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Background: KRASG12C-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. Methods: A multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/− bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment–effect interactions. KRASG12D-mutated patients were analysed as control. Results: One hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. However, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. No difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRASG12C-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations.

Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC), however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. Methods: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. Conclusions: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management.

Health-related quality of life (HRQoL) is not universally assessed in metastatic colorectal cancer (mCRC) patients. We tried to identify patient subgroups for whom HRQoL assessment should be strongly encouraged.Consecutive mCRC patients who had been deemed candidates for first-line chemotherapy were enrolled in a prospective study (NCT03873064) and asked to complete the HRQoL questionnaire EORTC QLQ-C30. Primary endpoint was the Global Health Status (GHS) of EORTC QLQ-C30. A nomogram was built for prediction of low GHS (i.e.,67%).Among recruited patients (n=173), a univariable logistic regression analysis (LRA) found that body mass index (BMI23), age (65 years) and sex (female) were significantly associated with low GHS. The multivariable LRA confirmed they were independently associated with the outcome (P values of 0.04-0.004). BMI, age and sex were included in a final predictive model (C-statistics, 67%; P=0.001) and used to build a nomogram. A total nomogram score ≥72 was associated with a risk of 28% or higher of having a low GHS. The 28% risk cut-off had a sensitivity of 90% and a specificity of 34% for identifying low GHS. A decision curve analysis revealed that a risk threshold of 28% of the model was associated to an added net benefit of ≥4% when using the nomogram. Low GHS was recorded in 58% vs. 23% of patients with28% vs.28% risk according to the nomogram, respectively (odds ratio 3.54, P=0.0004).High BMI together with young age and male sex were protective against HRQoL deterioration. In centers where HRQoL is not routinely assessed, such an assessment should be at least made for mCRC patients at risk according to the proposed nomogram (i.e., over 65-year-old females with BMI23).

Immune checkpoint inhibitors (ICIs) demonstrated improved overall survival (OS) in heavily pretreated unselected patients with metastatic gastro-esophageal junction (mGOJ)/gastric cancer (GC). Attempts to select patients based on programmed death-ligand 1 (PD-L1) expression appear to be suboptimal. A strong rationale suggests a prognostic role for inflammatory biomarkers for ICI-treated patients with mGOJ/GC. Our objective was to assess whether inflammatory markers are associated with survival in ICI-treated patients with mGOJ/GC. Ten inflammatory markers were retrospectively analyzed at baseline in 57 patients with mGOJ/GC with unknown PD-L1 status treated with second-line ICIs and correlated with OS. Selected variables were then analyzed in a multivariate Cox-regression model and used to build a GIPI nomogram. Neutrophil/lymphocyte ratio (NLR) and C-reactive protein (CRP) as continuous variables and albumin categorized as less than versus greater than 30 g/dL were the most significant predictors of OS and were used to build the GIPI nomogram. Nomogram-based lowest, mid-low, mid-high, and highest risk quartiles were associated with median OS (mOS) of 14.9, 7.1, 5.6, and 2.1 months, respectively (hazard ratio [HR] of highest vs. lowest risk 4.94; p = 0.0002). By optimally dichotomizing CRP and NLR, patients with one or more of the risk factors NLR > 6, CRP > 15 mg/L, and albumin

immune checkpoint inhibitors(ICIs) have shown contradictory results in patients with advanced gastro-oesophageal junction/gastric cancer(GOJ/GC).to identify specific patient subgroups that would derive survival benefit from ICIs.a subgroup meta-analysis of randomised clinical trials(RCTs) was carried out.four phase-III-RCTs were identified with data on the following variables: primary location(Gastric vs GOJ); age(≤ 65 vs65); gender(male vs female); ECOG PS(0 vs 1); ethnicity (Asian vs non-Asian), histology(intestinal vs diffuse), PD-L1 expression(≥ 1% vs1%). PD-L1 positivity was significantly associated with survival benefit from ICIs (HR: 0.82, p 0.047), with a significant interaction between PD-L1 expression and ICI efficacy (interaction HR: 1.41, p 0.02). Numerically, the second most relevant interaction was ICI efficacy and gender, with ICI being more effective in males.The PD-L1 positive patient subgroup derives significant survival benefit from ICI in GOJ/GC, however other predictors are eagerly needed to further refine patient selection.

