Claudin 18.2 as a New Biomarker in Gastric Cancer-What Should We Know?

Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.

Current clinical practice in the management of Brazilian patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC).

BACKGROUND AND OBJECTIVES: We aimed to describe the routine clinical practice of physicians involved in the treatment of patients with localized pancreatic ductal adenocarcinoma (PDAC) in Brazil. METHODS: Physicians were invited through email and text messages to participate in an electronic survey sponsored by the Brazilian Gastrointestinal Tumor Group (GTG) and the Brazilian Society of Surgical Oncology (SBCO). We evaluated the relationship between variable categories numerically with false discovery rate-adjusted Fisher's exact test p values and graphically with Multiple Correspondence Analysis. RESULTS: Overall, 255 physicians answered the survey. Most (52.5%) were medical oncologists, treated patients predominantly in the private setting (71.0%), and had access to multidisciplinary tumor boards (MTDTB; 76.1%). Medical oncologists were more likely to describe neoadjuvant therapy as beneficial in the resectable setting and surgeons in the borderline resectable setting. Most physicians would use information on risk factors for early recurrence, frailty, and type of surgery to decide treatment strategy. Doctors working predominantly in public institutions were less likely to have access to MTDTB and to consider FOLFIRINOX the most adequate regimen in the neoadjuvant setting. CONCLUSIONS: Considerable differences exist in the management of localized PDAC, some of them possibly explained by the medical specialty, but also by the funding source of health care.

Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure.

Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer-related mortality, and it is expected to play an even bigger part in cancer burden in the years to come. Despite concerted efforts from scientists and physicians, patients have experienced little improvement in survival over the past decades, possibly because of the non-specific nature of the tested treatment modalities. Recently, the discovery of potentially targetable molecular alterations has paved the way for the personalized treatment of PDAC. Indeed, the central piece in the molecular framework of PDAC is starting to be unveiled. KRAS mutations are seen in 90% of PDACs, and multiple studies have demonstrated their pivotal role in pancreatic carcinogenesis. Recent investigations have shed light on the differences in prognosis as well as therapeutic implications of the different KRAS mutations and disentangled the relationship between KRAS and effectors of downstream and parallel signaling pathways. Additionally, the recognition of other mechanisms involving KRAS-mediated pathogenesis, such as KRAS dosing and allelic imbalance, has contributed to broadening the current knowledge regarding this molecular alteration. Finally, KRAS G12C inhibitors have been recently tested in patients with pancreatic cancer with relative success, and inhibitors of KRAS harboring other mutations are under clinical development. These drugs currently represent a true hope for a meaningful leap forward in this dreadful disease.

Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas.

OBJECTIVE: To better understand the immune microenvironment of pancreatic ductal adenocarcinomas (PDACs), here we explored the relevance of T and B cell compartmentalisation into tertiary lymphoid structures (TLSs) for the generation of local antitumour immunity. DESIGN: We characterised the functional states and spatial organisation of PDAC-infiltrating T and B cells using single-cell RNA sequencing (scRNA-seq), flow cytometry, multicolour immunofluorescence, gene expression profiling of microdissected TLSs, as well as in vitro assays. In addition, we performed a pan-cancer analysis of tumour-infiltrating T cells using scRNA-seq and sc T cell receptor sequencing datasets from eight cancer types. To evaluate the clinical relevance of our findings, we used PDAC bulk RNA-seq data from The Cancer Genome Atlas and the PRINCE chemoimmunotherapy trial. RESULTS: We found that a subset of PDACs harbours fully developed TLSs where B cells proliferate and differentiate into plasma cells. These mature TLSs also support T cell activity and are enriched with tumour-reactive T cells. Importantly, we showed that chronically activated, tumour-reactive T cells exposed to fibroblast-derived TGF-ß may act as TLS organisers by producing the B cell chemoattractant CXCL13. Identification of highly similar subsets of clonally expanded CXCL13 + tumour-infiltrating T cells across multiple cancer types further indicated a conserved link between tumour-antigen recognition and the allocation of B cells within sheltered hubs in the tumour microenvironment. Finally, we showed that the expression of a gene signature reflecting mature TLSs was enriched in pretreatment biopsies from PDAC patients with longer survival after receiving different chemoimmunotherapy regimens. CONCLUSION: We provided a framework for understanding the biological role of PDAC-associated TLSs and revealed their potential to guide the selection of patients for future immunotherapy trials.

