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BACKGROUND: The Rome Trial is a randomized phase II trial (NCT04591431). The aim is to evaluate efficacy and safety of a tailored treatment (TT) compared to standard of care (SoC) in patients with solid tumors. Here we report the preliminary results of the molecular alterations, microsatellite status (MS) and tumor mutational burden (TMB) in metastatic breast cancer (mBC) cohort. METHODS: MBC patients who received at least 1 and no more than 2 systemic treatments were enrolled. Tissue samples were collected within 6 months from the screening. Centralized Next Generation Sequencing (NGS) was performed on both tissue and liquid biopsy. Molecular alterations were evaluated by the Molecular Tumor Board (MTB) using COSMIC, ClinVar, OncoKB and VarSome datasets. Genes with at least 10% frequency of mutation, MS and TMB are reported. RESULTS: From Oct 2020 to June 2022, 980 pts with solid tumors were enrolled. Complete screening mutational data are available for sixty-two pts from the mBC cohort (63% HR+/HER2-, 35% triple negative, 2% HR-/HER2+). NGS was available both on tissue and liquid biopsy in 48 (77%) pts, 14 had only liquid biopsy available due to tissue test failure. 328 genes resulted altered with a median of 7 alteration per pts (0-31). Some pathways were frequently altered: PIK3CA/AKT/MTOR (60%), TP53 (60%), Cell cycle/cycline (35%), FGF/FGFR (26%), BRCA1/2 (17%). The most frequent altered genes were: TP53 (61%), PIK3CA (50%), ESR1 (27%), CCND1 (27%), FGF19 (24%), FGF3 (24%), FGF4 (22%), MYC (22%), FGFR1 (21%), PTEN (21%), EMSY (16%), RB1 (14%), RAD21 (14%), TET2 (13%), BRCA2 (11%), GATA3 (11%), KRAS (10%). No pts with MSI status were reported. Eight (13%) had a high TMB (>10) and the overall median TMB was 5.5 (0-24). Median TMB was similar in tissue and liquid samples (5 and 5.3 mut/mb, p= 0.8). Actionable mutations were detected in 34 pts (54%). Twenty-eight (45%) pts were assigned to a specific TT after the MTB discussion: ipatasertib (16), pemigatinib (5), ipilimumab plus nivolumab (4), lapatinib plus trastuzumab, TDM1 and everolimus (1). MTB requested a germline test for 6 pts: 4 were confirmed (66%; 2 BRCA, 1 PALB2, 1 BRIP1). CONCLUSIONS: The extensive NGS analysis performed in the ROME trial shown that several pathways are commonly mutated in mBC, with target drug potentially available. About 15% of pts had a high TMB but MSI is confirmed as a rare event in breast cancer. Germline mutations have been identified in patients with no prior indication for germline testing. Citation Format: Andrea Botticelli, Simone Scagnoli, Pierfranco Conte, Chiara Cremolini, Paolo Antonio Ascierto, Federico Cappuzzo, Massimo Aglietta, Federica Mazzuca, Ettore Capoluongo, Giovanni Blandino, Umberto Malapelle, Marianna Nuti, Giulia D’Amati, Bruna Cerbelli, Giancarlo Pruneri, Mauro Biffoni, Giuseppe Giannini, Francesco Cognetti, Giuseppe Curigliano, Paolo Marchetti. Mutational landscape of breast cancer patients in ROME trial: preliminary results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-09.

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15–0.55; P KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.

Retrospective studies and single center experiences suggest a role of capecitabine combined with temozolomide (CAPTEM) in neuroendocrine tumors (NENs).We performed a systematic review to assess the efficacy and safety of CAPTEM in patients affected with NENs, with the aim to better clarify the role of this regimen in the therapeutic algorithm of NENs.A total of 42 articles and 1818 patients were included in our review. The overall disease control rate was 77% (range 43.5%-100%). The median progression free survival ranged from 4 to 38.5 months, while the median overall survival ranged from 8 to 103 months. Safety analysis showed an occurrence of G3-G4 toxicities in 16.4% of the entire population. The most common toxicities were hematological (27.2%), gastrointestinal (8.3%,) and cutaneous (3.2%).This systematic review demonstrated that CAPTEM was an effective and relatively safe treatment for patients with advanced well-moderate differentiated NENs of gastroenteropancreatic, lung and unknown origin.

