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Background Checkpoint inhibitors (CPIs) such as Pembrolizumab have recently become the standard treatment for Non-Small Cell Lung Cancers (NSCLC) in patients without Epidermal Growth Factor (EGFR) gene alterations. Previous reports suggest no significant benefit from CPI treatments among EGFR mutant NSCLC patients and recommend the use of Tyrosine Kinase Inhibitors such as Afatinib. Case presentation: Herein, we report a rare case of a 39-year old, light-smoker woman with a metastatic EGFR mutant NSCLC (exon-19 deletion) that exhibited rapid progression and an unusual clinical response to Afatinib without changes in tumor histology. Tumor was negative for PDL1. Biopsy analyses by NGS prior and after Afatinib treatment indicated an increase in focal somatic copy number alterations (fSCNAs) but no T790M or c-MET amplification, and a low Tumor Mutational Burden (TMB). Given her rapid progression and deterioration, and despite its PDL1- status and her low TMB patient started treatment with Pembrolizumab plus chemotherapy. Surprisingly, patient displayed a complete response after just 4 cycles and is soon to complete a year in remission. Conclusions We speculate intratumoral heterogeneity, the combination of radiotherapy plus immunotherapy or the concomitant use of chemotherapy plus immunotherapy could explain the observed response in this patient. Also, based in our data we suggest the SBRT/CPI combination could be an option for Tyrosine Kinase Inhibitor-refractory EGFR mutant NSCLC patients or as a second-line treatment.

Objective: Clinical guidelines recommend the use of endocrine therapy (ET) in advanced hormone receptor positive (HR+) human epidermal growth factor receptor type 2 negative (HER2-) breast cancer (...

PURPOSE Biliary tract cancers (BTCs), which include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC), and gallbladder cancer (GBC), have limited treatment options. We sought to comprehensively examine the clinical and molecular characteristics of BTCs with amplification or mutation of ERBB2. METHODS Demographic, outcome, and treatment response data were collected for patients with ERBB2-altered BTC identified by next-generation sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets from 2014 to 2018. RESULTS A total of 517 patients with BTC underwent next-generation sequencing (ICC, n = 313; EHC, n = 93; GBC, n = 111). Twenty-eight patients (5.4%) had ERBB2 alterations, including 2.7% with ERBB2 gene amplification, 2.3% with ERBB2 mutation, and 0.4% with concurrent amplification and mutation. The prevalence of ERBB2 gene alterations was significantly higher in GBC (12.6%) than in ICC (2.2%) and EHC (7.5%; P < .001). In ERBB2-amplified tumors, the median fold change was 6.4 (range, 2.1 to 19.7), while in ERBB2-mutant tumors, the most frequent mutated domain was the extracellular domain (32%), with all mutations in this region involving the S310 codon. Frequent co-altered genes in this cohort were TP53 (54%), PIK3CA (21%), and CDKN2A (18%); KRAS amplification/mutation was found in 7% of patients. One patient with ERBB2-amplified EHC who enrolled in a basket trial (ClinicalTrials.gov identifier: NCT02675829 ) had a partial response to the human epidermal growth factor receptor 2–targeted antibody-drug conjugate ado-trastuzumab emtansine. CONCLUSION ERBB2 alterations are present in 5.4% of BTCs. When present, the degree of ERBB2 gene amplification is often high, and S310 codon mutations are the most common hotspot. These features, along with the presented case, support further development of human epidermal growth factor receptor 2–targeted therapy in ERBB2-mutant and/or -amplified BTC.

