Treatment Of Metastatic Colorectal Carcinoma Research Articles

Nipavect: Phase II study of niraparib and panitumumab in advanced RAS WT colorectal cancer.

3579 Background: Panitumumab (Pmab) is a recombinant monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR) and it is indicated for the treatment of metastatic colorectal carcinoma (mCRC). However, the objective response rates (ORR) for the single agent are historically about 8-11%. EGFR inhibition induces synthetic lethality with poly ADP ribose polymerase inhibitors (PARPi) such as Niraparib, by attenuating DNA repair pathways. Combining PARP and EGFR inhibition has the potential to confer synergistic benefit, while also ameliorating resistance mechanism to EGFRi. We conducted this study to define the safety and efficacy of the combination of Niraparib and Pmab in RAS wildtype (WT) mCRC. Methods: Patients (pts) with RAS WT mCRC who have progressed on at least one line of systemic chemotherapy were eligible for the trial. Other selected inclusion criteria were ≥18 years of age, ECOG PS 0-1 and measurable disease per RECIST 1.1. Pmab was administered at 6 mg/kg IV on days 1 & 15 of each 28-day cycle, while Niraparib was taken orally at 200mg or 300mg (based on body weight and platelet count) daily throughout the cycle. The primary endpoint was clinical benefit rate (CBR) defined as complete (CR) + partial (PR) response + stable disease (SD) per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, ORR, progression-free survival (PFS), overall survival (OS), and duration of response (DoR). Results: A safety run-in cohort of 6 pts was initially enrolled. Following a preplanned safety analysis showing an acceptable toxicity profile, an additional 19 pts were enrolled. Of the total 25 enrolled pts, 24 were evaluable for response. Male - 50%; Whites/African Americans/Asians – 65.2%/21.7%/13%; median age – 58.5yrs. The majority had left sided tumor (92%) and the median line of prior therapy was 2 (range 1-4). CBR was 83.3% (0 CR, 6 PR, 14 SD) and ORR was 25%. mPFS – 5.6mos (95% CI: 3.7, 6.9); mOS – 20.9mos (95% CI: 9.2, NR). Six-month PFS and OS rates were 48.4% and 100% respectively. At a median follow up time of 7.5mos (95% CI: 4.2, 10.4), 3 patients remained on treatment and DoR was yet to be determined. Muco-cutaneous adverse events (AEs) of any grade included rash (58.4%), oral mucositis (20.8%), dry skin (16.7%) and paronychia (4.2%). Most common (grade > 2) treatment related AEs (TRAEs) were anemia (G3; 12.5%), dermatitis, oral mucositis, hypertension and neutropenia (G3; 4.2% each). There were no grade 4-5 TRAEs. Conclusions: The combination of Pmab and Niraparib had an acceptable safety profile, and showed considerable antitumor activity in pts with advanced RAS WT mCRC compared to historical rates. Additional biomarker analyses such as survival correlation with immune cell infiltration in paired skin biopsies and HER2/BRAF mutational status are ongoing. Funding and product (Niraparib) for the study were provided by GSK (NCT03983993). Clinical trial information: NCT03983993 .

Recovery of dialysis-dependent acute kidney injury after cessation of oxaliplatin

Oxaliplatin, a platinum-based compound, is the standard cancer therapy for treatment of metastatic colorectal carcinoma and other gastrointestinal malignancies. Oxaliplatin-induced nephrotoxicities include acute kidney injury due to acute tubular injury secondary to diarrhea and pre-renal azotemia, though intravascular hemolysis and thrombotic microangiopathy have been also reported. Patients with oxaliplatin-induced kidney failure partially recover kidney function after cessation of oxaliplatin therapy. We report a unique case of a 61-year-old female, with metastatic colon cancer to her lungs, liver, spleen, and peritoneum, who presented with acute anemia, sepsis, and kidney failure post-oxaliplatin treatment. Oxaliplatin cessation resulted in complete kidney recovery after 3 months of kidney replacement therapy.

