Mismatch Repair system protein deficiency as a resistance factor for locally advanced rectal adenocarcinoma patients receiving neoadjuvant chemo-radiotherapy.

BACKGROUND: Available data on Mismatch Repair system (MMR) deficiency are conflicting and derived from small studies. Our study aimed to evaluate the therapeutic implications of MMR status in patients with locally advanced rectal cancer (LARC). METHODS: We retrospectively collected data from 318 patients affected by LARC treated in Italy at the Medical Oncology Units of the University Hospital of Cagliari, Istituto Nazionale dei Tumori Milan, and AOU Ospedali Riuniti Ancona. All patients underwent neoadjuvant chemoradiotherapy. The primary objective was major TRG while secondary objectives were pathological complete response, disease-free survival (DFS) and overall survival (OS). RESULTS: One hundred sixty patients (148 pMMR and 12 dMMR) were included in the exploratory cohort and 158 (146 pMMR and 12 dMMR) were included in the validation cohort. A major TRG has been shown in 42.6% and 43.1% patients with pMMR in exploratory and validation cohort, respectively; while no major TRG have been shown in dMMR patients in both cohorts. Exploratory and validation cohorts showed a statistically significant higher mDFS in pMMR patients compared to dMMR: NR vs. 14 months and NR vs. 17 months, respectively. CONCLUSION: Our results indicated an association between dMMR and poor response to preoperative chemoradiotherapy and they represent a hypothesis-generating data for new neoadjuvant strategies.

A multicenter study of skin toxicity management in patients with left-sided, RAS/BRAF wild-type metastatic colorectal cancer treated with first-line anti-EGFR-based doublet regimen: is there room for improvement?

BACKGROUND: Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published. AIM AND METHODS: To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months). CONCLUSION: Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients' quality of life without compromising the continuity and efficacy of antineoplastic therapy.

Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer.

OPINION STATEMENT: Advanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An "immunoscore," based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

Prospective observational study of taste assay in patients with solid tumors treated with standard chemotherapy (POTATO).

PURPOSE: The aim of our study is to evaluate taste changes in patients affected by solid tumors not involving oral cavity within the first month of standard chemotherapy. METHODS: In this monocentric, prospective, cohort study, we enrolled patients treated at our institution for different types of solid tumors between February and July 2019. Taste cotton swabs assay was used to assess taste changes. RESULTS: Thirty-one patients were enrolled and most of them had at least one change in taste. The taste that changed less was acid (42% of the population) whereas the one that changed the most was the perception of sweet (reduced in 35% of the population and increased in 45% of the population) and sour (reduced in 35% of the population). We did not find any statistical significant difference in terms of changes of taste and type of chemotherapy (emetogenic vs not, p > 0.05 for salty, sweet, bitter, and acid tastes). The type of primary tumor (breast vs GI-related) had a significant impact on perception of both salty (p = 0.0163) and acid (p = 0.0312) flavor. Furthermore, body mass composition assessed by BIA showed that obese patients had different changes in acid flavor vs non-obese patients (p = 0.04). This could not be proven when the assessment was made using BMI calculation. CONCLUSIONS: Our study suggests that type of primary tumor (GI vs breast) more than type of chemotherapy used could be relevant in determining changes in taste during chemotherapy. Individualized dietary strategies based on these reported data are suggested, as to optimize patients' management.

First-line FOLFIRI and bevacizumab in patients with advanced colorectal cancer prospectively stratified according to serum LDH: final results of the GISCAD (Italian Group for the Study of Digestive Tract Cancers) CENTRAL (ColorEctalavastiNTRiAlLdh) trial.