Purpose: While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy. Experimental Design: We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3). Results: Forty patients with oncogenic non-V600 BRAF–mutant mCRC received anti-EGFR antibody treatment [n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P = 0.14). Conclusions: Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment. See related commentary by Fontana and Valeri, p. 6896

BACKGROUND: While 2–4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P 2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Background The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). Methods Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. Results In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P Conclusions EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

OBJECTIVES: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. MATERIALS AND METHODS: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. RESULTS: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p

Locally advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma are associated with a grim prognosis. The development of highly effective systemic therapies for these tumors has been challenging; however, numerous locoregional treatment alternatives have emerged, including transarterial hepatic embolization (TAE), transarterial chemoembolization (TACE), drug-eluting bead TACE (DEB-TACE), hepatic arterial infusion chemotherapy (HAI), radioembolization, and stereotactic body radiation therapy. Although there is potential for long-term disease control for these therapies, the evidence to guide adequate patient selection and choose among different treatment alternatives is still limited. This review focuses on the rationale and data supporting TAE, TACE, DEB-TACE, and HAI in hepatobiliary cancers.

Background Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC. Patients and Methods We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy – essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin – in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers. Results Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval [CI], 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations. Conclusions FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.

4114 Background: Gallbladder cancer (GBC) is a molecularly distinct entity among biliary tract tumors. ERBB2 amplification and mutation have been described in GBC, however, clinical and genomic characterization of the ERBB2-altered subgroup has been limited. Methods: Patients with GBC treated at Memorial Sloan Kettering and Pontificia Universidad Católica de Chile with genomic tumor profiling between 2014 and 2021 were included. Clinical information was retrieved from electronic medical records. Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: During the study period 260 GBC patients underwent genomic profiling. The prevalence of ERBB2 alterations was 14% including 8% with ERBB2 gene amplification, 4.2% with ERBB2 mutation, 1.5% with concurrent amplification and mutation and 0.4% with ERBB2 fusion. There was no age difference between GBC patients with and without ERBB2 alterations (63.6 vs. 65.4; p = 0.36) and in both subgroups there was a majority of female patients (75% vs. 84%; p = 0.44). Patients with ERBB2-altered tumors had a different genomic profile with lower concurrent KRAS alterations (2% vs. 12%; p = 0.14) and higher prevalence of TP53 alterations (81% vs. 59%; p = 0.01). There was no difference in the prevalence of PIK3CA mutations (13% vs. 9%; p = 0.38). GBC patients with ERBB2 alterations had a longer overall survival (22.3 vs. 12.1 months; HR 0.54 95% CI 0.3 to 0.98). Conclusions: ERBB2 amplification and mutation are the most frequent potentially targetable alterations in GBC (14%). ERBB2-driven GBC has higher concurrent alterations of TP53, while KRAS alterations appear to be less frequent. While no particular clinical feature was associated with this subgroup, overall survival was longer.

Few studies have evaluated programmed cell death ligand (PD-L1) expression and lymphocytic infiltrates in Basal Cell Carcinoma (BCC). The objectives of this study are to assess PD-L1 expression and markers of local immune response in nodular, superficial, and morpheaform BCC, and compare it to normal, sun-exposed skin from the periphery of intradermal nevi. This was a retrospective study that included three histological subtypes of BCCs, and sun-exposed skin from the periphery of dermal nevi as quality controls. Tissue microarrays (TMA) were constructed with subsequent staining of HE and immunohistochemistry (IHC) for CD4, CD8, FOXP3 and PD-L1. Non-automated quantification of the infiltrate in the intratumoral and stromal compartments on TMAs was performed. A total of 115 BCC (39 nodular, 39 morpheaform, and 37 superficial) and 41 sun-exposed skin samples were included (mean age 65.4 years; 52.6% females). BCC showed higher expression of PD-L1 (5.4 vs 0.7%, p 0.001), CD8 (29.8 vs 19.7%, p = 0.002), and FOXP3 (0.3 vs 0.06%, p = 0.022) compared to sun-exposed skin. There was a higher PD-L1 expression in nodular BCC compared with other subtypes. Low-risk BCC subtypes (superficial and nodular) exhibited more PD-L1 expression in intratumoral and stromal immune infiltrates as compared to high-risk BCC subtypes. As a limitation, no immune cells function was evaluated in this study, only the presence/absence of T-lymphocyte sub-populations was recorded. Substantial differences in both PD-L1 expression and lymphocytic infiltrates were found amongst the histological subtypes of BCC and sun-exposed skin. Highest PD-L1 expression was found in nodular BCCs which suggests a potentially targetable strategy in the treatment of this most common BCC subtype.