A Cost-effectiveness Analysis of Adding Cetuximab to the First-line Treatment of Metastatic Colorectal Carcinoma in Iran; Considering Genetic Screening for Precision Medicine.

This study aimed to evaluate the cost-effectiveness of cetuximab in different genetic populations of metastatic colorectal carcinoma patients, including KRAS and RAS wild types and mutants, when added to FOLFIRI treatment regimens for evidence-based disease management in Iran. A Markov decision model was designed in TreeAge software with the three states of stable, progress, and death. Clinical outcomes were extracted from published clinical studies, and costs were extracted from the Iranian local data. The primary outcome was an incremental cost-effectiveness ratio (ICER) in the simulated population. The cost-utility model from the perspective of the health system indicated that the average direct medical costs of a patient that has not been genetically screened are $56,985.27 and $20,767.74 in FOLFIRI + cetuximab and FOLFIRI regimens, respectively. However, costs per patient in the KRAS wild-type population were $21,845.52 in FOLFIRI and $78,321.22 in FOLFIRI + cetuximab. In RAS wild-type patients, FOLFIRI and FOLFIRI + cetuximab costs per patient were $23,111.62 and $84,976.39, respectively. Incremental QALYs for the above scenarios were 0.069, 0.193, and 0.285, respectively. Therefore, the ICER of add-on cetuximab in Iran compared to the treatment alternatives in the scenarios with and without KRAS screening was $520,771.55/QALY, $292,768.16/QALY, and $217,460.51/QALY. Although genetic screening in precision medicine reduces costs per outcome, according to the willingness-to-pay threshold of $4349.50 in the Iranian health system, add-on cetuximab to the FOLFIRI regimen is not a cost-effective strategy even with genetic screening and a 20% price reduction.

397P Early decreases in KRAS mutant allele frequency (MAF) predicts clinical benefit to the PLK1 inhibitor onvansertib in combination with FOLFIRI/bev in 2L treatment of metastatic colorectal carcinoma (mCRC)

Patients (pts) with mCRC have few treatment options and poor outcome, particularly those with KRAS mutation (mKRAS). After failure of 1L treatment, the ORR for FOLFIRI/bev is 5-13%, with PFS 4-6 mos, and OS 10-12 mos. Onvansertib (Onv), is a highly specific PLK1 inhibitor, currently being investigated in combination with FOLFIRI/bev in 2L treatment of mKRAS mCRC (NCT03829410). Preliminary results indicate that Onv+ FOLFIRI/bev is well tolerated and efficacious (Lenz et al, JCO 2022). We investigated the utility of measuring early changes of KRAS MAF, using liquid biopsies, to predict clinical benefit to Onv+FOLFIRI/bev.

Optimal duration of therapy in the first line treatment of metastatic colorectal cancer: Single center experience

