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Background: The impact of the new chemotherapy, fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) on body composition in gastric cancer (GC) patients remains unknown. We assessed body composition changes of GC patients receiving the FLOT regimen and their impact on treatment outcomes. Methods: Preoperative pre- and post-FLOT computed tomography (CT) scans of advanced GC patients were studied. Lumbar skeletal muscle index (SMI) and adipose indices were calculated before and after FLOT. Results: A total of 26 patients were identified between April 2019 and January 2020. Nineteen patients were sarcopenic at diagnosis. The mean BMI decreased (from 24.4 ± 3.7 to 22.6 ± 3.1; p < 0.0001) as well as the SMI (from 48.74 ± 9.76 to 46.52 ± 9.98; p = 0.009) and visceral adipose index (VAI) (from 49.04 ± 31.06 to 41.99 ± 23.91; p = 0.004) during preoperative FLOT therapy. BMI, SMI, and VAI variations were not associated with toxicity, Response Evaluation Criteria in Solid Tumors (RECIST), response, delay and completion of perioperative FLOT chemotherapy, and the execution of gastrectomy; a decrease of SMI ≥ 5% was associated with a higher Mandard tumor regression grade (p = 0.01). Conclusions: Almost three-quarters (73.1%) of GC patients were sarcopenic at diagnosis. Preoperative FLOT was associated with a further reduction in SMI, BMI, and VAI. These changes were not associated with short-term outcomes.

Clinical Practice Points • Standard chemotherapy plus surgery yields to unsatisfying results in BRAF-mutated colorectal liver metastases (CLM). Combination of targeted agents (encorafenib, a BRAF inhibitor, and cetuximab, an anti-EGFR) is the new standard of care for BRAF V600E-mutated mCRC refractory to a first-line standard chemotherapy. Up to now no evidence is available concerning the activity of this novel treatment as conversion therapy in CLM setting. • Our case provides evidence, for the first time to our knowledge, of the activity of encorafenib plus cetuximab as conversion regimen for BRAF V600E-mutated CLM. Additional observations in this case report concern mechanisms underlying rapid occurrence of acquired resistance and the role of CEA serum levels as biomarker to monitor treatment activity and occurrence of resistance, allowing to optimize the timing of surgery. • Further evidence on the role of doublet targeted regimen (encorafenib plus cetuximab) as conversion treatment in the setting of BRAF-mutant CLM is warranted.

Background On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti–epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice. Patients and Methods A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type–status tissue samples, who had received a first-line anti-EGFR–based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated. Results A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of 2 prior therapy lines and a longer anti-EGFR–free interval were associated with higher ORR, but not with longer PFS or OS. Conclusion Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.

Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age &lt, 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs.

e15589 Background: R is an emerging field of research based on the extraction of a large amount of F from biomedical images and on computed analysis algorithms of tumour architecture. Few data regarding mCRC are available, in particular no correlation of baseline RF both with m sites and clinical-pathological characteristics was so far investigated. Methods: Baseline chest-abdomen CT scans of mCRC patients (pts) were retrospectively analysed. RF were extracted from Regions of Interest (ROI) delineated on CT scan from each m sites, including primary tumor, when on site. The association of specific F and disease site (liver, lung, nodes, peritoneum and on-site primary tumor) was investigated. Sites similarity was assessed with Principal Component Analysis, an unsupervised learning technique to identify patterns and clusters. Then RFs were tested individually for correlation with clinical-pathological covariates of interest (gender, CEA level, synchronous disease, RAS/BRAF status, mucinous histology, grading, number of m site, primary tumor site). Wilcoxon-Mann-Whitney test was used for this purpose (significance level set at 0.05). Results: After RF extraction from the different ROIs, the dataset was composed of 433 observations of 236 variables. Observations referred to the number (N) of pts = 89 and the N of ROIs = 18. RF classes were divided in statistical F (grey-level histogram) (N of F = 10); morphological F (N = 14); texture F GLCM (grey level co-occurrence matrix) (N = 100); texture F GLRLM (grey level run length matrix) (N = 66); texture F GLSZM (grey level size zone matrix) (N = 32). Regarding the association of RF with m sites, an homogenous distribution with liver, nodes, peritoneum and primary tumor was detected, while lung metastases showed a different pattern for all the RF classes. A significant correlation of specific RF with clinical-pathologic characteristics was shown, in particular with gender, CEA level, synchronous disease, mucinous histology, RAS/BRAF status. Conclusions: Despite its retrospective nature and the limited number of pts, this is the first experience demonstrating I) a different pattern of RF for lung m versus an homogeneous RF distribution for the other m sites; and II) a significant association of specific RF with few clinical-pathologic characteristics. Our results, if confirmed in a prospective validation set, may represent an hypothesis generator regarding the different behaviour of lung metastases and a possible R signature able to identify different prognostic subgroups of pts.

