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BACKGROUND Amplification of the HER-2/neu oncogene has been proposed as a target for antibody-based therapies and as a predictor of chemoresponsiveness in advanced breast carcinoma. Few studies have concentrated on HER-2/neu gene evaluation by fluorescence in situ hybridization (FISH) on distant metastatic sites and none have been performed on cytologic samples. The current study evaluated HER-2/neu amplification by FISH on cytologic samples obtained from distant metastatic lesions of breast carcinoma to update HER-2/neu characterization through a safe and easier procedure than biopsy. METHODS Twenty-two cytologic samples from distant metastases (12 hepatic samples, 4 skin samples, 3 pleural samples, and 3 peritoneal samples) were submitted to HER-2/neu evaluation by FISH. Seventeen corresponding primary breast tumors also were evaluated by FISH on paraffin histologic sections or on destained archival cytologic smears. RESULTS Seven of the 22 metastases (32%) were amplified. Amplification was observed in 4 of the 12 liver metastases, in 1of the 3 ascitic fluid specimens, and in 2 of the 4 skin metastases. In all the three pleural fluid specimens, HER-2/neu was unamplified. Matched results from primary and metastatic lesions were obtained in 14 cases (5 were amplified and 9 were unamplified on both primary and metastatic tumors). CONCLUSIONS The results of the current study emphasized the feasibility and advantages of two rapid and very informative techniques, such as fine-needle aspiration biopsy and FISH. Both procedures were performed to ascertain the malignant nature of a suspicious lesion and to obtain predictive markers for response. Since the advent of trastuzumab, the characterization of the molecular profile in metastatic breast disease has become increasingly important for targeted therapy selection. Cancer (Cancer Cytopathol) 2003;99:310–5. © 2003 American Cancer Society.

Background Evidence-based guidelines, consensus conferences and experts’ opinion are rarely promptly transferred to patient care. We audited prescriptions of adjuvant systemic therapies for Italian breast cancer patients and compared them with recommendations of an International Consensus Panel. Patients and methods Disease characteristics and adjuvant therapies for 768 breast cancer patients referred to 87 Italian centers from 16 to 23 March 2000 were evaluated for adherence to the published recommendations. Results Endocrine therapy was not prescribed for 102 of 541 patients (19%) with endocrine-responsive disease and for 22 of 45 patients (49%) with unknown hormonal receptor status. Instead, endocrine therapy was prescribed for 22 of 182 patients (12%) with endocrine-unresponsive disease. Adjuvant chemotherapy was prescribed for 98% of the patients. The type of chemotherapy was the cyclophosphamide, methotrexate, 5-fluorouracil regimen for 453 of 754 (60%), while 253 of 754 (34%) received an anthracycline-based regimen. The proportion of patients with anthracyclines increased with the number of involved axillary nodes and grading, and decreased with age. Endocrine therapy was administered to 482 of 768 (63%) and was mainly represented by an antiestrogen. Conclusions Lack of adherence to evidence-based guidelines for adjuvant treatment of Italian breast cancer patients was as high as 19%. It might be wise for national health authorities to promote education on life-saving procedures, like adjuvant systemic treatments, in cancer medicine.