BACKGROUND: Previous findings suggested that bevacizumab might be able to improve response rate (RR) in colorectal cancer patients with high lactic dehydrogenase (LDH) basal levels. METHODS: We conducted a phase II trial to prospectively ascertain whether bevacizumab in combination with FOLFIRI could have an improved clinical activity in patients with high LDH serum levels. Primary end point of the study was RR; secondary end points were median overall survival and median progression-free survival (mPFS). RESULTS: A total of 81 patients were enrolled. No difference in terms of ORR (39% vs 31% for low vs high LDH level stratum, P=0.78) and mPFS (14.16 vs 10.29 months, HR: 1.07, 95% CI: 0.51-2.24, P=0.83) between the strata was observed, whereas overall survival (OS) was significantly longer for patients with low LDH (24.85 vs 15.14 months, HR: 4.08, 95% CI: 1.14-14.61, P=0.0004). In a not-pre-planned exploratory analysis using different cut-off ranges for LDH, we observed RR up to 70%, with no improvement in progression-free survival or OS. CONCLUSIONS: The CENTRAL trial failed to demonstrate that high LDH levels were related to a significantly improved RR in patients receiving first-line FOLFIRI and bevacizumab. The LDH serum levels should then no further be investigated as a predictive factor in this setting.

The role of primary tumour sidedness, EGFR gene copy number and EGFR promoter methylation in RAS/BRAF wild-type colorectal cancer patients receiving irinotecan/cetuximab.

BACKGROUND: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting. METHODS: We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months. RESULTS: Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001). CONCLUSIONS: In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies.

Outcomes of Advanced Gastric Cancer Patients Treated with at Least Three Lines of Systemic Chemotherapy.

BACKGROUND: Second-line therapy has consistently demonstrated survival benefit if compared with best supportive care; however, there is limited evidence whether further lines of treatment may improve the prognosis of advanced gastric cancer (AGC) patients. MATERIALS AND METHODS: Starting from a real-world cohort of 868 AGC patients, we retrospectively analyzed baseline parameters, tumor characteristics, and treatment data of those treated with at least three lines. Categorical features were described through cross-tables and chi-square test. We explored the impact of treatment intensity and progression-free survival (PFS) experienced in previous lines on PFS and overall survival in third-line by uni- and multivariate Cox regression models and described by Kaplan-Meier estimator plot with log-rank test. RESULTS: Overall, 300 patients were included in the analysis. The most common site of primary tumor was gastric body; 45.3% of cancers had an intestinal histotype, 14% were human epidermal growth receptor 2 positive. In third-line, 45.7% of patients received a single-agent chemotherapy, 49.7% a combination regimen. Patients who had experienced a first-line PFS ≥6.9 months had a better prognosis compared with those who had achieved a shorter one. Consistently, a second-line PFS ≥3.5 months positively influenced the prognosis. Patients receiving a third-line combination regimen had better outcomes compared with those treated with a single-agent chemotherapy. CONCLUSION: Our real-world study confirms that selected AGC patients may receive third-line treatment. Longer PFS in previous lines or a more intense third-line treatment positively influenced prognosis. Further efforts are warranted to define the best therapeutic sequences, and to identify the optimal candidate for treatment beyond second-line. IMPLICATIONS FOR PRACTICE: The benefit of third-line treatment to advanced gastric cancer patients is controversial. This study depicts a real scenario of the clinical practice in Italy, confirming that a non-negligible proportion of patients receive a third-line therapy. Longer progression-free survival in previous treatment lines or higher third-line treatment intensity positively influenced prognosis. Including a large number of real-world patients, this study provides information on third-line treatment from the daily clinical practice; moreover, its results help in defining the best therapeutic sequence and offer some hints to select the optimal candidate for treatment beyond second-line.

Mismatch repair deficiency may affect clinical outcome through immune response activation in metastatic gastric cancer patients receiving first-line chemotherapy.