Current Treatment of Potentially Resectable Pancreatic Ductal Adenocarcinoma: A Medical Oncologist's Perspective.

Pancreatic cancer has traditionally been associated with a dismal prognosis, even in early stages of the disease. In recent years, the introduction of newer generation chemotherapy regimens in the adjuvant setting has improved the survival of patients treated with upfront resection. However, there are multiple theoretical advantages to deliver early systemic therapy in patients with localized pancreatic cancer. So far, the evidence supports the use of neoadjuvant therapy for patients with borderline resectable pancreatic cancer. The benefit of this treatment sequence for patients with resectable disease remains elusive. In this review, we summarize the data on adjuvant therapy for pancreatic cancer and describe which evidence backs the use of neoadjuvant therapy. Additionally, we address important issues faced in clinical practice when treating patients with localized pancreatic cancer.

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications.

Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60-70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10-15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.

Evaluation of prognostic factors in patients undergoing first-line chemotherapy for advanced biliary tract cancer: a retrospective analysis from a South American cancer centre.

INTRODUCTION: Biliary tract cancers (BTCs) are rare tumours with regional differences. Prognostic factors are poorly understood. Gemcitabine + platinum (GP) is the standard first-line chemotherapy in metastatic patients. We aimed to search for prognostic factors in patients with advanced disease in a cancer centre in South America. METHODS: We conducted a retrospective analysis of patients with advanced BTC treated with chemotherapy. Variables were age (< or ≥70 years), Eastern Cooperative Oncology Group (ECOG) performance status (0/1 versus 2/3), gender, primary site (intrahepatic (IHC), extrahepatic (EHC), gallbladder (GB)), staging (locally advanced versus metastatic), metastatic sites, albumin (>3.5 g/dL versus <3.5 g/dL), biliary obstruction and first-line chemotherapy (GP, 5FU-based or single-agent). Cox regression method was used to explore factors. RESULTS: From 2010 to 2017, 104 patients were included. Median age was 62 years (32-86) and 22.1% were older than 70 years. Most patients had ECOG performance status 0/1 (63.4%), were female (51.9%) and were metastatic (82.7%). Bone metastases were found in 19.2%. Primary IHC, EHC and GB were 54.8%, 36.5% and 8.7%, respectively. GP was used by 79.8%. Median follow-up was 32.4 months. Median overall survival (mOS) was 11.4 months. In univariate analysis, male (p = 0.007), albumin < 3.5 g/dL (p = 0.001), biliary obstruction (p = 0.006), 5FU-based (p = 0.006) and single-agent (p < 0.0001) were associated with worse OS. ECOG performance status 2/3 (p = 0.058) and bone metastases (p = 0.051) were marginally related. In multivariate analysis, male (p = 0.003), bone metastases (p = 0.023), biliary obstruction (p = 0.001), 5FU-based (p = 0.016) and single-agent (p = 0.023) were independently associated with inferior OS. CONCLUSION: In this retrospective study, we observed that male patients, bone metastases, biliary obstruction and regimens other than GP had worse survival. Larger studies should be conducted to confirm our findings.

Short-term survival of patients with advanced pancreatic cancer admitted to intensive care unit: a retrospective cohort study.

Background: Little is known about the outcomes of patients with advanced pancreatic cancer admitted to the intensive care unit (ICU) due to medical complications. We designed a study to evaluate their short-term (30-day) survival, predictors of short-term survival and chances of additional chemotherapy. Methods: We reviewed all patients with advanced (stage III or IV) pancreatic adenocarcinoma admitted to an ICU in a dedicated Brazilian cancer centre from 2009 to 2018 due to medical reasons. We fitted multivariate regression models to identify predictors of 30-day survival and additional systemic chemotherapy. Results: The study population consisted of 171 patients. Ninety-four patients (55.0%) had Eastern Cooperative Oncology Group (ECOG) performance status 2-4 and 146 (85.4%) had metastatic disease. Most patients (N = 75; 43.9%) were admitted to the ICU during first-line treatment. Median overall survival was 32 days (95% confidence interval (95% CI): 20-49). Survival rate at 30 days was 50.6%. ECOG performance status 2-4 was the only variable associated with lower probability of survival at 30 days in multivariate analysis (odds ratio: 0.28; 95% CI: 0.14-0.54; p < 0.001). Overall, 58 patients (33.9%) received additional chemotherapy and among all patients, 13.5% experienced clinical benefit from this treatment. Conclusion: Patients with advanced pancreatic cancer admitted to the ICU for medical reasons have a dismal prognosis. Early palliative care and refined tools to establish those who would benefit from an ICU trial could help improve patients' care.