Background/Aim. Standard treatment options for the first-line treatment of metastatic colorectal carcinoma (mCRC) are 5-fluorouracil, folinic acid, oxaliplatin (FOL-FOX4)/capecitabine (CapOx), plus bevacizumab (bev) and 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus bev. The aim of this study was to compare overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with mCRC who were treated in the first line with FOLFIRI/bev vs. FOLFOX4/bev. At the same time, the aim was also to compare the safety profile in the observed groups of patients and to investigate optimal treatment duration and characteristics of patients who had the best treatment outcomes. Methods. The retrospective-prospective study included patients with mCRC treated with chemotherapy protocols for the first line in combination with bev (FOLFOX4/bev, respectively, FOLFIRI/bev). Treatment efficacy was evaluated on the basis of ORR, PFS, and OS, and the safety of treatment was evaluated by monitoring adverse drug reactions (ADR). Results. ORR was 70% in the FOLFIRI/bev group and 50% in the FOL-FOX4/bev group. Median PFS for FOLFIRI/bev (n = 30) and for FOLFOX4/bev (n = 30) was 15.6 months and 12.1 months, respectively [hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.47?1.53; p = 0.5591]. Median OS for FOLFIRI/bev and for FOLFOX4/bev was 24.7 months and 19.9 months, respectively (HR 0.67; 95% CI 0.37?1.23; p = 0.1552). In both patient groups, the patients who received more than 9 cycles of induction therapy had better treatment response compared with patients who received less than 9 cycles of therapy. In the FOLFOX4/bev group, PFS was 16.9 vs. 9.7 months, and OS was 22.1 vs. 17.6 months, respectively. In the FOLFIRI/bev group, PFS was 9 months for patients who received less than 9 cycles of therapy vs. 18.8 months for patients who received more than 9 cycles, and OS was 18.0 months vs. 27.7 months, respectively. ADR grade 3 and 4 had 7% of the patients in the FOLFIRI/bev group vs. 27% in the FOLFOX4/bev group. Conclusion. Patients who received FOLFIRI/bev compared to those treated with FOLFOX4/bev had better ORR (70% vs. 50 %, respectively), PFS (15.6 months vs. 12.1 months, respectively), and OS (24.7 months vs. 19.9 months, respectively). In both patient groups, the patients who received induction therapy for 4?6 months (more than 9 cycles of therapy) had a better treatment response.

Treatment of Metastatic Colorectal Carcinoma with Bevacizumab in First-Line and beyond First Progression: The KORALLE Non-Interventional Cohort Study.

The non-interventional study (NIS) KORALLE evaluated the effectiveness and safety of bevacizumab in patients with metastatic colorectal carcinoma (mCRC) treated with bevacizumab in combination with fluoropyrimidine-based chemotherapy in the first-line setting and beyond first progression in routine clinical practice. This prospective, multicenter NIS observed adult patients with mCRC who started first-line bevacizumab therapy. The planned maximum duration of observation per patient was 21 months. The primary effectiveness variable was progression-free survival in the first-line therapy setting (PFS-1). Secondary effectiveness variables included PFS after first progression as well as overall survival and overall response rate. All analyses were carried out descriptively for the full analysis population set (FAS). Effectiveness analyses were also assessed for predefined subgroups based on therapy goals. Between December 2012 and July 2016, 2,429 eligible patients were observed at 314 sites in Germany. In the first-line setting in the FAS, the median PFS-1 was 10.3 months (95% CI: 9.9; 10.8), the median overall survival was 16.9 months (95% CI: 16.3; 17.5), and the overall response rate (ORR-1) was 44.2% (95% CI: 41.6%; 46.8%). Effectiveness results of all subgroups were similar to the FAS. Overall, 80.9% of patients experienced any adverse events, 36.6% of patients experienced serious adverse events, and 8.8% of patients experienced fatal adverse events. The NIS KORALLE provided broad real-world evidence on effectiveness and safety of bevacizumab. Despite different treatment intentions, the combination of bevacizumab plus fluoropyrimidine-based chemotherapy was similarly effective in all subgroups in routine clinical practice. The safety information reported in this study is consistent with the known safety profile of bevacizumab.

Yttrium-90 Internal Radiation Therapy as Part of the Multimodality Treatment of Metastatic Colorectal Carcinoma

About 70% of patients with metastatic colorectal carcinoma (mCRC) have liver metastases. Hepatic failure accounts for most mCRC-related deaths. Therefore, controlling liver metastases may improve outcomes. A data overview of liver-directed treatment using yttrium-90 selective internal radiation therapy (SIRT) is provided as part of a multimodality treatment. SIRT in mCRC is discussed, and the prognostic factors for patient selection are defined. Pooled analyses of three recent trials incorporating SIRT plus chemotherapy revealed subsets of patients with mCRC who might benefit from SIRT. A multidisciplinary treatment for most mCRC patients is proposed to achieve long-term survival in this cohort of patients.