4017 Background: FGFR genetic aberrations have been implicated in the development and progression of a number of solid tumor types, including iCCA. Pts with unresectable advanced iCCA who relapse after first-line chemotherapy have limited treatment options with poor prognosis. Recently, FGFR2 fusions, observed in up to 20% of pts, have been recognized as a potential therapeutic target. ARQ 087 is a multi-kinase inhibitor with a potent pan-FGFR activity. Methods: 119 cancer pts were enrolled in the phase 1/2, open-label study of ARQ 087. Study design and results of the phase 1were reported previously. Assessments included response by RECIST v1.1 every 8 wks, safety (physical examination, vital signs, ECOG PS, laboratory tests), plasma concentrations of phosphate and FGF19, 21 and 23 (potential biomarkers). Results: As of 1Feb17, 35 iCCA pts with FGFR2 genetic aberrations were treated with ARQ 087 300 (n = 33) or 400 mg (n = 2) daily. FGFR2 status was identified by FISH or NGS, 29/35 pts were FGFR2 fusion positive (FISH n = 15/18; NGS n = 14/17). Pts were all white, female (60%) with ECOG PS 0 (69%) and median age 58 yrs (31-82). Median number of prior systemic therapies was 1(0-6). Drug-related AEs (all grades) were reported in 89% of pts; the most common (≥10%) included nausea (37%), dry mouth (29%), asthenia (26%), fatigue, vomiting (23%, each), abnormal LFTs, dysgeusia (20%, each), alopecia, diarrhea, vision blurred (14%, each), and conjunctivitis (11%). Grade 3/4 AEs occurring in ≥2 pts were asthenia and abnormal LFTs (6%, each). AEs were mostly (71%) of mild to moderate intensity, manageable and reversible. Median time on treatment was 183 days (95%CI: 166-289). 19 pts were on treatment for > 16 wks, nine are ongoing. 30 pts had at least one post-treatment radiographic assessment: 6 (20%) had PR (32-47% tumor reduction, all FGFR2 fusion positive), 17 SD (7 had tumor reduction between 10 to 25%), and 7 had PD. One pt died prior to scheduled assessment and assessment in 4 pts is pending. Conclusions: ARQ 087 demonstrated encouraging antitumor activity and manageable safety profile. Updated data, including safety, efficacy and biomarkers will be presented. Clinical trial information: NCT01752920.

Background To assess the safety and efficacy of Stereotactic Ablative Radiotherapy (SABR) in oligometastatic patients from colorectal cancer. Methods 82 patients with 1–3 inoperable metastases confined to one organ (liver or lung), were treated with SABR for a total of 112 lesions in an observational study. Prescription dose ranged between 48 and 75Gy in 3 or 4 consecutive fractions. Primary end-points were local control (LC), overall survival (OS) and progression-free survival (PFS). Secondary end-point was toxicity. Results Median follow-up was 24 months (range 3–47). One, two and three years LC rate was 90%,80% and 75% (85%,75% and 70% for lung and 95%, 90% and 85% for liver metastases; no statistically significance was found). The difference in LC between the subgroup of lesions treated with ≥60 Gy (n = 58) and those irradiated with 3 cm (p 3 toxicity. Conclusions SABR is a safe and feasible alternative treatment of oligometastatic colorectal liver and lung metastases in patients not amenable to surgery or other ablative treatments.

The Her2 / neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20 % of breast adenocarcinomas and is recognized by a humanized anti-Her2 / neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcγRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2 / neu+ (MCF-7Her2 / neu) and Her2 / neu– (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2 / neu and MDA-468 target cells by IL-2-activated NK cells was 35 % and 3 %, respectively (p

Background. Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma (HCC). The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated. Methods. Patients who experienced disease progression while on sorafenib 400 mg twice daily were randomized to sorafenib 600 mg twice daily (n = 49) or best supportive care (n = 52). The primary end point was progression-free survival (PFS). Time to progression, overall survival, and safety were also evaluated. Results. The study did not meet its primary end point. The difference in PFS between the sorafenib arm (3.91 months) and the best supportive care arm (2.69 months) did not reach statistical significance (p = 0.086). Adverse events were mainly grade 1–2 and similar across both groups. In the sorafenib arm, the most frequent events were diarrhea (80%), weight loss (75%), fatigue (67%), hand-foot-skin reaction (49%), abdominal pain (37%), and stomatitis (26%). Conclusions. Escalated-dose sorafenib in patients with advanced HCC who progressed while on sorafenib, failed to provide any clinical benefit. Second-line treatment still remains an open issue to be explored in appropriate clinical trials.