4082 Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, which a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to primary tumor site in third line. Methods: Pts affected by RAS/BRAF wt mCRC treated with third-line anti-EGFR-based tx or R/T were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to tumor site. Primary endpoint was PFS; secondary endpoints were OS and RR. PFS and OS analyses were performed using Kaplan-Meier method, and survival curves were compared using the log-rank test. RR was evaluated according to RECIST criteria and it was compared in the two groups using Fisher’s exact test. Statistical significance was set at p = 0.05 for a bilateral test. Univariate and multivariate analyses for PFS and OS were performed. Results: A total of 76 RAS/BRAF wt mCRC pts, treated with third-line anti-EGFR-based tx or R/T, were enrolled. Of those, 19 (25%) pts had R-sided tumor (9 pts received anti-EGFR tx and 10 pts received R/T) and 57 (75%) pts had L-sided tumor (30 pts received anti-EGFR tx and 27 pts received R/T). As shown in the table, a significant PFS and OS benefit in favor of anti-EGFR tx vs R/T was observed in L-sided pts, while no difference both in PFS and OS was observed in R-sided pts. RR was significantly higher in L-sided pts treated with anti-EGFR vs R/T, no difference was shown in R-sided pts. At the multivariate analysis, tx regimen was indipendently associated with PFS in L-sided pts, but not in R-sided pts. Conclusions: Our study confirmed the results deriving from the retrospective analysis of the phase III study 20020408. Our results demonstrated a different benefit from third-line anti-EGFR tx according to primary tumor site, confirming the role of L-sided tumor in predicting benefit from third-line anti-EGFR vs R/T, while no difference was observed in R-sided tumors. [Table: see text]

3556 Background: The optimal treatment for mCRC beyond 2nd line is still questioned. Recently, REG and TAS-102 showed to improve survival compared to BSC. While in real-world practice CTr/r is often considered in this setting, supporting evidences are limited. In absence of studies comparing all these strategies, we aimed to compare the prognostic performance of CTr/r, REG and TAS-102 in mCRC treated beyond 2nd line. Methods: mCRC pts progressing after at least 2 lines of CT, treated with CTr/r, REG or TAS-102 between Jan-10 and Jan-19 were considered eligible. The primary endpoint was OS; secondary endpoints were PFS and RR. Cox’s proportional hazard models for survivals were estimated. A propensity score (PS) adjustment for baseline characteristics was further accomplished for survival analysis. Results: The clinical data of 341 pts (CTr/r 133, REG 150, TAS-102 58) were retrospectively collected. At multivariate analysis type of treatment, ECOG PS, number of metastatic sites and treatment line independently correlated with OS ( p < .001, p .001, p < .001 and p .029, respectively). The mOS was 18.5 (95% CI, 14.3–22.7), 6 (95% CI, 5.6–9.5) and 7.6 months (95%CI, 5.6–9.5), for CTr/r, REG and TAS-102 group, respectively (log-rank p < .0001). mOS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (15.8 vs 7.1 months; adjusted HR 1.96, 95% CI 1.44-2.66; p < .0001) at the PS analysis, adjusted for ECOG PS, number of metastatic sites and treatment line; 2-yrs OS was 34% and 11.6% for CTr/r and REG/TAS-102, respectively. PFS was significantly longer for pts receiving CTr/r than for those treated with REG/TAS-102 (5.5 vs 3.9 months; HR 1.45, 95% CI 1.11-1.91; p .006) at the PS analysis. Accordingly, RR was higher in pts receiving CTr/r compared to REG/TAS-102 (29.0 vs 1.5%; Chi-square p < .00001). Conclusions: Our analysis, although underpowered, generates the hypothesis of a superiority of CTr/r in comparison to REG or TAS-102, in both efficacy and activity. Given the retrospective nature of our analysis, and the potential role of selection bias in treatment assignment, a prospective validation is mandatory.