Erratum: Comparative efficacy of modified FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine plus nab-paclitaxel as adjuvant treatment for resected pancreatic cancer: a Bayeasian network meta-analysis.

[This corrects the article on p. 1 in vol. 15.].

Comparative efficacy of modified FOLFIRINOX, gemcitabine plus capecitabine and gemcitabine plus nab-paclitaxel as adjuvant treatment for resected pancreatic cancer: a Bayesian network meta-analysis.

BACKGROUND: There are no head-to-head comparisons evaluating the efficacy of the main polychemotherapy regimens used for patients with pancreatic cancer in the adjuvant setting. We aimed to describe the relative efficacy of modified FOLFIRINOX (mFOLFIRINOX), gemcitabine plus capecitabine (GEM-CAP) and gemcitabine plus nab-paclitaxel (GEM-NAB) in this setting using a Bayesian network approach. METHODS: We collected data from the ESPAC-4, PRODIGE 24 and APACT trials. Disease-free survival (DFS), according to the investigators, and overall survival (OS) for the three polychemotherapy regimens were compared using gemcitabine as the reference arm. We ran Markov chain Monte Carlo simulations with a fixed-effect model to generate the posterior distribution of the hazard ratios (HRs) using non-informative priors. Relative efficacy was measured by HRs, surface under cumulative ranking and rankograms. RESULTS: mFOLFIRINOX was the chemotherapy regimen most likely to be the most effective in the adjuvant setting (98.9% and 89.6% probability for DFS and OS, respectively). GEM-NAB marginally improved DFS (HR = 0.97, 95% credible interval (95% CrI) = 0.77-1.21) and OS (HR = 0.98, 95% CrI = 0.76-1.25) when compared to GEM-CAP. However, GEM-NAB had the highest chances of being the second most active chemotherapy regimen (61.4% and 52.5% probability for DFS and OS, respectively), whereas GEM-CAP was less likely to represent the second most active regimen (37.7% and 40.1% probability for DFS and OS, respectively). CONCLUSION: For patients eligible and fit enough to undergo adjuvant treatment with mFOLFIRINOX, this constitutes the treatment of choice. For those with contraindications to mFOLFIRINOX, while both GEM-NAB and GEM-CAP can be considered appropriate alternatives, GEM-NAB is likely the most effective regimen.

Disparities in access to health care system as determinant of survival for patients with pancreatic cancer in the State of São Paulo, Brazil.

Little is known about the features and outcomes of Brazilian patients with pancreatic cancer. We sought to describe the socio-economic characteristics, patterns of health care access, and survival of patients diagnosed with malignant pancreatic tumors from 2000 to 2014 in São Paulo, Brazil. We included patients with malignant exocrine and non-classified pancreatic tumors according to the International Classifications of Disease (ICD)-O-2 and -O-3, diagnosed from 2000 to 2014, who were registered in the FOSP database. Prognostic factors for overall survival (OS) in the subgroup of patients with ductal or non-specified (adeno)carcinoma were evaluated using Cox proportional hazard model. The study population consists of 6855 patients. Median time from the first visit to diagnosis and treatment were 13 (Interquartile range [IQR] 4-30) and 24 (IQR 8-55) days, respectively. Both intervals were longer for patients treated in the public setting. Median OS was 4.9 months (95% confidence interval [95% CI] 4.7-5.2). Increasing age, male gender, lower educational level, treatment in the public setting, absence of treatment, advanced stage, and treatment from 2000 to 2004 were associated with inferior OS. From 2000-2004 to 2010-2014, no improvement in OS was seen for patients treated in the public setting. Survival of patients with malignant pancreatic tumors remains dismal. Socioeconomical variables, especially health care funding, are major determinants of survival. Further work is necessary to decrease inequalities in access to medical care for patients with pancreatic cancer in Brazil.

Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients.

INTRODUCTION: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. METHODS: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3-5) infections in univariate and multivariable logistic regression models. RESULTS: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2-40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8-30.4) having a serious infection and 7 (6.3%; 95% CI 2.6-12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02-1.60; p = 0.03) as an independent risk factor for serious infection. CONCLUSION: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.