INTRODUCTION: The microsatellite-instable gastric cancer subtype, because of its supposed high antigenic potential, is a promising candidate for immunotherapy. We analyzed if the presence of a defective mismatch repair (MMR) system is associated with other markers of immune response and their relationship with outcome in advanced gastric cancer patients. METHODS: We analyzed the relationship between clinical outcome and MMR status, the presence of tumor-infiltrating lymphocytes (TIL), lymphocytosis, and neutrophil-to-lymphocyte ratio (NLR) in metastatic gastric cancer patients treated with a chemotherapy doublet in the first-line setting. Other stratification factors were sex, age, Eastern Cooperative Oncology Group performance status, adjuvant/neoadjuvant chemotherapy, metastatic sites, and histotype. RESULTS: One hundred three patients were eligible for analysis. Defective MMR was found in 15 patients (14 %), TILs were found in 18 patients (17 %), lymphocytosis was found in 24 patients (23 %), and high NLR was found in 75 patients (72 %). Significant correlations were found between defective MMR and TIL positivity (p = 0.0004), between defective MMR and lymphocytosis (p = 0.0062), between defective MMR and low NLR (p = 0.000069), and between TIL positivity and lymphocytosis (p = 0.000147). All factors had a statistically significant impact on overall survival, although on multivariate analysis only defective MMR (p = 0.0001) and TIL positivity (p = 0.0192) maintained their independent prognostic role. Similar results were observed for progression-free survival, with defective MMR (p = 0.0001) and TIL positivity (p = 0.0195) maintaining their prognostic role on multivariate analysis. CONCLUSIONS: Our analysis confirms the favorable prognosis of metastatic gastric cancer patients with a defective MMR system and suggests that expression of TILs might also be linked to better outcome. Because of the correlation between defective MMR status and measures of immune system activity, this group of patients would be the best candidates for novel immunotherapy-based therapies.

Prognostic factors in 868 advanced gastric cancer patients treated with second-line chemotherapy in the real world.

BACKGROUND: Although second-line therapy is often considered for advanced gastric cancer patients, the optimal candidates are not well defined. METHODS: We retrospectively collected baseline parameters, tumour features, and treatment data for 868 advanced gastric cancer patients exposed to multiple treatment lines at 19 Italian centres. Cross-tables and chi-square tests were used to describe categorical features. To predict the impact of clinical variables on progression-free survival and overall survival, Kaplan-Meier and Cox regression analyses were performed. RESULTS: At the start of second-line therapy, median age was 64.8 years (25th-75th percentiles: 55.2-71.9 years). Overall, 43% of patients received single-agent chemotherapy, 47.4% a doublet, and 7.3% a triplet. Median second-line progression-free survival was 2.8 months (25th-75th percentiles: 1.8-5.2 months) and median second-line overall survival was 5.6 months (25th-75th percentiles: 2.9-10.0 months). Multivariate analysis showed that performance status, LDH level, neutrophils/lymphocytes ratio, and progression-free survival in the first-line therapy all impacted on prognosis. Based on these four prognostic factors, a prognostic index was constructed that divided patients into good, intermediate, and poor risk groups; median second-line overall survival for each group was 7.7, 4.5, and 2.0 months, respectively (log-rank p < 0.0001). CONCLUSIONS: Advanced gastric cancer patients with a favourable ECOG performance status, lower LDH levels, and a lower neutrophils/lymphocytes ratio at the start of second-line therapy seem to have better outcomes, regardless of age and intensity of treatment. A longer progression-free survival in the first-line therapy also had positive prognostic value. Our real-life study might help clinicians to identify the patients who may benefit most from a second-line therapy.

Selecting patients for gastrectomy in metastatic esophago-gastric cancer: clinics and pathology are not enough.

AIM: To evaluate the impact on overall survival (OS) of gastrectomy in asymptomatic metastatic esophago-gastric cancer. PATIENTS & METHODS: Five hundred and thirteen patients were included. The role of surgery and other clinico-pathological factors was evaluated by univariate and Cox regression analyses. OS was the primary end point. RESULTS: Multivariate analysis confirmed that gastrectomy was a predictor of longer OS (p < 0.001), as well as preserved performance status and benefit from first-line chemotherapy. None of the investigated clinico-pathological variables identified preferable candidates for surgery (all p > 0.05). CONCLUSION: Palliative gastrectomy might play a role in asymptomatic metastatic esophago-gastric cancer patients with good performance status who received benefit from first-line chemotherapy. Future prospective trials integrating tumor biology among inclusion criteria may help defining the optimal candidates.

Prospective study of a molecular selection profile for RAS wild type colorectal cancer patients receiving irinotecan-cetuximab.