e15038 Background: Right- (R) and left-sided (L) mCRCs exhibit different clinical and molecular features. Several retrospective analyses showed that the survival benefit of anti-EGFR-based tx is limited to RAS/BRAF wt L-sided mCRC pts, with a larger effect in the first-line setting. Few data are available concerning the anti-EGFR efficacy according to TL in 2nd and following lines. Methods: Pts affected by RAS/BRAF wt mCRC treated at our Institution with anti-EGFR-based tx in 2nd and following lines were retrospectively collected. The objective of the analysis was to compare tx activity and efficacy according to TL. Primary endpoint was overall survival (OS); secondary endpoints were progression free survival (PFS) and response rate (RR). Results: A total of 47 RAS/BRAF wt mCRC pts treated with an anti-EGFR-based tx in 2nd and following lines were identified. Of those, 32 (68%) were L-sided and 15 (32%) R-sided, respectively. Pts (age, gender, PS ECOG) and tumor (number of metastatic sites) characteristics and number of tx lines were well balanced between the two 21 pts received anti-EGFR alone, 26 pts anti-EGFR plus CT. mOS was 22.3 in L-sided and 7.3 months in R-sided group (HR 2.3, 95%CI 1.02-5.14, p = 0.04). At multivariate analysis TL and PS ECOG independently correlated with OS ( p = 0.02 and p =0.0089). mPFS was 8.4 and 3.9 months in pts with L-sided and R-sided tumor, respectively (HR 1.3; 95%CI 0.64-2.80, p =0.43). RR was higher in L-sided compared to R-sided tumor (37.5 vs 13.3) ( p= 0.09). Conclusions: Our analysis, although limited by the small sample and by its retrospective nature, indicates a better OS in L-sided compared to R-sided tumors treated with anti-EGFR-based tx in 2nd and following lines. A prospective validation is warranted.

e15039 Background: Unlike liver metastases surgery, the resection of colorectal cancer lung metastasis (CCLM) is not standardized and data are still poor. Therefore, we conducted a retrospective analysis to evaluate the management of CCLM at our Centre. Methods: We retrospectively analyzed patients (pts) with CCLM treated at our Institution from Jan-2007 to Jan-2017. Aim of the study was to evaluate the impact of clinical and pathological features with survival outcomes (DFS and OS). Differences were compared with the use of log-rank test and parameters considered statistically significant ( p value < 0.5) at univariate were compared at multivariate analysis. Results: 141 pts were included in the analysis. 87 pts received a preoperative chemotherapy (pCT) and 54 an adjuvant (a)CT. In the whole population median DFS (mDFS) was 24 m (20-24) and median OS (mOS) 54 m (46-82), while 21 m (20-34) and 65 m (45-108) for pts undergoing pCT and 15 m (20-28) and 53 m (38 – 76) for those receiving aCT respectively, without statistically significant differences (p=0.4). Age, gender, PS, disease-free interval (DFI) (> or 2), metastasis location (uni vs bilateral) and liver resection were evaluated at univariate and multivariate analysis. DFS was correlated with DFI > 24m (p=0.02), timing (p=0.03), number (p

3554 Background: Recently, 3 classes of BRAF MTs have been described. BRAF V600 MTs, which identify mCRC with poor prognosis and not benefitting from anti-EGFR drugs, belong to class 1. Class 2 and 3 include BRAF non-V600 MTs, which occur in about 1-2% mCRC and are associated to favourable prognosis and specific clinicopathologic features. Class 2 and 3 differ in kinase activity and sensitivity to anti-EGFR: class 2 are activated and RAS-independent MTs; class 3 are kinase-dead and sensitive to inhibition of This study aims to retrospectively evaluate features and prognostic role of rare BRAF non-V600 compared to BRAF V600E MTs in mCRC pts treated at 2 Italian Institutions. Methods: mCRC pts harboring BRAF MTs, assessed by means of NGS, pyrosequencing or RT-PCR, treated between Jan-13 and Dec-18 at 2 Italian Institutions, were retrospectively analyzed. Clinico-pathological and treatment characteristics and survival data were collected. Results: 55 pts bearing BRAF MTs were identified. Of those, 46 (84%) harbored a V600E and 9 (16%) a non-V600 MT. Within the non-V600 group, 3 MTs (K601E, G469A, G469R) belonged to class 2, while 5 MTs (G466E, G466A, 2 D594G, D594N), belonged to class 3. One pt harboured a T599I MT, whose kinase activity is unknown. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided ( p .017) and displayed a lower grade ( p .045). In addition, non-V600 mCRC pts had a lower tumor burden (involving one metastatic site) ( p .026) and underwent more frequently to resection of metastases with radical intent (77.7 vs 18%; p .000175). mOS was significantly longer in the non-V600 compared to the V600E group (61.3 vs 20.4 m; HR 0.41, 95%CI 0.18-0.93; p .05). No difference in activity and efficacy of anti-EGFR agents was observed between class 2 and 3. Conclusions: Despite the small size of our retrospective analysis, the results were consistent with previous evidences. BRAF non-V600 MTs identified a subgroup of mCRC, differing both in terms of clinicopathologic characteristics and prognosis from BRAF V600 mCRC. Interestingly, the better prognostic features allowed more frequently radical resection of metastases, positively impacting on survival.

e12665Background: The prognostic value of pathological complete response (pCR) on survival is still debated. Previous studies have revealed that breast cancer intrinsic subtypes show different mole...