Clinical factors related to severe enterocolitis after adjuvant CAPOX for colorectal cancer: a retrospective analysis.

BACKGROUND: CAPOX regimen is a standard option in stage III adjuvant colon cancer. Gastrointestinal toxicity is well described with fluoropyrimidine regimens and can be life-threatening. Identification of risk factors associated with severe gastrointestinal toxicity may help clinicians when choosing the adjuvant regimen. MATERIALS AND METHODS: We retrospectively analysed 61 patients treated with adjuvant CAPOX. Our primary objective was to estimate the incidence of severe chemotherapy-induced enterocolitis among patients treated with CAPOX. A secondary objective was to describe the main demographic and clinical characteristics of these patients. A univariate logistic regression was performed to estimate the odds ratio (OR) with a 95% CI to identify a predictor for severe enterocolitis. RESULTS: Grade 3 diarrhoea was reported in 10 patients (16.3%). Admissions to hospital due to toxicity occurred in nine cases. Reasons for hospitalisation were severe enterocolitis in eight cases (13.1%) and rectal bleeding plus thrombocytopenia in one case. Age > 70 years (OR 9.6; 95% CI 1.81-50.6; p = 0.008), primary surgery involving right/transverse colon (OR 16.8; 95% CI 2.88-98.8; p = 0.002) and Angiotensin II Receptor Blocker (ARB) use (OR 8.14; 95% CI 1.64-40.3; p = 0.010) were associated with severe enterocolitis. CONCLUSION: Our data showed that adjuvant CAPOX induced severe enterocolitis in 13.1% of patients. In addition, we found that advanced age, right colectomy and concurrent use of ARB were statistically associated with these events. Awareness of these factors could be easily incorporated into the treatment decision and patient orientation.

Primary Tumor Location Is a Predictor of Poor Prognosis in Patients with Locally Advanced Esophagogastric Cancer Treated with Perioperative Chemotherapy.

BACKGROUND: Esophagogastric cancer (EGC) is a leading neoplasm worldwide. Perioperative chemotherapy (periCT) is currently a standard of care for most patients (pts). Prevalence of esophagogastric junction (EGJ) tumors is increasing over the last years. METHODS: The aim of this study was to retrospectively search for prognostic factors in pts. with locally advanced EGC treated with periCT. Three-year overall survival (OS) and Event-Free Survival (EFS) were main end-points. HER-2 positive tumors were defined by immunohistochemistry or FISH. RESULTS: Between June/2007 and November/2015, 128 pts. started periCT for esophagogastric junction (EGJ) or gastric adenocarcinoma (GC). Median age was 59.5 y and 64% were male. Primary site was EGJ in 27% and 65% were cN+. Diffuse subtype was seen in 42%. Ninety-seven pts. were assessed for HER-2; 14 (14.4%) were positive. After median follow-up time of 45 m, 48 deaths occurred. The 3-year OS and EFS rate was 61.3% and 51.2%, respectively. Main prognostic factors were: AJCC ypT3-T4yN1-N3 (HR 6.75 p 0.002) and EGJ primary (HR 2.64, p 0.004). Overall HER-2 was not prognostic. Still, a difference in 3-year OS was observed for GC/HER2+ compared to EGJ/HER2+ (88.9% versus 20%, p = 0.002). This difference is greater for 3-year EFS with no patient with EGJ/HER2+ free-of-event against 62.5% for GC/HER+ (p = 0.011). CONCLUSION: In our analysis, pathological staging and primary site were main prognostic factors. Moreover, a small group of EGJ/HER2+ had very poor survival.

A modified recursive partitioning analysis for predicting overall survival in patients with non-small cell lung cancer and central nervous system metastases.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a major cause of brain metastases. Nonetheless, patients with central nervous system (CNS) spread are poorly represented in clinical trials. We sought to evaluate the overall survival (OS) of patients with NSCLC and CNS metastases. METHODS: Patients with NSCLC and CNS metastases treated at A. C. Camargo Cancer Center from January 2007 to December 2017 were selected. The primary endpoint was OS following the diagnosis of CNS metastasis. The Kaplan-Meier method was applied to calculate OS. Prognostic factors were assessed by the Cox Proportional Hazards model. As an exploratory analysis, a survival tree was generated based upon the two most statistically significant variables in the multivariate model and one additional clinically meaningful variable. RESULTS: In total, 311 patients were included. Median OS was 10.3 months (95% CI, 8.7-13.1 months). ECOG performance status 2-4 (HR 2.12; 95% CI, 1.40-3.20; P<0.01) and the absence of a driver mutation (HR 3.30; 95% CI, 1.85-5.90; P<0.01) were strongly associated with worse OS. A Modified Recursive Partitioning Analysis (mRPA) was developed based on the curves generated by the survival tree. mRPA stratified our cohort in four subgroups with significantly different OS (3.1 to 43 months) and it outperformed both RPA and GPA in predicting OS in our population. CONCLUSIONS: OS in our cohort was better than previously reported. However, prognosis is widely variable and is mostly dictated by performance status and the presence of a driver mutation.