Background/aim In local staging of gastric adenocarcinoma CT is the modality of choice. Less frequently used in a few selected patients is echo-endoscopy. Aim of this study was to evaluate the accuracy of hydro-multidetector-computed tomography (hydro-MDCT) in the evaluation of gastric adenocarcinomas with subsequent surgical and histopathological correlation to select cases for echo-endoscopy. Patients and methods A total of 65 patients with gastric adenocarcinomas, diagnosed by endoscopy and biopsy, underwent contrast-enhanced hydro-MDCT with subsequent tumor, nodes, metastases (TNM) classification. The distension of the gastric lumen was obtained after the oral administration of 500 ml of water. Results Hydro-MDCT always detected gastric cancer and in 49/65 patients the assessment of T-parameter was identical to the histopathological results (accuracy: 75%). We found overstaging in 12 and understaging in 4 cases. N-parameter with MDCT was in agreement with histo-pathology in 69%of patients; in metastatic disease hydro-MDCT had an accuracy of 99%. Hydro-MDCT has proven to be a reliable diagnostic technique in evaluating gastric cancer T3-T4 stages in comparison to T1 and T2: in defining T2-stage we found the highest number of errors (37%). Conclusion Hydro-MDCT is a reliable technique in the preoperative staging of gastric adenocarcinoma. Echo-endoscopy could be particularly useful in doubtful cases to evaluate the muscularis propria infiltration (T2 vs. T3) and characterize the peri-gastric lymph nodes.

Background Electrochemotherapy (ECT) is a minimally invasive and safe treatment gaining positive and long-lasting antitumoral results that are receiving the attention of the scientific community. It is a local treatment that combines the use of electroporation and the administration of cytotoxic drugs to induce cell death in the target tissue. ECT is largely used for the treatment of cutaneous and subcutaneous lesions, and good results have been reported for the treatment of deep visceral tumors. The latest literature review is provided. Moreover, in line with its development for the treatment of visceral tumors in this article, we describe a novel approach of ECT: endoscopic treatment of colorectal cancer. Endoscopic ECT application was combined with systemic chemotherapy in the treatment of obstructing rectal cancer without prospective surgery. A good response after ECT was described: concentric involvement of the rectum was reduced, and no stenosing lesions were detected. Conclusions Clinical studies have demonstrated that ECT is a very effective treatment for tumors of different histologic types and localizations. Endoscopic treatment for gastrointestinal cancer is an innovative application of ECT. The combination of systemic treatment and ECT was safe and highly effective in the treatment of colorectal cancer, especially when obstructive, giving the patient a significant gain in quality of life.

Background: Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution. Methods: Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis. Results: Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; P=0.09). Primary tumor site and stage were independent predictors of OS. Conclusions: Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA.