197 Background: Tivantinib, an oral MET inhibitor, showed activity in patients (pts) MET-High at immunohistochemistry (IHC) in randomized, placebo controlled studies in HCC, NSCLC, CRC, and prostate cancer. ARQ 197-215 was a RCT of tivantinib in second-line HCC. The study randomized 107 pts 2:1 to tivantinib capsules or placebo, reached the primary endpoint of time to progression in the intent-to-treat population and the pre-specified secondary efficacy endpoints, including OS, in MET-High pts. Tumor MET was also found to be a strong independent prognostic factor. This analysis aims to study prognostic and predictive value of tumor and circulating biomarkers. Methods: Circulating MET, HGF, and AFP were centrally analyzed by ELISA and median values were used as cut-offs to determine High or Low status except for AFP, where the 75th percentile was also used. Tumor MET was centrally analyzed and considered High if staining was >2+ in >50% of cells at IHC. Results: Circulating MET was prognostic (N=102; OS: 4.6 vs 8.9 months in High vs Low, HR=0.61, p=0.023) and trended towards predicting tivantinib’s activity. MET was also a pharmacodynamic marker: pts on tivantinib with a MET reduction over time survived longer; MET was reduced in pts stable on tivantinib but not on placebo. Circulating HGF was prognostic (N=102; OS: 5.0 vs 9.0 months in High vs Low, HR=0.6, p=0.02) and changes over time correlated with outcome. AFP by the 75th percentile was prognostic (N=104; OS: 3.0 vs 7.9 months in High vs Low, HR=0.36, p

Summary Background Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. Methods In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. Findings 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4–2·8]) than placebo (1·4 months [1·4–1·5]; hazard ratio [HR] 0·64, 90% CI 0·43–0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4–8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4–1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19–0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. Interpretation Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. Funding ArQule, Daiichi Sankyo (Daiichi Sankyo Group).

We read with great interest the study by Llovet and colleagues ([1][1]), who reported on plasma biomarkers in a phase III trial of sorafenib for advanced hepatocellular carcinoma (HCC; ref. [2][2]). One of the main scopes of this correlative study was to identify predictive markers of survival and

Background: Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. Methods: Twenty-seven patients with advanced-stage disease resistant to either locoregional (59% range, 1–3), systemic treatments (52% range, 1–3) or both (33%) received NGR-hTNF 0.8 μg m−2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS). Results: No grade 3–4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7–2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5–10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months. Conclusion: NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest.

Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.

Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). Patients and methods: We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression. Results: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size > 9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)]. Conclusions: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.

Over the last decades, the introduction of several new agents into clinical practice has significantly improved disease control and obtained some, albeit rare, survival benefits in metastatic breast cancer (MBC). Despite these results, the choice of treatment for the majority of patients is still empirically based, since the only two predictive factors with level 1 evidence for clinical use are hormonal receptor status for endocrine therapy and HER-2 status for trastuzumab therapy. Important improvements in the endocrine therapy of both pre- and postmenopausal women with hormone-responsive disease have been achieved. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogs combined with tamoxifen has become the standard treatment, although aromatase inhibitors plus ovarian function suppression are under evaluation. In postmenopausal patients, aromatase inhibitors have proved to be superior to standard endocrine therapies in either first- or second-line treatment and a novel antiestrogen compound, fulvestrant, has been introduced in clinical practice. Chemotherapy remains the treatment of choice for hormone unresponsive or resistant patients. Anthracyclines and taxanes have been used either alone or in combination as first-line chemotherapy, but with the more frequent use of these agents in the adjuvant setting, new standards are needed for first-line chemotherapy, and new and more efficacious treatments are required. In the subgroup of patients with tumors that overexpress HER-2, the use of trastuzumab alone or in combination with chemotherapy has modified the natural history of these tumors, even if only about one out of two patients obtains a clinical response. In this review we summarize the main achievements and the currently available treatment options for patients with MBC.