Characteristics and survival of older patients with metastatic pancreatic cancer: a retrospective analysis of the AC Camargo Cancer Center experience.

BACKGROUND: Advanced age is the most important risk factor for pancreatic cancer and about half of patients are diagnosed with metastatic disease. In the first-line setting, multidrug chemotherapy regimens were shown to be more effective than gemcitabine alone. However, the older population was under-represented in randomized clinical trials. We aimed to describe the clinical profile of older patients with metastatic pancreatic cancer and their survival outcomes. MATERIALS AND METHODS: This was a retrospective, unicentric study that included patients diagnosed with metastatic pancreatic cancer (non-neuroendocrine), aged 65 years and over. RESULTS: The study population comprised 196 patients. The median age was 73 years; 67% of these patients presented Eastern Cooperative Oncology Group performance status (ECOG) ⩽ 1 and the median Charlson Comorbidity score was 10. Chemotherapy was given to 89% of the patients. The most frequently used chemotherapy regimens were gemcitabine (44%), 5-fluorouracil and oxaliplatin [FOLFOX; 26%], and 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX; 20%). Patients treated with FOLFIRINOX were younger and they presented better performance status. After a median follow up of 19.8 months, the median overall survival (OS) was of 7.2 months and the median time to first-line-treatment failure was 4.6 months. Among patients treated with chemotherapy, the median OS was highest for those treated with FOLFIRINOX (13.8 months), as compared with FOLFOX (7.0 months) or gemcitabine (6.7 months); p = 0.004. Nonetheless, treatment with FOLFIRINOX was associated with increased risk of severe toxicity (p = 0.008). CONCLUSION: Older patients with metastatic pancreatic cancer benefit from palliative chemotherapy, and FOLFIRINOX is a therapeutic option in rigorously selected older patients.

Survival outcomes of patients with pathological stage I gastric cancer using the competing risks survival method.

BACKGROUND: Patients with stage I gastric cancer are considered to have an exquisite prognosis. Nonetheless, the fact that some patients experience disease relapse highlights that a subgroup might benefit from multimodality treatment. We aimed to evaluate the survival of patients with stage I gastric cancer and look for harbingers of gastric cancer recurrence. METHODS: We looked for patients with stage I gastric cancer treated exclusively with surgery from 1996 to 2015. The competing risks survival method was used to allow for concurrent causes of mortality. Also, we calculated subdistribution hazards (SH) to reveal factors associated with cancer recurrence and death from unrelated causes. RESULTS: A total of 185 patients constitute the study population. Thirty-seven patients had pT2N0 tumors. Most patients (80.5%) were treated with D2 lymphadenectomy. The probability of relapse at 5 years was 3.0% and 8.6% in the study population and the pT2N0 subgroup, respectively. Among all 26 deaths, only six were related to gastric cancer. In multivariate analysis, perineural invasion (PNI) was associated with increased risk of gastric cancer recurrence. CONCLUSIONS: The prognosis of stage I gastric cancer treated with D2 lymphadenectomy is excellent. PNI may indicate higher likelihood of recurrence. Further work in this field should account for the higher risk of death from unrelated causes.

Retrospective analysis of efficacy and safety of Gemcitabine-based chemotherapy in patients with metastatic pancreatic adenocarcinoma experiencing disease progression on FOLFIRINOX.