Multimodal, interdisciplinary therapeutic concepts for liver metastasized colorectal cancer

About half of all patients with colorectal carcinoma (CRC) develop metastases mainly in the liver during the course of their disease. Metastatic disease is associated with a low 5-year overall survival rate of only 5-7 %, particularly when there is no possibility of local treatment. However, if there is an opportunity to resect the metastases, especially isolated liver metastases, the chance of long-term survival is approximately 15-27 % after both primary resection or secondary resection after neoadjuvant pretreatment. Overall, long-term survival of patients with metastatic CRC has improved significantly in recent years due to a combination of modern systemic therapies, advanced liver surgery and local ablative procedures.Of note, for the vast majority of patients, metastatic resection does not mean cure, but a significant prolongation of overall survival with a good quality of life. Chemotherapy-free intervals after metastasis resection maintain quality of life and can help to reduce toxicity.In this review, we would like to present the "toolbox" for the multidisciplinary treatment of metastatic CRC and give recommendations how the individual modalities should be optimally used, considering tumor-specific characteristics and patient preferences.

P43-9 A 10-year marathon, race against time: Challenges in management of metastatic colon cancer

This poster illustrates the management of initially locally advanced colon carcinoma and followed by metastatic disease over a course of 10 years. It reflects our challenges in managing not only the cancer itself but also the toxicities related to treatment. In the last 10 to 15 years there are major advancements in treatment of metastatic colorectal carcinoma. With 5-Fluorouracil (5-FU) alone, the median survival has been reported as 11 to 12 months. However with more new agents other than 5-FU, for example other new cytotoxic agents, biologic agents targeting angiogenesis and the epidermal growth factor receptor (EGFR), the average median survival is approaching 3 years (Heinemann et al). Past and current treatment history was obtained retrospectively through electronic medical records. Madam L was first diagnosed with Dukes C Transverse Colon Carcinoma pT3N2M0 in 2010. However she developed metastatic disease subsequently in 2011. She failed a total 11 lines of chemotherapy and targeted therapy, including XELOX, XELIRI, FOLFIRI, TS-1, Regarofenib used with combination of Cetuximab, Panitumumab, Aflibercept. She suffered from side effects of both chemotherapy and targeted therapy, which some has been managed medically and some disabling enough to lead to cessation of the agent. She was given multiple chemo-holidays in between treatments. Over the course of 10 years, with advancement in treatment and new laboratory investigations for mutation, this patient has been on newer treatments. She is still undergoing palliative chemotherapy and is asymptomatic now. This patient has beaten the odds, by proper sequencing of chemotherapy and targeted therapy, besides adequate management of treatment related toxicity.

Evaluating the value of Amphiregulin, Phosphatase and Tensin Homologue (PTEN) and P21 Expression for Anti-EGFR Treatment in Metastatic Colorectal Carcinoma.

Background:Despite the significant progress in target therapy for the treatment of metastatic colorectal carcinoma (mCRC), the overall survival isn’t satisfactory. Methods:We assessed the expression of Amphiregulin, PTEN, and P21 in sections from 23 paraffin blocks prepared from 23 patients with left-sided mCRC using immunohistochemistry (IHC). The relationship between their level of expressions, clinicopathological parameters, response to anti-EGFR, and prognosis were analyzed. Results:High Amphiregulin, PTEN and low P21 expression levels were associated with low tumor grade (p= 0.038 and 0.025 respectively), better response to anti-EGFR treatment (p <0.001), and favorable outcome {progression-free survival (PFS) and overall survival (OS)} (p <0.05). There was a direct relation between Amphiregulin and PTEN expressions (phi coefficient=+0.840), while there was an inverse relation between P21expression and both Amphiregulin (phi coefficient= -0.840) and PTEN expressions (phi coefficient = -1.000), which was statistically significant (P <0.001). Conclusion: High Amphiregulin and PTEN expression levels and low P21 expression levels were associated with better response to anti-EGFR therapy and improved survival outcome. They might be considered predictive markers of response to anti-EGFR therapy in mCRC.