3087 Background: The Rome Trial is a randomized, prospective, multicenter, multi-basket, Phase II clinical trial (EudraCT n° 2018-002190-21; NCT04591431). The aim is to evaluate the efficacy of Tailored Therapy (TT) vs Standard of Care (SoC) in patients (pts) with metastatic solid tumors who received at least one and no more than two lines of treatment. Pts with a molecular alteration were discussed in a Molecular Tumor Board (MTB), assigned to one or a combination of the 20 available treatments, and randomized to TT or SoC. Methods: Tissue (collected within 6 months) and blood samples from pts with refractory solid tumors were analyzed centrally with next generation sequencing (NGS, FoundationOneCDx and FoundationOneLiquid). MTB discussed all screened pts with any actionable genomic alterations using common mutational database and ESCAT. Genomic data, MTB reports and treatment outcomes were collected. The 3 outcomes of the MTB were: A) assignment of a TT and randomization, B) screening failure (SF) C) SF for the trial but with relevant information from the genomic test. Outcome C was divided into 3 groups: 1) indication to receive a personalized standard treatment different from the planned one, 2) indication to access to another clinical trial/compassionate use/expanded access, 3) indication to perform a germline test (GT). Results: From Oct 2020 to Dec 2021, 497 pts were enrolled in 38 Italian accrual sites, 303 (61.0%) had relevant genomic alterations and were discussed to the MTB. Molecular profiling was determined both on tissue and liquid biopsy in 262/303 (86.5%) pts, while in 11 (3.5%) and 30 (10.0%) only on tissue or liquid, respectively. After applying clinical and molecular exclusion criteria and considering multiple actionable or resistance-conferring mutations (detected in 95 and 70 out of 303 patients): 135 pts (45%) were randomized (outcome A), 19 (30%) were SF (outcome B), and 78 (25%) SF but with an additional indication (outcome C). Of them, 14 patients (18%) were group 1 and 42 (54%) had indication to a target therapy outside from the trial (group 2). MTB suggested a GT to 60/303 pts (20%, group 3). To date, 8 out of 9 GT performed confirmed a germline mutation (4 BRCA1/2, 2 PALB2, 1 MUTHY, 1 ATM). Finally, 213 pts, 71% of those discussed to MTB and 43% of the entire screened population, were randomized or received at least one specific indication following the extended molecular assessment with NGS. Conclusions: We demonstrated the feasibility of screening a large numbers of pts from numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse to investigate combination targeted-therapy regimens. The Rome trial MTB, even when no actionable alterations were detected, provided a therapeutic and diagnostic indication with a potential impact on patient’s outcomes. Clinical trial information: NCT04591431.

Drug&ndash, drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN&reg, (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug&ndash, drug&ndash, gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC, (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) &le, 2, (iii) &ge, 5 concomitant drugs, and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN&reg, system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3&ndash, G4 toxicity. Drug-PIN&reg, software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

Drug–drug interactions (DDIs) can affect both treatment efficacy and toxicity. We used Drug-PIN® (Personalized Interactions Network) software in colorectal cancer (CRC) patients to evaluate drug–drug–gene interactions (DDGIs), defined as the combination of DDIs and individual genetic polymorphisms. Inclusion criteria were: (i) stage II-IV CRC; (ii) ECOG PS (Performance status sec. Eastern coperative oncology group) ≤2; (iii) ≥5 concomitant drugs; and (iv) adequate renal, hepatic, and bone marrow function. The Drug-PIN® system analyzes interactions between active and/or pro-drug forms by integrating biochemical, demographic, and genomic data from 110 SNPs. We selected DDI, DrugPin1, and DrugPin2 scores, resulting from concomitant medication interactions, concomitant medications, and SNP profiles, and DrugPin1 added to chemotherapy drugs, respectively. Thirty-four patients, taking a median of seven concomitant medications, were included. The median DrugPin1 and DrugPin2 scores were 42.6 and 77.7, respectively. In 13 patients, the DrugPin2 score was two-fold higher than the DrugPin1 score, with 7 (54%) of these patients experiencing severe toxicity that required hospitalization. On chi-squared testing for any toxicity, a doubled DrugPin2 score (p = 0.001) was significantly related to G3–G4 toxicity. Drug-PIN® software may prevent severe adverse events, decrease hospitalizations, and improve survival in cancer patients.

Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I&ndash, IV TCC were included in this multicenter study, clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with &le, 70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index &ge, 5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27&ndash, 25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01&ndash, 7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97&ndash, 9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98&ndash, 14.01) and BRAF mutation status (3.71, 95% CI 1.07&ndash, 12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome.