4530 Background: ICIs demonstrated improved overall survival (OS) in heavily pre-treated mGOJ/GC pts. Pts selection exclusively based on PD-L1 tissue expression appears to be suboptimal, despite data from subgroup analyses of KEYNOTE trials. Strong rationale suggests a potential predictive role of inflammatory biomarkers in ICIs treated mGOJ/GC pts. Methods: Ten systemic inflammatory markers [platelets, monocytes, neutrophil/lymphocyte ratio (NLR), platelets-lymphocyte ratio, lymphocytes, sum of mononuclear cells, albumin, lactate dehydrogenase, c-reactive protein (CRP) and serum globulin] were retrospectively analyzed at baseline in 57 mGOJ/GC pts with unknown PD-L1 status treated in second-line with ICIs, and correlated with OS. Least Absolute Shrinkage and Selection Operator (LASSO) method was used to select variables (preliminarily subject to optimal coding using HR smoothed curves for OS) with the highest prognostic value. Selected variables were then analyzed in a multivariate Cox Regression Model and used to build a GIPI nomogram. Results: NLR and CRP taken as continuous variables and albumin categorized as < vs > 30 g/dL were found as the most meaningful independent predictors of OS and used to build the GIPI nomogram. Nomogram-based lowest (l), mid-low, mid-high and highest (h) risk quartiles were associated with median(m)OS of 14.9, 7.1, 5.6 and 2.1 months (mos), respectively [HR of l vs h 4.94, p 0.0002]. By optimally dichotomizing CRP and NLR, pts with one or more of the following risk factors: NLR >6, CRP >15 mg/L, albumin

Background Breast metastases from extra mammary tumors are extremely rare. Case report Here we report the case of a 50-year-old female with histologically-confirmed gastric cancer metastasis to the breast who was adequately treated with loco-regional hyperthermia plus standard second-line chemotherapy (paclitaxel plus ramucirumab). The best response achieved was a relatively long disease stabilization. Conclusion Chemotherapy plus regional hyperthermia has been shown to have a synergistic antitumor effect and possible favorable immunomodulatory effects. Such an approach merits further investigation especially for the treatment of rare superficial metastatic sites.

A platinum salt (oxaliplatin or cisplatin) is widely used to enhance chemoradation (CRT) response. The potential of cisplatin in neoadjuvant CRT for locally advanced rectal cancer (LARC) has not been fully investigated. Consecutive patients with histologically confirmed LARC were treated with standard pelvic radiotherapy and concurrent cisplatin plus capecitabine (CisCape CRT). Surgery and eight cycles of adjuvant FOLFOX4 were offered to all patients after CRT. Common biochemical variables and key germline genetic polymorphisms were analyzed as predictors of pathological complete response (pCR). Fifty-one patients were enrolled. pCR (regression AJCC grade 0) was documented in 7 patients (14%), nearly complete response (AJCC grade 1) in 10 pts. There was a strong association between disease-free survival and AJCC grade (p 0.0047). Grade 3-4 toxicities (mainly diarrhea) was observed in 41% of patients. Among all analyzed variables, baseline hemoglobin (Hb) was significantly associated with AJCC grade 0-1 response (p 0.027). As for the pharmacogenetic analysis, XRCC1 rs25487 polymorphism was significantly associated with AJCC grade 0-1, Odds Ratio 25.8, p 0.049. AJCC grade 0-1 response rate for patients with high Hb and/or XRCC1 rs25487 G/G genotype was as high as 57%. Baseline Hb and XRCC1 polymorphisms are valuable selection criteria for the CisCape CRT regimen, given its otherwise meaningful toxicity.

Few data are available regarding the treatment of metastatic colorectal cancer elderly patients with anti-EGFR agents in combination with chemotherapy. FOLFOX plus panitumumab is a standard first-line option for RAS wild-type metastatic colorectal cancer. Slight adjustments in chemo-dosage are commonly applied in clinical practice to elderly patients, but those modified schedules have never been prospectively tested. Clinical definition of elderly (≥70 years old) patients that may deserve a more or less intensive combination therapy is still debated. Several geriatric screening tools have been developed to predict survival and risk of toxicity from treatment. Among those, the G8 screening tool has been tested in cancer patients showing the strongest prognostic value for overall survival, while the CRASH score can stratify patients according to an estimated risk of treatment-related toxicities. The PANDA study is a prospective, open-label, multicenter, randomized phase II trial of first-line therapy with panitumumab in combination with dose-adjusted FOLFOX or with 5-fluorouracil monotherapy, in previously untreated elderly patients (≥70 years) with RAS and BRAF wild-type unresectable metastatic colorectal cancer. RAS and BRAF analyses are centralized. Geriatric assessment by means of G8 and CRASH score is planned at baseline and G8 will be re-evaluated at disease progression. The primary endpoint is duration of progression-free survival in both arms. Secondary endpoints include prospective evaluation of the prognostic role of G8 score and the correlation of CRASH risk categories with toxicity. The PANDA study aims at exploring safety and efficacy of panitumumab in combination with FOLFOX or with 5FU/LV in elderly patients affected by RAS and BRAF wild-type metastatic colorectal cancer, to identify the most promising treatment strategy in this setting. Additionally, this is the first trial in which the prognostic role of the G8 score will be prospectively evaluated. Results of this study will drive further experimental developments for one or both combinations. PANDA is registered at Clinicaltrials.gov : NCT02904031 , July 11, 2016. PANDA is registered at EudraCT-No.: 2015–003888-10, September 3, 2015.