Unusual case of colorectal carcinoma with sarcoid-like mediastinal adenopathy and near-fatal DPD deficiency

The liver is the commonest site for metastases in colorectal carcinoma; other isolated sites are considered extremely rare. 5-fluorouracil (5-FU) is the backbone of treatment for metastatic colorectal carcinoma (mCRC) and without it survival may be significantly reduced. It is primarily metabolised by dihydropyrimidine dehydrogenase (DPD). Testing for DPD deficiency is not a routine practice and toxicity will only manifest following drug challenge. There are limited standardised treatment guidelines in managing patients with severe drug reactions following 5-FU exposure. We describe a delayed presentation of life-threatening DPD deficiency in a patient with colorectal carcinoma and mediastinal lymphadenopathy. We describe our experience with chemotherapy in this difficult clinical scenario and highlight the importance of histological confirmation in unusual sites of metastatic disease.

Ziv-aflibercept: A cost-effective, off-label, highly potent antagonist of vascular endothelial growth factor.

Ziv-aflibercept (Zaltrap® ), a recombinant fusion protein that binds diffusible vascular endothelial growth factor (VEGF), is approved for the treatment of metastatic colorectal carcinoma. Its molecular structure is the same as aflibercept (Eylea® ), thus making it an attractive option for the off-label treatment of chorioretinal vascular conditions. Ziv-aflibercept is distributed in 4 and 8ml vials for intravenous use, and its cost after compounding is similar to bevacizumab. Studies with retinal pigment epithelium cytotoxicity, animal histologic sections and electroretinography have demonstrated its safety, and mathematical modelling combined with over four dozen clinical publications from different ophthalmic centres throughout the world attest to its efficacy. No appreciable differences in visual or anatomic outcomes between 1.25mg (0.05ml) and 2.5mg (1.0ml) doses have been noted. The long duration of action combined with the low cost make ziv-aflibercept an attractive anti-VEGF treatment option, especially in low- and middle-income countries where its popularity is increasing.

Relation between sarcopenia and dose-limiting toxicity in patients with metastatic colorectal cancer who received regorafenib.

Sarcopenia is related to poor prognosis and drug toxicities in solid tumors. The aim of our study is to investigate the predisposition of patients with metastatic colorectal carcinoma who started regorafenib treatment to sarcopenia and prolonged survival. Patients with metastatic colorectal carcinoma who receives regorafenib were search retrospectively. Dose-limiting toxicity was defined as dose reduction or toxicity requiring drug withdrawal. Sarcopenia evaluation was made with computed tomography performed within a month before treatment. Progression-free survival and overall survival were estimated. Thirty-six patients were found as suitable for the study. 63.9% of patients were found as basally sarcopenic. Dose-limiting toxicity occured 13 of 23 patients (56.5%) with basal sarcopenia, whereas only 1 of 13 patients (7.6%) with no sarcopenia exhibited dose-limiting toxicity (p = 0.005). Three patients suffered from grade 3-4 toxicity. Hand-foot syndrome, hypertension, and mucosal rash were the most seen side effects. Mean regorafenib treatment duration was 3.36months. There was no significant difference in the progression-free survival (PFS) and the overall survival (OS) between sarcopenic patients and patients with no sarcopenia. Durations were as OS 24.2weeks in patients with sarcopenia (95% CI 16.7-31.7), 28.1weeks in patients with no sarcopenia (95% CI 20.5-35.7) (p = 0.36), and as PFS 14.2weeks in patients with sarcopenia (95% CI 12.1-16.4), 14.8weeks in patients with no sarcopenia (95% CI 9.7-20.1) (p = 0.65). Dose-limiting toxicity was significantly higher in basally sarcopenic patients who were started regorafenib as treatment of metastatic colorectal carcinoma. There was no significant relationship between overall survival and progression-free survival with sarcopenia.