BACKGROUND: The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed might be able to predict patients' clinical outcome more accurately than RAS status alone. METHODS: K-RAS (exons 2, 3, 4) wild type colorectal cancer patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated into 2 groups on the basis of their profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) or unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible. Primary aim was response rate (RR). To detect a difference in terms of RR among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%), with a probability alpha of 0.05 and beta of 0.05, required sample size was 46 patients. Secondary endpoints were progression free survival (PFS) and overall survival (OS). RESULTS: Forty-six patients were enrolled. Seventeen patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p = 0.007) respectively. The favourable group also showed an improved PFS (8 months vs. 3 months, p < 0.0001) and OS (15 months vs. 6 months, p < 0.0001). CONCLUSIONS: Our results suggest that prospective selection of optimal candidates for cetuximab treatment is feasible and may be able to improve clinical outcome.

[Treatment of pancreatic cancer. Actuality and perspective]. / Trattamento del carcinoma del pancreas. Attualità e prospettive.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest solid malignancies, with an extremely poor prognosis, with a 1-year survival rate of approximately 20%. Low survival rates of PDAC mainly derive from late diagnosis, with only a minority of patients amenable to surgery, as well as high rates of relapse and lack of effective treatments for advanced disease stages. As a result, there is an urgent need for the development of new effective therapies. At present, the greatest step towards an improvement of treatment has been made with the introduction of two combination chemotherapy regimens, namely FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. However, current research is also taking a multidirectional approach aiming at developing new treatment options, such as the use of agents targeting the oncogenic network signaling of KRAS or the extracellular matrix, as well as immune therapies.

VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study.

Although new treatment modalities changed the global approach to hepatocellular carcinoma (HCC), this disease still represents a medical challenge. Currently, the therapeutic stronghold is sorafenib, a tyrosine kinase inhibitor (TKI) directed against the vascular endothelial growth factor (VEGF) family. Previous observations suggested that polymorphisms of VEGF and its receptor (VEGFR) genes may regulate angiogenesis and lymphangiogenesis and thus tumour growth control. The aim of our study was to evaluate the role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib. From a multicentre experience 148 samples (tumour or blood samples) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients' progression-free survival (PFS) and overall survival (OS) were analysed. At univariate analysis VEGF-A alleles C of rs25648, T of rs833061, C of rs699947, C of rs2010963, VEGF-C alleles T of rs4604006, G of rs664393, VEGFR-2 alleles C of rs2071559, C of rs2305948 were significant predictors of PFS and OS. At multivariate analysis rs2010963, rs4604006 and BCLC (Barcelona Clinic Liver Cancer) stage resulted to be independent factors influencing PFS and OS. Once prospectively validated, the analysis of VEGF and VEGFR SNPs may represent a clinical tool to better identify HCC patients more likely to benefit from sorafenib. On the other hand, the availability of more accurate predictive factors could help avoiding unnecessary toxicities to potentially resistant patients who may be optimal candidates for different treatments interfering with other tumour molecular pathways.

The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management.

BACKGROUND: In many tumour types serumlactate dehydrogenase (LDH) levels proved to represent an indirect marker of tumour hypoxia, neo-angiogenesis and worse prognosis. As we previously reported LDH is an important predictive factor in hepatocellular carcinoma (HCC) patients undergoing transarterial chemoembolization (TACE). Sorafenib represents the therapeutic stronghold in advanced HCC patients. As a tyrosine kinase inhibitor (TKI) mainly directed against the angiogenetic pathway, the correlation of sorafenib administration with markers of hypoxia could be an important tool in patients management. Aim of our analysis was to evaluate the role of LDH pre-treatment levels and its variation during treatment in HCC patients receiving sorafenib. METHODS: 78 patients were available for our analysis. For all patients LDH values were collected within one month before the start of treatment and after the end of therapy. For study purposes we divided our patients into two groups, according to LDH pre-treatment levels, cut-off levels was determined with ROC curve analysis. Patients were, also, classified according to the variation in LDH serum levels pre- and post-treatment (increased vs decreased). RESULTS: Patients proved homogeneous for all clinical characteristics analyzed. In patients with LDH values under the cut-off median progression free survival (PFS) was 6.7 months, whereas it was 1.9 months in patients above the cut-off (p = 0.0002). Accordingly median overall survival (OS) was 13.2 months and 4.9 months (p = 0.0006). In patients with decreased LDH values after treatment median PFS was 6.8 months, and median OS was 21.0 months, whereas PFS was 2.9 months and OS 8.6 months in patients with increased LDH levels (PFS: p = 0.0087; OS: p = 0.0035). CONCLUSIONS: In our experience, LDH seemed able to predict clinical outcome in terms of PFS and OS for HCC patients treated with sorafenib. Given the correlation between LDH levels and tumour angiogenesis we can speculate that patients with high LDH pretreatment levels may be optimal candidates for other emerging therapeutic agents or strategies targeting different molecular pathways.