OBJECTIVES The value of HER-2/neu status as a predictor of response to anthracycline-based chemotherapy is still a matter of debate. We evaluated the contribution of HER-2/neu gene amplification and other biologic markers in predicting response to different doses of neoadjuvant anthracycline-based chemotherapy. METHODS Clinical and pathologic records of 115 primary breast cancer patients were reviewed. Forty-eight and 67 patients received high (doxorubicin > or =20 mg/m2/wk; epirubicin > or =30 mg/m2/wk) and moderate-low anthracycline dose intensity regimens, respectively. Pathologic diagnosis, hormonal receptor status (HR), Ki67, and HER-2/neu status were assessed on tumor samples before neoadjuvant chemotherapy. HER-2/neu was determined by fluorescence in situ hybridization (FISH). RESULTS HER-2/neu amplification was observed in 29/115 (25%) tumors, 18 from moderate-low-dose and 11 from high-dose group. In the univariate analysis, a high Ki67 index (> or =20%) and positive clinical axillary nodes were predictive of an objective tumor response (P = 0.033 and 0.001, respectively). In the multivariate analysis, Ki67 was the only factor predictive of response (OR = 3.08, 95% CI = 1.1-8.5, P = 0.03). HER-2/neu status was not a factor in predicting objective response to different anthracycline dose intensities. The same finding was observed with regards to HR and Ki67. CONCLUSIONS In our series, no significant dose-response relationship was found according to HER-2/neu status.

Despite staining positive for the epidermal growth factor receptor (EGFR), a significant number of EGFR-expressing colorectal cancers are resistant to cetuximab, a chimeric monoclonal antibody directed against EGFR. Activation of EGFR through the autophosphorylation of its tyrosine residues stimulates different signaling downstream pathways and may reflect the level of receptor utilization by the tumor. This study investigated activated/phosphorylated EGFR (pEGFR) in 23 patients with EGFR-positive metastatic colorectal cancer refractory to irinotecan and treated with cetuximab, alone or in combination with irinotecan. Seven patients received cetuximab, and 16 patients received cetuximab plus irinotecan. Among the 23 patients, six (26%) had a partial response, 10 (44%) had stable disease, and seven (30%) had progressive disease. Median duration of disease control (partial response + stable disease) was 6 months. Nineteen out of 20 EGFR-positive tumors (95%) stained positive for pEGFR and had a median pEGFR immunohistochemical score of 5. Disease control rates differed between patients with a pEGFR immunohistochemical score >or= 7 (7/7, 100%) and less than 7 (7/13, 53.8%), showing a trend toward higher disease control in patients with high levels of pEGFR (>or= 7) who were treated with cetuximab with or without irinotecan (P = .05).

e14611 Background: Retrospective studies showed that efficacy of C increases in molecularly-defined subsets of KRAS wt mCRC pts. In pretreated pts, biweekly C seems as effective as a weekly schedule. Aim of this field-practice study was to evaluate the efficacy of FOLFIRI plus biweekly C (C-FOLFIRI) as first-line treatment for mCRC and prospectively validate PTEN expression as a prognostic marker. Methods: Pts with previously untreated metastatic KRAS wt mCRC not suitable for curative-intent resection were eligible. Initially, pts were randomized to receive FOLFIRI alone or in combination with C (500 mg/m2 every two weeks). After a protocol amendment, pts were assigned to receive only C-FOLFIRI, while the FOLFIRI alone arm was discontinued. Clinical outcome was assessed according to expression of PTEN and MET by immunohistochemistry (IHC), as well as to BRAF mutations. Results: From April, 2009 to June, 2012, a total of 89 pts were enrolled. 35 pts were randomly assigned to receive FOLFIRI alone, while 54 pts received C-FOLFIRI: 33 were treated in the random phase and 21 after protocol amendment. Median overall survival (OS) was 17.7 months for FOLFIRI and 23.3 months for C-FOLFIRI. Corresponding median progression-free survival was 8.2 and 6.8 months, respectively. Objective response rate was 52.0% for FOLFIRI and 52.3% for C-FOLFIRI. The toxicity profile of C-FOLFIRI was consistent with that expected from a weekly C schedule. 23/38 pts (61.0%) assessed for PTEN were positive for IHC expression, 8/39 pts (21.0%) had a MET high status, 6/45 pts (13.3%) had BRAF mutations. In pts treated with C-FOLFIRI, only BRAF mutations negatively affected OS (Hazard ratio mutations vs. wt: 4.77; 95%CI 1.41-16.13; p = 0.01). Conclusions: Safety, effectiveness and generalizability of C-FOLFIRI validate in field practice results gained with FOLFIRI plus a weekly C schedule. Despite the small sample size, analysis of BRAF mutations reaffirms the strong prognostic impact of this biomarker. The extended analysis of BRAF mutations, PTEN and MET expression on all pts is ongoing. Data will be presented. Clinical trial information: NCT01068132.