Background: Thymic epithelial tumors are rare and highly heterogeneous. Reports from the United States suggest an overall incidence of 0.15 per 100,000/year. In contrast, the incidence of these tumors in Latin America is largely unknown and reports are scarce, somewhat limited to case reports.Methods: Herein, we report a series of 38 thymic tumors from a single institution, retrospectively incorporated into this study. Patient characteristics and outcomes including age, sex, stage, paraneoplastic syndromes, treatment regimens and the date of decease were obtained from medical records.Results: Most cases in our series were females and young age (

Background Convalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression. Methods and findings The study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32–2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54–17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54–17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19–2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion. Conclusions In the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration. Trial registration NCT04375098., In this randomized trial, María Elvira Balcells and colleagues demonstrate that there is no benefit in immediate versus delayed convalescent plasma administration for COVID-19 patients., Author summary Why was this study done? The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a matter of worldwide concern, and except for corticosteroids, no other validated treatment against SARS-CoV-2 has been found so far. Plasma from convalescent patients containing antibodies against the virus is being widely used as a treatment alternative against this virus, but few randomized clinical trials have been carried out to show any clinical benefit for patients with COVID-19. What did the researchers do and find? We conducted a randomized clinical trial. Fifty-eight hospitalized patients in the early stages of COVID-19 (≤7 days of symptoms) and with a high risk of progression into respiratory failure were recruited. Patients were randomized into 2 groups: The early plasma group received convalescent plasma at enrollment, and the deferred plasma group received convalescent plasma only in case of respiratory aggravation or if the patient still required hospitalization for symptomatic COVID-19 >7 days after enrollment. The proportion achieving the combined primary outcome of mechanical ventilation, prolonged hospitalization, or in-hospital death was 32.1% with immediate plasma versus 33.3% in the arm deferring plasma until aggravation, a non-significant difference. What do these findings mean? Our study failed to show that early convalescent plasma administration improves the outcome compared to convalescent plasma use only in case of clinical deterioration. The small sample size of the study precludes any definitive conclusions, but the results are in agreement with observations from other trials on convalescent plasma for patients hospitalized with COVID-19.

Background Breast cancer (BC) is the leading cause of cancer death for Chilean women. About 11% of cases are triple-negative (TN) BC. These are characterised by poor prognosis, higher risk of early recurrence and visceral dissemination versus other BC subtypes. Current standard treatment for early-stage non-metastatic TNBC patients consists of neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy. Pathological complete response (pCR) to NACT is associated with an increase in survival rates. In general, NACT and adjuvant regimens involve similar cytotoxic drugs. Recent studies have postulated that the use of platinum compounds in TNBC would increase response rates. However, their effects on patient survival remain uncertain. Materials and methods We retrieved and analysed medical records from a total of 156 Chilean stage I-III TNBC female patients that received NACT and compared survival rates using carboplatin (Cb)-containing versus non-Cb-containing regimens at two health cancer centres. Results Median age was 51 years (range: 24-81); 13.5% (n = 21) received Cb-containing regimens, 80.1% (n = 125) received sequential anthracyclines plus taxanes; 29.5% (n = 46) of the total group achieved pCR, 28% for the standard treatment and 35% (n = 8) for the Cb-containing group (p = 0.59). We confirmed pCR was associated with prolonged overall survival, invasive and distant disease-free survival (Log-rank p = 0.0236). But the addition of Cb was not associated with differences in survival measures (Log-rank p = 0.5216). Conclusions To the best of authors' knowledge, this is the first report on real-world data in the Chilean population assessing the effect of Cb-containing NACT in TNBC. The authors' results suggest no survival benefit by the addition of Cb to standard NACT. However, we confirm an increase in survival associated to pCR regardless of treatment.

BackgroundConvalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.MethodsOpen-label, single-center, randomized clinical trial performed in an academic center in Santiago, Chile from May 10, 2020, to July 18, 2020, with final follow-up August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptoms onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted in immediate CP (early plasma group) versus no CP unless developing pre-specified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days or death. Key secondary outcomes included: time to respiratory failure, days of mechanical ventilation, hospital length-of-stay, mortality at 30 days, and SARS-CoV-2 RT-PCR clearance rate.ResultsOf 58 randomized patients (mean age, 65.8 years, 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We found no benefit in the primary outcome (32.1% vs 33.3%, OR 0.95, 95% CI 0.32-2.84, p>0.99) in the early versus deferred CP group. In-hospital mortality rate was 17.9% vs 6.7% (OR 3.04, 95% CI 0.54-17.2, p=0.25), mechanical ventilation 17.9% vs 6.7% (OR 3.04, 95% CI 0.54-17.2, p=0.25), and prolonged hospitalization 21.4% vs 30% (OR 0.64, 95%CI, 0.19-2.1, p=0.55) in early versus deferred CP group, respectively. Viral clearance rate on day 3 (26% vs 8%, p=0.20) and day 7 (38% vs 19%, p=0.37) did not differ between groups. Two patients experienced serious adverse events within 6 or less hours after plasma transfusion.ConclusionImmediate addition of CP therapy in early stages of COVID-19 -compared to its use only in case of patient deterioration-did not confer benefits in mortality, length of hospitalization or mechanical ventilation requirement.Clinical Trials RegistrationNCT04375098

Highlights • After oxaliplatin treatment rats developed mechanical and cold hyperalgesia. • We observed intraepidermal nerve fiber degeneration, and mild spinal cord gliosis. • Co treatment with Metformin could prevent all these pathological outcomes. • This suggests metformin as a candidate drug to prevent oxaliplatin-induced neuropathy., Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.

In an integrated genomic and clinical analysis, we evaluate the effects of Wnt and DNA damage response pathway alterations on metastatic colorectal cancer.

Background Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge. Methods This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge. Results Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035). Conclusions In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.

Recent years have seen dramatic clinical advances in targeting the ERK pathway with the FDA approval of several selective inhibitors of RAF and MEK1–5. Clinical trials of these agents indicate that near complete inhibition of pathway signaling is necessary to effectively inhibit tumor growth6. Targeted approaches have been most successful in BRAF V600E tumors because of the relatively wide therapeutic index of RAF inhibitors (vemurafenib and dabrafenib), which inhibit signaling in cells with BRAF V600 mutants but cause “paradoxical activation” of ERK signaling in normal cells that are wild-type for RAF kinases. In contrast, MEK inhibitors (trametinib and cobimetinib) suppress ERK signaling in all cells, and their clinical activity has been limited by a narrow therapeutic index. Combining these agents – with RAF and MEK inhibitors for BRAF V600E melanoma or lung cancer and with RAF, MEK, and EGFR inhibitors for BRAF V600E colorectal cancer – to profoundly inhibit ERK signaling has led to improved antitumor activity7. Combination therapy has also been shown to offset the toxicities caused by RAF inhibitors, such as the development of keratoacanthomas and squamous cell carcinoma, resulting from paradoxical ERK activation with these agents. The role of RAF inhibitors to offset MEK inhibitor toxicity and the need for dose intensity to modulate opposing toxicities is less clear. Recent observations in clinical trials have suggested that RAF inhibitors offset dermatologic toxicity from MEK or EGFR inhibitors. In the phase III trial of trametinib in melanoma, grade 3 or 4 acneiform dermatitis occurred in 8% of trametinib-treated patients, whereas in the phase III trial of the combination of dabrafenib and trametinib, no patient had grade 3 or 4 acneiform dermatitis8,9. Combinations of RAF and EGFR inhibitors have also had a lower incidence of acneiform rash than seen with EGFR inhibitors alone7,10,11. This is also likely due to the opposite effects of RAF and EGFR inhibitors on MEK activation in normal cells. However, the doses of RAF inhibitors needed for these clinically opposing effects and how these doses compare to clinically efficacious doses have not been studied. We now report the course of a patient with BRAF V600E CRC treated with dabrafenib, trametinib, and panitumumab in a phase II clinical trial, and within this patient characterize the effect on toxicities of different dose levels of these agents. Further, we find that, within the clinical dose range, there is a RAF inhibitor dose that is an inflection point for the toxicity and efficacy of this regimen.