Background: The optimal anti-angiogenic strategy as second-line treatment in RAS wild-type metastatic colorectal cancer (mCRC) treated with anti-EGFR (Epidermal Growth Factor Receptor) based first-line treatment is still debated. Methods: This multicenter, real-world, retrospective study is aimed at evaluating the effectiveness of second-line Bevacizumab- and Aflibercept-based treatments after an anti-EGFR based first-line regimen. Clinical outcomes measured were: objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) profiles. Results: From February 2011 to October 2019, 277 consecutive mCRC patients received Bevacizumab-based (228, 82.3%) or Aflibercept-based (49, 17.7%) regimen. No significant difference was found regarding ORR. The median follow-up was 27.7 months (95%CI: 24.7&ndash, 34.4). Aflibercept-treated group had a significantly shorter PFS compared to Bevacizumab-treated group (5.6 vs. 7.1 months, respectively) (HR = 1.34 (95%CI: 0.95&ndash, 1.89), p = 0.0932). The median OS of the Bevacizumab-treated group and Aflibercept-treated group was 16.2 (95%CI: 15.3&ndash, 18.1) and 12.7 (95%CI: 8.8&ndash, 17.5) months, respectively (HR= 1.31 (95%CI: 0.89&ndash, 1.93) p = 0.16). After adjusting for the key covariates (age, gender, performance status, number of metastatic sites and primary tumor side) Bevacizumab-based regimens revealed to be significantly related with a prolonged PFS (HR = 1.44 (95%CI: 1.02&ndash, 2.03), p = 0.0399) compared to Aflibercept-based regimens, but not with a prolonged OS (HR = 1.47 (95%CI: 0.99&ndash, 2.17), p = 0.0503). The incidence of G3/G4 VEGF inhibitors class-specific AEs was 7.5% and 26.5% in the Bevacizumab-treated group and the Aflibercept-treated group, respectively (p = 0.0001). Conclusion: Our analysis seems to reveal that Bevacizumab-based regimens have a slightly better PFS and class-specific AEs profile compared to Aflibercept-based regimen as second-line treatment of RAS wild-type mCRC patients previously treated with anti-EGFR based treatments. These results have to be taken with caution and no conclusive considerations are allowed.

// Andrea Botticelli 1, 2 , Concetta Elisa Onesti 1, 2 , Ilaria Zizzari 3 , Bruna Cerbelli 4 , Paolo Sciattella 5 , Mario Occhipinti 1 , Michela Roberto 1, 2 , Francesca Di Pietro 1, 2 , Adriana Bonifacino 6 , Michele Ghidini 7 , Patrizia Vici 8 , Laura Pizzuti 8 , Chiara Napoletano 3 , Lidia Strigari 9 , Giulia D’Amati 4 , Federica Mazzuca 1, 2 , Marianna Nuti 3 and Paolo Marchetti 1, 2 1 Medical Oncology Department, Sant’Andrea Hospital, Rome, Italy 2 Department of Clinical and Molecular Medicine, “Sapienza” University of Rome, Rome, Italy 3 Department of Experimental Medicine, “Sapienza” University of Rome, Rome, Italy 4 Department of Radiological Oncological and Pathological Sciences, “Sapienza” University of Rome, Rome, Italy 5 Statistical Department, “Sapienza” University of Rome, Rome, Italy 6 Breast Diagnosis and Treatment Unit, Sant’Andrea Hospital, “Sapienza” University of Rome, Rome, Italy 7 Oncology Unit, ASST Cremona, Cremona, Italy 8 Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy 9 Laboratory of Medical Physics and Expert Systems, IRCCS Regina Elena National Cancer Institute, Rome, Italy Correspondence to: Concetta Elisa Onesti, email: elisaonesti@gmail.com Keywords: immune checkpoint inhibitors; anti-CTLA-4; anti-PD-1; sex differences; gender differences; Immunology Received: July 28, 2017 Accepted: October 10, 2017 Published: November 01, 2017 ABSTRACT Background: Immune checkpoint inhibitors, targeting the molecules CTLA-4, PD-1 and PD-L1, showed efficacy against several type of cancers and are currently used in clinical practice. An important biological variable that influences innate and adaptive immunity is the sex, acting through genetic, hormonal and environmental factors. The overall differences between sexes could be crucial to evaluate the response to ICIs. Materials and methods : We performed a meta-analysis of Phase II-III Clinical Trials published up to June 2017 in which anti-CTLA-4, anti-PD-1 and anti-PD-L1 were studied. We extracted the OS and PFS HR differentiated by sex from subgroups analysis of each trial. We analyzed the three classes of drugs separately. Results: We selected 36 Phase II-III Clinical Trials, 9 of which reported results for OS and 6 for PFS. We analyzed 2 Clinical Trials for OS with anti-CTLA-4, including 1178 patients, observing a benefit for males vs females (HR 0.65, 95% CI 0.55-0.77 vs HR 0.79, 95% CI 0.65-0.96, p 0.078). Not statistically significant results were observed with anti-PD-1 neither for OS (males vs females: HR 0.72, 95% CI 0.64-0.83 vs HR 0.81, 95% CI 0.70-0.94, p 0.285) neither for PFS (males vs females: HR 0.66, 95% CI 0.52-0.82 vs HR 0.85, 95% CI 0.66-1.09, p 0.158). We cannot perform a meta-analysis for anti-PD-L1 due to the lack of data. Conclusions: Different mechanisms could be involved in sex differences with regard to immunotherapy. These differences could be relevant to identify immunological targets in order to draw studies exploring novel combinations of immunotherapy agents.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