417 Background: ICIs demonstrated improved overall survival (OS) in heavily pre-treated mGOJ/GC pts. Pts selection exclusively based on PD-L1 tissue expression appears to be suboptimal, despite data from subgroup analyses of KEYNOTE trials. Strong rationale suggests a potential predictive role of inflammatory biomarkers in ICIs treated mGOJ/GC pts. Methods: 11 systemic inflammatory markers [platelets, monocytes, neutrophil/lymphocyte ratio (NLR), platelets-lymphocyte ratio, lymphocytes, sum of mononuclear cells, albumin, lactate dehydrogenase, alkaline phosphatase (ALP), c-reactive protein (CRP) and serum globulin] were retrospectively analyzed at baseline in 57 mGOJ/GC pts with unknown PD-L1 status treated in second-line with ICIs, and correlated with OS. Least Absolute Shrinkage and Selection Operator (LASSO) method was used to select variables (preliminarily subject to optimal coding using HR smoothed curves for OS) with the highest prognostic value.Selected variables were then analysed in a multivariate Cox Regression Model and used to build a GIPI nomogram. Results: NLR and CRP taken as continuous variables and ALP categorized as < vs > 150 IU/L were found as the most meaningful independent predictors of OS [(HR 1.30 (95%CI 1.02-1.65), 2.00 (95%CI 1.09-3.66), 2.82 (95%CI 1.29-6.20) and p values 0.04, 0.01, 0.02, respectively)] and used to build the GIPI nomogram. Nomogram-based lowest(l), mid and highest(h) risk tertiles were associated with median(m)OS of 14.5,10.6 and 2.4 months(mos), respectively [HR of l vs h 0.26 (95%CI 0.12-0.53), p 0.0002]. By optimally dichotomizing CRP and NLR, pts with one or more of the following risk factors: NLR > 6, CRP > 15 mg/L, ALP < 150 IU/L (n: 31) had a mOS of 3.9mos vs 14.5mos of pts with no risk factor (n: 26) (HR 2.72, p 0.0005). Conclusions: GIPI, combining NLR, CRP and ALP, is the first inflammatory index with a significant prognostic value in mOGJ/GC pts receiving second line ICIs. Its implementation with analysis of PD-L1 expression in the present cohort is ongoing. GIPI merits validation in external cohorts and prospective clinical trials.

249 Background: Relationship between BMI and HR-QoL has been extensively studied in CRC survivors. Increasing BMI has been recently associated with improved survival in mCRC pts, however data on the relationship between BMI and common HR-QoL measures in mCRC are scarce Methods: The EORTC QLC C30 and the NCCN distress thermometer (DT) and problem list (PL) questionnaires were administered to consecutive mCRC pts candidate for firstline chemotherapy. The effect of BMI on HR-QoL were analyzed using the Kruskal-Wallis and Mann-Whitney tests. The interaction between BMI and other variables of interest (such as inflammatory indexes) for the effect on HR-QoL was also analysed using a logistic regression analysis Results: Of 135 screened pts, 119 completed the questionnaires. A direct association was observed between BMI and GH score, with the score gradually improving from BMI 14 to 21, then plateauing between 21 and 41. A significantly lower GH was observed for BMI < 21 vs > 21 (GH 50 vs 67, p 0.014). DT and BMI were not correlated. BMI was inversely associated with practical problems (mean number of reported problems 0.7 vs 0.4 for BMI < 24 vs > 24, p0.012). The other components inversely associated with BMI were appetite loss, pain and fatigue (which were higher for BMI < 21 , p values 0.033, 0.015 and 0.007, respectively). A direct association with BMI was also observed for social and physical functioning (p values 0.002 and 0.05, respectively). Median BMI in pts with GH score < 25 vs > 25 was 19 vs 25, p 0.05. Percentage of pts with very low BMI (BMI < 21) was 38% vs 2% for pts with GH < 25 vs > 25, respectively, Odds Ratio 32.4, p 0.0007. Among 15 common clinical and biochemical analysed variables, the inflammatory index neutrophil/lymphocyte ratio (NLR) demonstrated a significant interaction with BMI for the effect on GH, with the direct association between BMI and GH only retained in pts with low NLR and a deteriorated GH in pts with high NLR regardless of BMI, test for interaction p 0.013 Conclusions: Low BMI is associated with deteriorated HR-QoL in mCRC pts with low NLR approaching a first-line treatment. Adequate nutritional support and anti-inflammatory approaches would improve HR-QoL in these pts.