e14672 Background: Abnormalities of TOP2A, a major target of anthracyclines, have been reported as positive predictive markers of response to anthracycline-based therapy in breast cancer. We determined abnormalities of TOP2A and HER2, and HER2 protein expression, in a cohort of patients with gastric or gastro-oesophageal junction adenocarcinomas treated with epirubicin-based chemotherapy. Methods: We studied 50 patients that received either adjuvant (74%) or perioperative (26%) epirubicin, cisplatin and 5-fluorouracil. All patients were screened for TOP2A amplification/deletion by fluorescent in situ hybridization (FISH), and for HER2 protein expression by immunohistochemistry (IHC). For each patient at least two paired surgical samples were examined. Tumors exhibiting a HER2 score of 2+ were further screened for gene amplification by FISH. We studied the association of TOP2A abnormalities and HER2 amplification/expression with recurrence free survival (RFS) and overall survival (OS). Results: By IHC, HER2 overexpression (score 3+) was detected in 9 patients. Intra-tumor heterogeneity of HER2 staining, resulting in discrepant HER2 scores, was detected in 4 of 50 (8%) paired samples analyzed. HER2 amplification was detected in 1 of 8 tumors with a HER2 score 2+. TOP2A amplification was observed in 1 of 50 tumors; none exhibited TOP2A deletions. In patients whose tumors showed HER2 overexpression or gene amplification (HER2-positive) and in patients with HER2-negative tumors, median RFS was 11.0 and 13.9 months, respectively (p= 0.35); median OS was 28.8 and 29.9 months, respectively (p= 0.56). A pathological complete response was observed in 1 of 4 HER2-positive patients that underwent perioperative chemotherapy. Conclusions: In this cohort of patients with early-stage gastroesophageal cancers who were treated with epirubicin-based chemotherapy, neither HER2 amplification nor HER2 overexpression were associated with outcome. TOP2A abnormalities are rare and their putative role as a determinant of responsiveness to anthracycline-based chemotherapy in gastroesophageal cancers is not supported by our findings.

2521 Background: Combined targeting of ERBB receptors and VEGF-dependent signaling pathways has proven to be a successful strategy in preclinical studies. L is a dual HER2/EGFR tyrosine kinase inhi...

4092 Background: Evidence suggests that AFP response predicts survival in HCC patients (pts) treated with locoregional procedures or systemic therapies. Its impact on outcome prediction in pts rece...

11093 Background: KRAS mutations (mut) occur in 40% of colorectal cancers (CRC) and together with increased EGFR gene copy number (GCN) are determinants of outcome in CRC patients (pts) treated wit...