Selected news from the 2014 Genitourinary Cancers Symposium: translating novel strategies into clinical practice.

2014 Genitourinary Cancers Symposium San Francisco, CA, USA, 30 January-1 February 2014 The American Society of Clinical Oncology symposium dedicated to genitourinary tumors represents an unmissable opportunity for the whole oncology community with a special interest in the diagnosis and treatment of genitorurinary tract malignancies, in particular kidney and prostate tumors. The 2014 Genitourinary Cancers Symposium focused attention on the need to find a personalized therapy for metastatic renal cell carcinoma and castration-resistant prostate cancer patients. The development of biomarkers for tumor response and/or resistance will represent a major step in this context and has been the focus of several researches at the symposium.

Translational challenges from the 2014 Gastrointestinal Cancers Symposium: toward a true tailored therapy through effective research.

Gastrointestinal Cancers Symposium 2014, San Francisco, CA, USA, 16-18 January 2014. The Gastrointestinal Cancers Symposium represents an indisputable occasion for sharing results and research opportunities for investigators around the globe. Across the years along with clinical trials presentations the meeting increasingly acquired a distinct role as a scientific arena for translational research. Also, this year the need for predictive markers for first-generation targeted agents and research about novel biologically driven therapeutic options characterized most of the studies presented. We focus here on reports from the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium indicating an opportunity for biological selection of either the pharmacological target or the patient population in order to enhance clinical outcome.

The role of micro-RNAs in hepatocellular carcinoma: from molecular biology to treatment.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer deaths. microRNAs (miRNAs) are evolutionary conserved small non-coding RNA that negatively regulate gene expression and protein translation. Recent evidences have shown that they are involved in many biological processes, from development and cell-cycle regulation to apoptosis. miRNAs can behave as tumor suppressor or promoter of oncogenesis depending on the cellular function of their targets. Moreover, they are frequently dysregulated in HCC. In this review we summarize the latest findings of miRNAs regulation in HCC and their role as potentially diagnostic and prognostic biomarkers for HCC. We highlight development of miRNAs as potential therapeutic targets for HCC.

Pemigatinib for patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements: A joint analysis of the French PEMI-BIL and Italian PEMI-REAL cohort studies.

BACKGROUND: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting. MATERIAL AND METHODS: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included. RESULTS: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs. CONCLUSIONS: These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

Role of ß4 integrin in HER-3-negative, K-RAS wild-type metastatic colorectal tumors receiving cetuximab.

AIMS: Altered α6ß4 integrin expression has been demonstrated in HER-3-negative tumors and may be responsible for anti-HER treatment resistance. The current study aimed to evaluate the interaction between polymorphisms of α6 and ß4 integrins and clinical outcome in HER-3-negative, K-RAS wild-type colorectal cancer patients receiving cetuximab. PATIENTS & METHODS: K-RAS analysis was performed via direct sequencing, HER-3 was evaluated by immunohistochemistry and genotyping of α6 and ß4 integrins was performed by real-time PCR. RESULTS: An univariate analysis, the ß4 rs8669, rs871443 and rs9367 polymorphisms correlated with progression-free and overall survival. On multivariate analysis, only the ß4 rs8669 maintained an independent role in influencing progression-free survival. CONCLUSION: We believe that ß4 rs8669 genotyping may help to identify a subgroup of HER-3-negative, K-RAS wild-type colorectal cancer patients who are more likely to benefit from anti-EGFR treatment. Our findings could also be relevant in planning future trials testing treatment strategies against the integrin-activated molecular pathways.