BACKGROUND Taxanes are widely used to treat breast cancer patients. Taxanes are metabolized in human liver by the cytochrome CYP3A and are substrate of ATP-binding cassette multidrug transporters ABCB1. Single-nucleotide polymorphisms (SNPs) in genes involved in taxanes' metabolism could affect the inter-individual variability in reported toxicities. MATERIALS AND METHODS In this retrospective study, 152 women, affected by breast cancer and receiving a taxane-based chemotherapy, were enrolled. A peripheral blood sample was taken for genotyping the following polymorphisms: CYP3A4* 1B (A>G), CYP3A5 *3 (G>A) and ABCB1 (C1236T; C3435T). RESULTS We observed an association between ABCB1 3435 T/T and lower grade of toxicities (p=0.05). No other association were found for CYP 3A4 *1B, 3A5*3 and ABCB1 C1236T. CONCLUSION ABCB1 3435 T/T seems to be associated to lower rate of toxicity in patients receiving taxanes. Further prospective and larger studies should be performed to clarify the role of this polymorphism.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/10 cells/min (range: 0.42-2.57 ng/ml/10 cells/min). Severe, rate-limiting toxicities (grades 3-4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.

Purpose: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy. Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. Results: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28months, P = 0.005 in BRAF mutant v BRAF wt, respectively). Conclusions: Our study demonstrated that BRAF status makes the difference in treatment’s outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.

Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose to modulate tumor microenvironment acidification thus restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). Methods: A phase II study in which patients with gastrointestinal cancer, refractory to standard treatments, who had a life expectancy &gt, 3 months, were blind randomized 1:1 to mCAP, 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg bid, three days a week. The primary endpoint was 3-months progression-free survival (PFS). The secondary endpoints were clinical benefit (CB) and overall survival (OS). Safety and plasma concentrations of capecitabine and its metabolites (5&prime, DFUR and 5-FU) were also evaluated. Results: Sixty-seven (median age 69 years, 63% male, 84% colorectal cancer, 76% ECOG-PS &pound, 1, 84% pretreated with two or more lines of chemotherapy) out of 90 patients screened for eligibility, were randomized to receive mCAP+rabeprazole (n = 32) vs. mCAP (n = 35). All patients were evaluable for response. No significant difference between mCAP+rabeprazole vs. mCAP, in terms of 3-months PFS rate (HR = 1.43, 95%CI 0.53&ndash, 3.85, p = 0.477), median PFS (HR = 1.22, 95%CI 0.75&ndash, 2.00, p = 0.420), CB (RR = 0.85, 95%CI 0.29&ndash, 2.44, p = 0.786) and median OS (HR = 0.89, 95%CI 0.54&ndash, 1.48, p = 0.664) was observed. However, a 3-year OS rate of 10% and 12% was reported in the mCAP-rabeprazole and mCAP groups, respectively. Overall, no grade 3 or 4 toxicity occurred but grade 1 or 2 adverse event of any type were more frequently in the mCAP+rabeprazole group than in the mCAP (OR 2.83, 95%CI 1.03&ndash, 7.79, p = 0.043). Finally, there was not statistically significant difference in the plasma concentration of capecitabine and its metabolites between the two groups. Conclusions: Although the adjunct of high dose rabeprazole to mCAP was not shown to affect mCAP activity, as PPI are being investigated worldwide as drugs to be repositioned in cancer treatment and also considering the limited sample size as well as the favorable safety profile of the combination in the present study, further clinical investigations are desirable.