10569 Background: Recent studies suggest that increased epidermal growth factor receptor (EGFR) gene copy number assessed by in situ hybridization predicts response to cetuximab in patients (pts) with advanced colorectal cancer (mCRC). Additionally, preclinical data indicate that HER2, a member of the EGFR family, can modulate the efficacy of anti-EGFR monoclonal antibodies. Methods: We assessed EGFR and HER2 gene copies by fluorescent in situ hybridization (FISH) on paraffin-embedded samples from 70 pts with mCRC treated with cetuximab alone or with irinotecan. FISH was assessed either on primary tumors (55 pts) or on metastases (15 pts) according to two parameters: the absolute copy number of genes and chromosome (chr) centromeres, and their frequencies in 100 tumor cells. A sensitivity analysis was performed and fitted to outcome data in an attempt to define relevant cutoffs. EGFR protein expression by immunohistochemistry was deemed positive with =10% tumor cells being stained. Multiple paired samples originating from different tumor sources were analyzed whenever available (27 pts). Results: The overall response rate was 25%. Prevalent FISH patterns were disomy (8%) and balanced polysomy (90%) for EGFR gene and chr 7. EGFR amplification was seen in two pts (2%), of which only one responded. HER2 amplification was seen in two of 54 pts (3%), both experiencing stable disease. Average EGFR copies and frequency of tumor cells with >2 copies respectively ranged from 1.6 to 4.0 and from 10% to 90%, thus reflecting a substantial tumor heterogeneity. Despite assessing multiple centile cutoffs of gene copy numbers and their frequencies in tumor cells, we found no association between EGFR and HER2 copy numbers and objective response, time to progression, and overall survival. Analysis of paired samples did not improve the predictive value of EGFR copies by FISH. Excluding EGFR amplification, associated to a strong (3+) EGFR staining, we found no correlation between EGFR copy number and protein expression. Conclusions: Neither EGFR nor HER2 copies by FISH, nor EGFR expression, are predictors of outcome in mCRC pts treated with cetuximab. FISH might still play a role in screening EGFR and HER2 amplification, but cost-effectiveness is debatable. [Table: see text]

4132 Background: A recent study has shown that the presence of a KRAS mutation is associated with the absence of objective response to cetuximab (CTX) in advanced colorectal cancers (mCRC). Our hypothesis was that CTX cannot induce any tumor shrinkage in KRAS mutant mCRC. Methods: We analyzed KRAS exon 2 mutation status by Taqman, PCR and sequencing on 37 available tumor samples from patients with mCRC progressive on chemotherapy. Twenty patients received CTX combined with irinotecan (BOND) and 17 received CTX in monotherapy (7 BOND, 10 SALVAGE). We measured the change in tumor size between baseline and the consecutive evaluations. At week 12 and at week 24, we statistically tested the change from baseline between the groups with KRAS wild type (WT) and KRAS mutation (MUT) using the t-test. RECIST criteria for tumor response were used. Results: 3 patients had progressive disease (PD), 26 stable disease (SD), 8 partial response (PR) and 0 complete response. A KRAS MUT was found in 17 tumors (46%): 2 in PD (66.7%), 15 in SD (57.7%) and none in PR patients (p [Table: see text]

665 Background: Not all the patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR). To date, patients with disease progression during chemotherapy are excluded from surgery. The present study aims to elucidate if the CLM behavior in the interval between the end of chemotherapy and LR (stable disease vs. progression) impacts prognosis. Methods: All the consecutive patients undergoing LR for CLM between 2004 and 2014 after a tumor response or stabilization during chemotherapy were considered. The patients having received two separate imaging modalities after chemotherapy (one at the end of chemotherapy and one before LR) with an interval between the two > 3 weeks were included. Any variation of CLM size was registered. Tumor progression was defined according to the RECIST criteria. Results: Overall, 130 patients were analyzed. One fourth of the patients with partial response or stable disease during chemotherapy had a disease progression after the end of chemotherapy before LR, 16% if the interval chemotherapy-surgery was < 8 weeks. The risk of progression was not associated with the response to chemotherapy. Patients with progression after the end of chemotherapy had lower survival than patients with stable disease (5-year overall survival (OS) 19.0% vs. 27.6%; three-year recurrence-free survival (RFS) 6.7% vs. 21.3%, p < 0.001 for both). Survival was extremely poor in case of early progression ( < 8 weeks) (0% two-year RFS and OS). Progression was an independent prognostic factor of OS and RFS (HR = 3.243 and HR = 2.874, p < 0.0001). Eleven patients had a complete radiologic response to chemotherapy and underwent LR at disease reappearance without further chemotherapy after a median delay of 8.7 months. They had excellent survival (five-year OS 39.0%, three-year RFS 36.4%). Conclusions: Early disease progression between the end of chemotherapy and LR occurs in ~15% of patients. It is associated with extremely poor survival and should be considered a contraindication to surgery. Patients with a complete radiologic response can be resected upfront at recurrence without further chemotherapy.