Leukocytoclastic vasculitis with purpura and renal failure induced by the anti-epidermal growth factor receptor antibody panitumumab: a case report

BackgroundPanitumumab is the first human combinatorial antibody for the treatment of metastatic colorectal carcinoma. Dermatologic toxicity of all grades occurs in more than 90% of patients. However, there are few reports of purpura induced by anti-epidermal growth factor receptor antibody. Renal failure is also uncommon as an adverse event of anti-epidermal growth factor receptor antibody.Case presentationA 67-year-old Japanese man with advanced colon cancer received monotherapy with panitumumab. General malaise, bilateral edema of his legs, and bilateral purpura of his forearms developed 2 days after the second cycle of panitumumab. A skin biopsy was performed to evaluate the purpuric lesions on his left leg and leukocytoclastic vasculitis was diagnosed. Blood tests showed grade III acute renal failure with a blood urea nitrogen level of 33.8 mg/dL and a creatinine level of 3.10 mg/dL.ConclusionsThis is the first reported case of leukocytoclastic vasculitis followed by purpura and acute renal failure associated with panitumumab.

BRAF mutation: Current and future clinical pathological applications in colorectal carcinoma.

The aims are to review the relevance of the BRAF mutations in the clinical settings of colorectal carcinoma. All the literature concerning BRAF mutations and colorectal carcinoma published in PubMed from 2010 to 2018 was reviewed. Multiple variants of BRAF mutations exist in colorectal cancer, the most common type being V600E. The mutation is found in 5 to 15% of colorectal carcinomas and is less common in Asian populations. BRAF mutations are linked with older age, female gender, cigarette smoking and are more common in the right (proximal) portion of the large intestine. BRAF mutations are associated with carcinomas of high histological grade and advanced cancer stages. Often BRAF mutated carcinomas demonstrate adverse histological features such as lymphovascular invasion, perineural invasion, tumour budding and lymph node metastases. BRAF mutations are found in serrated polyposis syndrome and have a negative correlation with hereditary nonpolyposis colorectal cancer (HNPCC). An array of methods of detection of BRAF mutation in colorectal carcinoma are available, such as immunohistochemistry and next generation sequencing, etc. Combinatorial approaches involving anti-BRAF therapies targeting both MAPK signalling as well as the PI3K/mTOR pathway could be a new approach for treatment of metastatic colorectal carcinoma. To conclude, BRAF mutation is important in the pathogenesis of colorectal cancer. Further research on the detection method as well as its role in target therapy will help to improve the management of patients with colorectal cancer.

3:27 PM Abstract No. 124 MIRD-based activity calculation may improve outcomes over body surface area for resin microsphere radioembolization of metastatic colorectal carcinoma

To compare clinical outcomes of resin microsphere Y90 radioembolization (RE) using standard Body Surface Area (BSA) activity prescription versus Medical Internal Radiation Dose (MIRD) prescription for treatment of metastatic colorectal carcinoma (mCRC). Patients with mCRC treated with resin microsphere RE between 2004-2015 were retrospectively reviewed. Standard BSA activity prescription was used from 2004-2012. Starting 2013, MIRD-based activity prescription was substituted, with treated region absorbed doses ranging from 40-65 Gy depending on performance status, liver function, volume of treatment, hypervascularity, and previous treatment history. Radiographic, biochemical, and clinical outcomes were compared. 109 patients (61 M/48 F), median age 60, underwent 118 treatment sessions (96 BSA/ 22 MIRD). 77 underwent whole liver treatment, either single session (72) or staged (5). In the MIRD group, 7 (36%) patients had activity prescribed >10% greater and 3 (15%) had activity >10% lower than what would have been prescribed by BSA. Disease control rate (DCR) by RECIST 1.1 showed a trend favoring MIRD over BSA (71% vs 53%, p = 0.1). MIRD patients showed more mild laboratory toxicity changes at 90 days (CTCAE 4.03, ≤ 2 grade change from baseline) (28% vs 18%, p = NS), but slightly less moderate and severe toxicity changes than BSA patients (>2 grade change from baseline) (0% vs 3%, p = NS). Median changes in serum carcinoembryonic antigen (CEA) in MIRD and BSA groups at 8 weeks after RE were -16% and -8%, (p = NS). Differences in median hepatic progression-free survival did not reach statistical significance (MIRD 150 days vs BSA 90 days, p = 0.5). Likewise, the study was underpowered to show a difference in overall survival (210 vs 321 days, p = 0.4). Using MIRD rather than BSA for activity calculation for resin microsphere Y90 RE of mCRC resulted in increase in dose in 36% and decrease in 15% of patients. Although additional statistical power is needed, consideration of the target liver volume rather than body surface area is a promising approach to increase the efficacy and decrease the toxicity of resin microsphere RE.