The immune checkpoint inhibitors, a class of drugs able to block immune suppressive pathways in order to prime an anticancer immunity, revolutionized standard of care in platinum-refractory recurrent and/or metastatic head and neck carcinoma (R/M HNSCC). The PD-1/ PD-L1 axis is involved in the genesis, maintenance and progression of HNSCC and represents the target of checkpoint inhibitors. HNSCC is an immunosuppressive disease with a high inflammatory component in tumor microenvironment. Recent clinical trials showed that only a small subset of patients really benefits from immunotherapy. This review aims to highlight the five W-points of immunotherapy: why immunotherapy is promising in HNSCC, what is currently available in daily clinical practice, when immunotherapy can be integrated into the therapeutic strategy, where it can be useful according to predictive response biomarker, who, among patients, could get the best benefit from immunotherapy and how improve the achieved results.

Melanoma onset and progression are associated with a high variety of activating mutations in the MAPK-pathway, most frequently involving BRAF (35-45%) and NRAS (15-25%) genes, but also c-KIT and PTEN. Targeted therapies with BRAF and MEK inhibitors showed promising results over the past years, but it is known that most responses are temporary, and almost all of patients develop a tumor relapse within one year. Different drug-resistance mechanisms underlie the progression of disease and activation of both MAPK and PI3K/AKT/mTOR pathways. Therefore, in this article we reviewed the main studies about clinical effects of several target inhibitors, describing properly the most prominent mechanisms of both intrinsic and acquired resistance. Furthermore, suggestive strategies for overcoming drug resistance and the most recent alternative combination therapies to optimize the use of MAPK pathway inhibitors were also discussed.

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.

This multicenter retrospective study aims to evaluate the correlations between Body Weight Loss (BWL), Body Mass Index (BMI) and clinical outcomes (ORR, PFS, and OS) of advanced gastric cancer (aGC) patients treated with second-line ramucirumab-based therapy in a “real-life” setting. From December 2014 to October 2018, 101 consecutive aGC patients progressed to a first-line chemotherapy were treated with ramucirumab alone (10.9%) or in combination with paclitaxel (89.1%). Median BMI was 21.2 kg/m2 and mBWL since first-line treatment commencement was 4.5%. Among 53 patients who underwent primary tumor resection (PTR), 73.6% experienced BWL, while 26.4% did not experience BWL (p = 0.0429). Patients who underwent PTR had a significantly higher probability of experiencing BWL (yes vs no) [OR = 2.35 (95% CI 1.02–5.42), p = 0.0439]. Among the 89 evaluable patients, ORR was 26.9% (95% CI 17.2–40.1). At a median follow-up of 17.3 months, mPFS was 5.4 months (95% CI 3.6–6.8) and mOS was 8.7 months (95% CI 7.3–11.9). In the multivariate analysis, only ECOG-PS and BMI were confirmed independent predictors for shorter PFS [HR = 1.69 (95% CI 1.01–2.82), p = 0.04] [HR = 1.97 (95% CI 1.12–3.46), p = 0.01] and OS [HR = 1.69 (95% CI 1.01–2.83), p = 0.04] [HR = 2.08 (95% CI 1.17–3.70), p = 0.01]. Efficacy of ramucirumab is confirmed in this “real-life” analysis. BWL seems not to have correlations with clinical outcomes in these patients, while BMI and ECOG-PS remain major prognostic factors. A possible explanation for the lack of prognostic effect of BWL might be the proportion of patients subjected to PTR in this series (52.5%).

