-Met gene copy number assessment. There was a trend for increased PFS and OS in pts with increased c-Met, CH 7 or the ratio between the two. Further studies are needed to determine the predictive value of c-Met gene copy number in pts receiving molecular targeted therapeutics. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B45.

7524 Background: IGF1R is a promising target for NSCLC therapy. We have evaluated IGF1R protein expression, mRNA expression and gene copy number in primary tumors from surgically treated NSCLC patients (pts) as a reference for correlative biomarker studies in trials using IGF1R inhibitors. Methods: The study included 189 consecutive NSCLC pts who underwent curative pulmonary resection. There were 24% females, 54% squamous cell carcinomas (SCC), 29% adenocarcinomas (AC), 3% large cell carcinomas, 14% other histologies; p stage I: 41%, pII: 22%, pIII: 32% and pIV: 4%. IGF1R expression was evaluated in tissue microarrays by immunohistochemistry (IHC) with Ventana CONFIRM (N=179) and Novus (#NB600–559) anti-IGF1R Ab scored by two observers (H score 0–400). IGF1R gene copy number was assessed by FISH using customized probes (N=181). IGF1R gene expression was evaluated using qRT-PCR from 114 corresponding fresh-frozen samples. Results: Patterns of IHC staining were different for the Ventana and the Novus Ab (inverse correlation, r=-0.16, p=0.04, N=177). IGF1R protein expression detected by Ventana Ab (> median score) was more frequent in SCC (76%) than AC and other histologies (14%, p [Table: see text]

7550 Background: IGF1R represents a novel molecular target in NSCLC. We aimed to evaluate the association between IGF1R expression, clinical characteristics and survival in operable NSCLC pts. Methods: 184 consecutive surgically treated pts (median follow up of 32 months [range: 13–51 months]) were included in the study. There were 23% females, 55% pts with squamous cell carcinoma, 28% with adenocarcinoma, 3% with large cell carcinoma, 13% with mixed carcinoma and 1% with other types, 5% were never-smokers. Median age was 64 years (range: 37–85 years). Pathological stage I was diagnosed in 41%, stage II –22%, stage III –33% and stage IV –4% pts. Induction or adjuvant treatment was not routinely used. IGF1R was evaluated in tissue microarray by immunohistochemistry and scored by two observers according to H-score, taking into account proportion of cells with positive staining times staining intensity (scale 0–400). Results: IGF1R IHC expression was low in analyzed samples (median H-score 20, range: 0–223). Higher IGF1R score was observed in adenocarcinomas vs. squamous-cell carcinomas (p=0.02) and never-smokers vs. smokers (p=0.02). IGF1R score did not depend on stage (p=0.98) and sex (p=0.83). When analyzed as a continuous variable, IGF1R score tended to associate with worse survival in the entire cohort (p=0.10), and was significantly associated with inferior survival in patients with complete (R0) resections (p=0.04). When categorized with cut-off point of 50 (30% of patients positive), IGF1R expression was again associated with poor survival (p=0.05). This association was confined to pathological stage I (hazard ratio, HR=3.07; 95% confidence interval, CI=1.41–6.70, p=0.005) vs. all other stages (HR=1.03; 95% CI=0.63–1.70, p=0.90), and to patients with adenocarcinoma histology (HR=2.67; 95%CI=1.17–6.70, p=0.02 vs. all other histologies (HR=1.28; 95%CI=0.79–2.11, p=0.32). Conclusion: In this cohort of operable NSCLC pts, high IGF1R expression was associated with never-smoking history, adenocarcinoma histology, and poor survival, particularly in stage I disease and in patients with adenocarcinoma. These results support involvement of IGF pathway in the progression of early-stage NSCLC. No significant financial relationships to disclose.

7657 Background: Our aim was to determine the genes predictive for relapse-free and overall survival in stage I-II NSCLC. Methods: We analyzed the gene expression profiles in lung cancer specimens collected from 70 NSCLC patients (pts) who underwent curative pulmonary resection between 1999 and 2004 in two Polish centers (Gdansk, Bialystok). There were 54 men and 16 women aged 37–77 yrs (median 62.5 yrs), 45 with squamous cell ca, 22 with adenoca and 3 with large cell ca. Eight pts were staged pT1, 59 pT2 and 3 pT3; there were 49 and 21 pN0 and pN1 pts, respectively. 30 pts had a relapse and 32 pts died (median follow-up 36 months). Samples of tumor tissue were collected intraoperatively and snap-frozen, total RNA was isolated and gene expression profiling was carried out by Affymetrix HG-U133 2.0 Plus oligonucleotide microarray. Samples were pre-processed with RMA algorithm, gene selection was carried out by Support Vector Machines and Bayesian Compound Covariate Classifier, using own procedures and BRB-Array software developed by Simon and Peng Lam. Survival time prediction was carried out by method developed by Bair and Tibshirani (PLoS Biology 2004). Results: Based on the microarray gene expression profiling, the relapse could be predicted with 75.0% specificity and 53.3% sensitivity (positive predictive value [PPV] 61.5%, negative predictive value [NPV] 68.2%). The classifier, obtained by cross-validation of 70-sample dataset, consisted of 170 transcripts. Further gene selection was based on the prediction of the relapse-free survival: 1,919 genes, selected by fitting Cox proportional hazard model (p No significant financial relationships to disclose.

10508 Background: Brain relapse is a common occurrence in HER2-positive breast cancer pts. We assessed factors determining the risk of this event in a large unselected series of HER2-positive MBC pts. Methods: Study group included 233 consecutive HER2-positive (IH 3+ or FISH+) MBC pts (median age 53 years); 49% premenopausal, 49% postmenopausal and 2% with unknown menopausal status. Dominant site of disease included viscera (78%), soft tissue (11%) and bones (10%). Of the 206 pts (88%) with known steroid receptor status, ER+/PgR+, ER+/PgR-, ER-/PgR+, ER-/PgR- phenotypes included 58%, 15%, 5% and 21% of pts, respectively. Prior (neo)adjuvant chemotherapy, endocrine therapy or a combination thereof was administered in 40%, 6% and 35% of pts, respectively. Disease-free interval to the development of MBC ranged between 0 and 142 months (median 16 months). 184 pts (79%) received trastuzumab for MBC, usually in combination with chemotherapy. Statistical analysis included contingency tables, chi-square test, Kaplan-Meier survival analysis and Cox proportional hazard model. Results: Median follow-up from the development of MBC was 25 months (range 0.5–130 months). 54 pts (23%) developed brain metastases after a median of 13 months (range, 0 to 81 months). Cumulative risk of brain relapse was 11% (95% CI: 7–16%) and 24% (95% CI: 17–32%) at one and two years, respectively. Trastuzumab treatment was associated with insignificantly reduced risk of brain metastases (HR 0.63, 95% CI 0.29–1.39, p = 0.25). In the univariate analysis, premenopausal status was the only significant factor associated with increased risk of brain relapse (HR 2.56, 95% CI 1.28–5.00, p = 0.008). Conclusion: HER-2 positive MBC pts carry high risk of brain relapse, in particular prior to menopause. Protective role of trastuzumab warrants further research. [Table: see text]