Purpose: To assess the efficacy of stereotactic body radiotherapy in patients with unresectable locally advanced pancreatic cancer. Materials and Methods: All patients received a prescription dose of 45 Gy in 6 fractions. Primary end point was freedom from local progression. Secondary end points were overall survival, progression-free survival, and toxicity. Actuarial survival analysis and univariate or multivariate analysis were investigated. Results: Forty-five patients were enrolled in a phase 2 trial. Median follow-up was 13.5 months. Freedom from local progression was 90% at 2 years. On univariate ( P < .03) and multivariate analyses ( P < .001), lesion size was statistically significant for freedom from local progression. Median progression-free survival and overall survival were 8 and 13 months, respectively. On multivariate analysis, tumor size ( P < .001) and freedom from local progression ( P < .002) were significantly correlated with overall survival. Thirty-two (71%) patients with locally advanced pancreatic cancer received chemotherapy before stereotactic body radiotherapy. Median overall survival from diagnosis was 19 months. Multivariate analysis showed that freedom from local progression ( P < .035), tumor diameter ( P < .002), and computed tomography before stereotactic body radiotherapy ( P < .001) were significantly correlated with overall survival from diagnosis. Conclusion: Stereotactic body radiotherapy is a safe and effective treatment for patients with locally advanced pancreatic cancer with no G3 toxicity or greater and could be a promising therapeutic option in multimodality treatment regimen.

e16116 Background: IRI is widely used in the treatment of gastrointestinal cancers. Consistent with current guidelines, UGT1A1 genotyping may drive IRI dose reductions, but the usefulness of this approach is still unclear. We assessed potential clinical variables that may predict grade ≥3 neutropenia and more specifically the upfront genotyping of UGT1A1 polymorphisms associated with IRI toxicity, according to predefined IRI dose reductions. Methods: We genotyped UGT1A1*28 polymorphisms in 247 patients with metastic colorectal, gastric and pancreatic cancers who received second or third-line IRI-based chemotherapy in clinical practice at a single academic center. Concomitant DPYD sequencing was undertaken in 179 patients receiving also fluoropyrimidines. We compared the incidence of severe neutropenia with full-dose IRI in UGT1A1 6/6 and 6/7 carriers, and in UGT1A1 7/7 carriers who underwent initial IRI dose reductions by at least 30%. Results: The incidence of UGT1A1 7/7, 6/7, 6/6 genotypes was 11.3%, 51.4%, and 37.2%, respectively. IRI dose reductions were significantly more frequent with UGT1A 7/7 and 6/7 genotypes (odds ratio [OR] = 9.5; 95% confidence interval [CI]: 4.3-21.7), and combination chemotherapy (OR = 3.8; 95%CI: 1.3 – 11.1). Other clinical parameters, including sex, cancer type, baseline neutrophils levels, performance status were not significantly associated with IRI dose reductions. Despite initial IRI reductions driven by the UGT1A1 panel, patients with UGT1A1 7/7 genotype had an increased, albeit non-significant, risk of grade ≥3 neutropenia, compared to patients with UGT1A1 6/6 and 6/7 genotypes who received full dose IRI (incidence: 39% versus 21%; OR = 2.4; 95%CI: 0.85 – 7.03). Conclusions: UGT1A1 testing is a determinant of IRI dose reductions, however this strategy does not reduce the burden of grade ≥3 neutropenia in UGT1A1 7/7 carriers. Further studies beyond the UGT1A1*28 genotype are needed to fully understand the increased risk of neutropenia in patients candidate to IRI-based chemotherapy.