Purpose: Multidisciplinary approach is widely advised for an effective care of patients with neuroendocrine neoplasia (NEN). Since data on efficacy of multidisciplinary management of NENs patients in referral centers are scanty, this study aimed at analyzing the modality of presentation and clinical outcome of patients with NENs managed by a dedicated multidisciplinary team. Methods. In this prospective observational study, we included all consecutive new patients visiting the Sant&rsquo, Andrea Hospital in Rome (ENETS&mdash, Center of Excellence) between January 2014 and June 2018. Results. A total of 195 patients were evaluated. The most frequent sites were pancreas (38.5%), small bowel (22%), and lung (9.7%). Median Ki67 was 3%. After the first visit at the center, additional radiological and/or nuclear medicine procedures were requested in 163 patients (83.6%), whereas histological data revision was advised in 84 patients (43.1%) (revision of histological slides: 27.7%, new bioptic sampling: 15.4%). After that, disease imaging staging and grading was modified in 30.7% and 17.9% of patients, respectively. Overall, a change in therapeutic management was proposed in 98 patients (50.3%). Conclusions. Multidisciplinary approach in a dedicated team may lead to change of disease imaging staging and grading in a significant proportion of patients. Enhancing referral routes to dedicated-NEN center should be promoted, since it may improve patients&rsquo, clinical outcome.

Background and Aims: Sarcopenia, the loss of both lean body and skeletal muscle mass, may interfere in cancer patients outcome. As investigated, whey proteins could prevent the onset of sarcopenia. We have conducted a study to evaluate the effects of whey protein in colorectal cancer patients, undergoing 5-fluorouracil-based chemotherapy. Methods: After written informed consent, patients were blind randomized 1:1 to whey protein (ProLYOtin; arm A) versus placebo (arm B). The patients were assessed both physically and nutritionally before chemotherapy and after 3 (T2) and 6 months (T3) by body impedance assessment, L3-computed tomography scan, Mini Nutritional Assessment (MNA), and Malnutrition Universal Screening Tool (MUST) tests. Results: Forty-seven patients were included in this preliminary analysis. Baseline characteristics were well balanced between the 2 arms. During chemotherapy, 33 patients were reevaluated: anthropometric parameters (lean body mass from 68.5% to 71.2% vs 68.7% to 66.3%, and sarcopenia from 84% to 54% and 83% to 77% from baseline to T2 evaluation in arms A and B, respectively), nutritional status (MNA >24 = 100% [A] vs 73.7% [B]), and toxicity (no adverse effects in 86% [A] vs 29% [B] and 94% [A] vs 29% [B] for hematological and gastrointestinal toxicities, respectively) resulted to be significantly different. At univariate analysis, a condition of malnutrition risk according to MUST (relative risk [RR] = 7.5, P = .02) or MNA (RR = 1.45, P = .02) and ProLYOtin intake (RR = 0.12, P = .01) were found to be significantly predictive of chemotherapy toxicity. Conclusions: At present, our study shows how whey protein could be an important therapeutic option to improve nutritional status, and particularly to prevent severe toxicity during chemotherapy.

This study aimed to identify clinicopathological factors associated with the outcome of elderly patients with gastric cancer (GC), and to construct a nomogram for individual risk prediction. Tumor characteristics of 143 patients aged ≥ 80 years underwent surgery for GC were collected and analyzed by uni- and multivariate analyses. A prognostic nomogram was constructed using the factors which resulted to be significantly associated with overall survival. Discrimination of nomogram was tested by Kaplan–Meier (KM) curves and boxplots. With a median follow up of 18.37 months, overall 1-year survival rate was 51% and it was 60 and 40% for older and younger than 83 years, respectively (P = 0.003). Univariate analysis indicated that age (P = 0.008), pre-operatory performance status (P