Immunohistochemical Expression of Debiquitinating Enzyme OTUB1 in Colorectal Carcinoma

AbstractBackground and Objective: Colorectal Carcinoma (CRC) is the most common malignancy of the gastrointestinal tract. The overall five-year survival for colon cancer and rectal cancer are 65% and 68%, respectively with liver metastasis being the leading cause of death. Despite the use of active targeted drugs for treatment of metastatic CRC in the past decade, cure rates remain low. Therefore, research on novel markers for earlier diagnosis and target therapy of CRC is of a great concern. OTUB1 (OTU deubiquitinase, ubiquitin aldehyde binding 1) is a deubiquitinating enzyme (DUB) that belongs to the OTU (ovarian tumor) superfamily. The aim of this work is to study the immunohistochemical expression of OTUB1 in CRC and its correlation with the available clinico-pathological variables.Material and Methods: This retrospective study was conducted on a total number of 45 cases of CRC. All cases were retrieved from the archival files of the pathology labs of Ain Shams University Hospitals (from 2012-2016). Immu-nohistochemistry using rabbit polyclonal anti OTUB 1 antibody was performed.Results: OTUB 1 was overexpressed in CRC tissues, and the expression level of OTUB1 was correlated significantly with histologic grade (p<0.001), depth of invasion (pathological T) (p=0.03) and location of CRC (p=0.002). On the other hand, no significant correlation was found with age, gender, metastasis whether nodal or distant, TNM stage and size of tumor.Conclusion: OTUB1 may have a possible role in tumor differentiation as well as local tumor invasion, thus could be useful in identification of biologically aggressive tumors in colonoscopic biopsies in addition to providing a basis for targeted therapy which could play a major role in the treatment of CRC.

PROX: Primary resistance to oxaliplatin containing regimen in the first line treatment of metastatic colorectal carcinoma—Retrospective analysis.

855 Background: The rate of primary resistance to modern first line (FL) chemotherapy regimen in the treatment of metastatic colorectal cancer (mCRC) is low. Progression Disease (PD) to FOLFOX in the FL is less than 15% in most trials. Prognostic factors associated with worse outcome in mCRC have been identified. However, primary resistance to Oxaliplatin (PROX) containing regimen is not well understood, as well as the role of salvage therapy in further lines of treatment. The aim of the study was to analyze clinical and pathological characteristics of patients with PROX. Methods: A retrospective, single center study included patients that presented PD in the first response evaluation with an Oxaliplatin containing regimen in the FL treatment of mCRC. We also evaluated the Overall Survival (OS) and progression free survival (PFS) of these patients to second and third line. Clinical and pathological variables were analyzed and correlated with (OS). Results: A total of 55 patients were inclued. Median age these cohort was 57 years. Female/Male rate was 42%/58%. Mucinous component was 27%. Right and Left colon was 27% and 66%, respectively. BRAF mutation (2/16 pts). Wild type KRAS was 44%. Synchronic metastasis was 75%. Ressection of metastasis was performed in 20%. Liver limeted disease was found in 45%. Main chemotherapy regimen containing oxaliplatin was FOLFOX (78%) in first line. Bevacizumab, Cetuximab and Panitumumab were used in 21.8%, 9%, 1.8%, respectively. OS was 9.4 months. PFS in second line 3.8 months (47 pts) and third line 3.5 months (18 pts). The only variable associated with longer survival was resection of metastasis (25.6 x 8.6 months, p=0.039). Conclusions: No clinical and pathological variable were able to predict primary resistance to Oxaliplatin containing regimen. However, we found a higher proportion of mucinous subtype. Patients submitted to resection of metastasis had almost three fold the survival of patient that did not underwent surgery. Refractory patients have a very short survival. Further lines of treatment are not able to rescue these patients. Further studies focusing in patients with primary resistance to chemotherapy in first line are needed.