BACKGROUND: Metastatic pancreatic adenocarcinoma (MPA) represents a highly lethal condition. Despite the improvements seen with FOLFIRINOX, there is no randomized data to guide treatment selection beyond this regimen. We aimed to evaluate the outcomes of patients with MPA progressing on FOLFIRINOX who were treated with Gemcitabine-based chemotherapy afterwards. METHODS: We included patients aged 18 years or older, treated for MPA with FOLFIRINOX in the first-line setting and who experienced disease progression, with Eastern Cooperative Oncology Group (ECOG) performance status 0-2, and treated with at least one cycle of Gemcitabine-based chemotherapy in second or further lines of treatment. We used descriptive statistics to characterize the study population and Cox proportional-hazards models to describe factors associated with survival. As an exploratory analysis, we compared the outcomes of patients treated with single-agent Gemcitabine with those of patients undergoing Gemcitabine-based polychemotherapy. RESULTS: The study population consisted of 42 patients. Median age was 59 years and 78.6% of patients presented ECOG 0-1. Thirty-three patients (78.6%) were treated with Gemcitabine-based chemotherapy in the second-line setting and 27 patients (64.3%) were treated with single-agent Gemcitabine. Objective response rate and disease control rate were 2.4% and 33.4%, respectively. Median progression-free survival (PFS) and median overall survival (OS) were 2.9 and 5.5 months, respectively. Six-month PFS and OS rates were 19.2% and 46.2%, respectively. We observed no significant difference in OS according to the type of Gemcitabine-based chemotherapy, despite numerically improved disease control rate and PFS for those treated with Gemcitabine-based polychemotherapy. In multivariate analysis, ECOG 2 (vs. ECOG 0-1) was the only factor significantly associated with inferior PFS and OS. CONCLUSIONS: a subgroup of patients with MPA derives benefit from treatment with Gemcitabine-based regimens after FOLFIRINOX. There is a suggestion that Gemcitabine-based combinations, in particular Gemcitabine plus Nab-Paclitaxel, provide superior outcomes compared to single-agent Gemcitabine. Additionally, treatment in this setting should be offered carefully to patients with ECOG 2, as they present shorter survival and increased risk of toxicity.

The roles of PTEN, cMET, and p16 in resistance to cetuximab in head and neck squamous cell carcinoma.

There is no established biomarker for cetuximab efficacy in recurrent head and neck squamous cell carcinoma (HNSCC). The aim of the present study was to evaluate the prognostic and predictive impact of PTEN, cMET, and p16 expression in recurrent HNSCC. In this retrospective study, 112 patients with recurrent HNSCC received chemotherapy (CT) alone (n = 37) or chemotherapy with cetuximab (n = 75). PTEN, cMET, and p16 protein expression were evaluated by immunohistochemistry. The median overall survival (mOS) for the patients treated with cetuximab + CT versus CT alone was 11.4 months and 7.0 months, (p = 0.949). The median progression-free survival (mPFS) was 6.2 months versus 3.0 months (p = 0.154). Patients with PTEN loss exhibited a mOS of 5.8 months versus 10.5 months (p = 0.002) and a mPFS of 3.2 months versus 4.7 months (p = 0.019). A multivariate analysis identified an independent association between PTEN loss and OS (HR 2.27; 95% confidence 95% CI 1.27-4.08; p = 0.006) and with PFS (HR 1.85; 95% CI 1.09-2.99; p = 0.022). A negative prognostic impact of PTEN loss was observed in the patients treated with cetuximab + CT, and not in the CT only group. Expression of cMET and p16 showed no impact on OS or PFS. The present findings confirm that PTEN is a prognostic factor for metastatic HNSCC and they support further studies of PTEN expression to evaluate its predictive value to cetuximab response.

Update on hepatocellular carcinoma from the 2018 Gastrointestinal Cancer Symposium (ASCO GI).

At the 2018 Gastrointestinal Cancer Symposium, sponsored by the American Society of Clinical Oncology, significant advances in the management of hepatocellular carcinoma (HCC) were announced. In intermediate-stage disease (Barcelona Clinic Liver Cancer stage B), interest in combining transarterial chemoembolization and sorafenib has been reignited as a consequence of the TACTICS trial. In advanced-stage disease (BCLC C), external-beam radiotherapy combined with transarterial chemoembolization proved to be superior to sorafenib in patients with portal vein thrombosis according to the START trial. Also, in patients with advanced-stage HCC, the CELESTIAL trial demonstrated survival benefits for patients undergoing treatment with cabozantinib in the second-line setting. Lastly, recent data on the activity of pembrolizumab in patients with HCC highlight the role of immunotherapy in the management of this disease in the years to come.