AIM To investigate the possible predictive role of routinely used glycemic parameters for a first venous thromboembolism (VTE) episode in gastrointestinal (GI) cancer ambulatory patients - with or without clinically diagnosed type 2 diabetes (T2D) or obesity - treated with chemotherapy. METHODS Pre-treatment fasting blood glucose, insulin, glycated hemoglobin (HbA1c) and homeostasis model of risk assessment (HOMA) were retrospectively evaluated in a cohort study of 342 GI cancer patients. Surgery was performed in 142 (42%) patients with primary cancer, 30 (21%) and 112 (79%) of whom received neoadjuvant and adjuvant therapies, respectively. First-line chemotherapy was administered in 200 (58%) patients with metastatic disease. The study outcome was defined as the occurrence of a first symptomatic or asymptomatic VTE episode during active treatment. RESULTS Impaired glucose tolerance (IGT) or T2D were diagnosed in 30% of GI cancer patients, while overweight/obesity had an incidence of 41%. VTE occurred in 9.4% of patients (7% of non-diabetic non-obese), especially in those with a high ECOG score (P = 0.025). No significant association was found between VTE incidence and T2D, obesity, different tumor types, metastatic disease, Khorana class of risk, or different anti-cancer drugs, although VTE rates were substantially higher in patients receiving bevacizumab (17% vs 8%, P = 0.044). Conversely, all glucose metabolic indexes were associated with increased VTE risk at ROC analysis. Multivariate Cox proportional analyses confirmed that HOMA index (HR = 4.13, 95%CI: 1.63-10.5) or fasting blood glucose (HR = 3.56, 95%CI: 1.51-8.39) were independent predictors of VTE occurrence during chemotherapy. CONCLUSION The results here reported demonstrate that evaluating glucose metabolic asset may allow for VTE risk stratification in GI cancer, helping to identify chemotherapy-treated patients who might benefit from thromboprophylaxis. Further multicenter prospective studies involving a larger number of patients are presently needed.

The treatment of metastatic colorectal cancer has undergone significant improvements over the last decade with the introduction of molecularly targeted monoclonal antibodies (mAbs). Among these, cetuximab, a chimeric IgG1 antibody directed against the extracellular domain of EGFR, has demonstrated a survival benefit for KRAS wild type (WT) tumors. Even though KRAS genotyping has significantly refined patient selection allowing an increase in tumor radiological response from 25% of the whole metastatic colorectal cancer (MCRC) population to 45% of the KRAS-WT subset, still for a significant proportion of patients anti-EGFR mAbs will be ineffective, thus resulting in unnecessary toxicity and cost. Polymorphisms of Fragment C gamma receptor (FCGR) gene have the potential for being used as predictive biomarkers of cetuximab activity since part of this drug’s tumoricidal effect is immune-mediated via FcγR-triggered ADCC (antibody-dependent cellular cytotoxicity). The aim of the present review is to summarize available data on the predictive/prognostic value of FCGR polymorphisms for cetuximab-treated MCRC patients and to discuss possible future directions in this area of research.

AIM To investigate the clinical significance of routinely used glycemic parameters in a cohort of colorectal cancer (CRC) patients. METHODS Pre-treatment fasting blood glucose, insulin, HbA1c and homeostasis model of risk assessment (HOMA-IR) were retrospectively evaluated in a case-control study of 224 CRC and 112 control subjects matched for sex, obesity and diabetes frequency and blood lipid profile. Furthermore, the prognostic value of routinely used glycemic parameters towards progression-free (PFS) and overall survival (OS) was prospectively evaluated. RESULTS Fasting blood glucose, insulin, HOMA-IR and HbA1c (all P < 0.0001) levels were higher in non-diabetic CRC patients compared with obesity-matched controls. All parameters were associated with increased CRC risk at ROC analysis, but no relationship with clinical-pathological variables or survival outcomes was observed for glycemia, insulinemia or HOMA-IR. Conversely, advanced CRC stage (P = 0.018) was an independent predictor of increased HbA1c levels, which were also higher in patients who had disease progression compared with those who did not (P = 0.05). Elevated HbA1c levels showed a negative prognostic value both in terms of PFS (HR = 1.24) and OS (HR = 1.36) after adjustment for major confounders, which was further confirmed in a subgroup analysis performed after exclusion of diabetic patients. CONCLUSION HbA1c might have a negative prognostic value in CRC, thus suggesting that glycemic metabolic markers should be carefully monitored in these patients, independently of overt diabetes.

e20675 Background: Increased BMI is associated with a higher risk of developing polyps and subsequently CRC. In patients (pts) with curatively resected CRC (crCRC) the relationship between post-sur...