Biochemical liver function tests parameters do not indicate any difference in the degree of hepatotoxicity in patients with metastatic colorectal carcinoma treated with conventional anticancer drugs regardless the use of bevacizumab

Background/Aim. Colorectal carcinoma (CRC) is one the most frequent malignant disease with early liver metastasis. It requires the timely use of anticancer drugs. Current treatment of metastatic CRC consists of conventional anticancer drugs use, but they cause liver damage which is manifested by disorder in biochemical liver function parameters. The addition of one of monoclonal antibodies, e.g. bevacizumab improves their therapeutic effect, but its influence on caused biochemical disturbances is not completely known. Therefore the aim of this study was to compare the level of liver function test parameters in patients treated with conventional anticancer drugs with parameters in patients additionally treated with bevacizumab. Methods. The study was performed on the two groups of adult patients with liver metastatic CRC assigned according to the treatment protocol. One group of the patients (n = 44) was treated with FOLFOX4 (the group 1), and the other one (n = 52) with bevacizumab added to FOLFOX4 treatment protocol (the group 2). Depending on the response of patients, the duration of treatment varied from 2 to 6 months. Standard liver function tests were performed before and after the completion of the treatment. Results. Initial values of some biochemical function test parameters [alkaline phosphatase (ALP) in the group 1 of patients, gamma-glutamyl transferase (GGT) and lactate dehydrogenase (LDH) in both groups] were increased in relation to the normal reference values, with some intergroup differences (p = 0.001). Biochemical disturbances of liver function tests in the group of patients treated with conventional anticancer drugs were due to not only their metastases but also due to the hepatotoxic effect of drugs used. After the treatment, significant differences in biochemical liver tests parameters were found in aspartate aminotransferase (AST), alanine aminotransferase (ALP), GGT and LDH, being lower in the group 2 (patients additionally treated by bevacizumab) (p values were: 0.002 for AST; 0.001 for ALP and GGT; 0.000 for LDH). The levels of the other studied parameters, alanine aminotransferase (ALT) bilirubin, and proteins did not differ significantly between groups both pre- or post-treatment. Conclusion. Both, metastatic CRC and treatment with the conventional anticancer drugs induce significant disturbances of several liver function parameters. The addition of bevacizumab to the conventional anticancer drugs did not affect these disturbances.

Cetuximab response in CRC patient-derived xenografts seems predicted by an expression based RAS pathway signature.

Cetuximab is an approved treatment for metastatic colorectal carcinoma (mCRC) with codon 12/13-KRAS mutations, recently questioned for its validity, and alternative mutation-based biomarkers were proposed. We set out to investigate whether an expression signature can also predict response by utilizing a cetuximab mouse clinical trial (MCT) dataset on a cohort of 25 randomly selected EGFR+ CRC patient-derived xenografts (PDXs). While we found that the expression of EGFR and its ligands are not predictive of the cetuximab response, we tested a published RAS pathway signature, a 147-gene expression signature proposed to describe RAS pathway activity, against this MCT dataset. Interestingly, our study showed that the observed cetuximab activity has a strong correlation with the RAS pathway signature score, which was also demonstrated to have a certain degree of correlation with a historic clinical dataset. Altogether, the independent validations in unrelated datasets from independent cohort of CRCs strongly suggest that RAS pathway signature may be a relevant expression signature predictive of CRC response to cetuximab. Our data seem to suggest that an mRNA expressing signature may also be developed as a predictive biomarker for drug response, similarly to genetic mutations.