PurposeIncreasing numbers of reports have shown acceptable short-term mortality of patients with cancer admitted into the intensive care unit (ICU). The aim of this study was to determine the mortality of critically ill patients with cancer admitted to the ICU in a general hospital in Chile.Materials and MethodsThis was a prospective cohort trial in which we included all patients with cancer admitted to the ICU between July 2015 and September 2016. Demographic, physiologic, and treatment data were registered, and survival at 30 days and 6 months was evaluated. A prespecified subgroup analysis considering the admission policy was performed. These subgroups were (1) ICU admission for full code management and (2) ICU trial (IT).ResultsDuring the study period, 109 patients with cancer were included. Seventy-nine patients were considered in the full code management group and 30 in the IT. The mean age of patients was 60 years (standard deviation [SD], 15), and 56% were male. Lymphoma was the most frequent malignancy (17%), and 59% had not received cancer treatment because of a recent diagnosis. The mean Acute Physiology and Chronic Health Evaluation and Sequential-Related Organ Failure Assessment scores were 22.2 (SD, 7.3) and 7 (SD, 3), respectively. There were no differences in vasopressor, fluid, or transfusion requirements between subgroups. Lactate levels, Sequential-Related Organ Failure Assessment scores (day 1, 3, and 5), complications, and ICU length of stay were similar. In the entire cohort, 30-day and 6-month mortality was 47% and 66%, respectively. There was no difference in mortality between subgroups according to the admission policy.ConclusionPatients admitted to the ICU in a developing country are at high risk for short-term mortality. However, there is a relevant subgroup that achieves 6-month survival, even among patients who undergo an IT.

Hepatic arterial infusion (HAI) chemotherapy has been used over the last 30 years in patients with liver metastases from colorectal cancer and intrahepatic cholangiocarcinoma. Its rationale has been well established and is based on the preferential blood supply of these tumors from the hepatic artery and the first-pass extraction by the liver of some chemotherapy drugs. However, the generation of high-quality evidence for HAI treatment and the technical expertise required for administration have limited its widespread adoption. In this review, we will describe the relevant aspects of HAI treatment and summarize the evidence supporting its use in the treatment of colorectal cancer and intrahepatic cholangiocarcinoma. We will also review the complications associated with HAI and the precautions to minimize their incidence. Based on the current evidence, HAI has emerged as an effective and safe treatment alternative leading to renewed enthusiasm toward this therapeutic strategy. Future research will refine the selection of patients and the optimal combination with systemic treatments.

BACKGROUND: Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma, however there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial. METHODS: Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2 weeks. The primary endpoint was 6-month progression free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity. RESULTS: We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62 years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4 months, the 6-month PFS was 73% (95% CI, 51% - 86%). The objective response rate was 65%, the median PFS was 13 months (95% CI, 6.4 – 20.7) and the median OS was 24.9 months (95% CI, 14.4 – 42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia. CONCLUSION: The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number .

Gastric cancer (GC) is a heterogeneous disease. This heterogeneity applies not only to morphological and phenotypic features but also to geographical variations in incidence and mortality rates. As Chile has one of the highest mortality rates within South America, we sought to define a molecular profile of Chilean GCs (ClinicalTrials.gov identifier: NCT03158571/(FORCE1)). Solid tumor samples and clinical data were obtained from 224 patients, with subsets analyzed by tissue microarray (TMA, n = 90) and next generation sequencing (NGS, n = 101). Most demographic and clinical data were in line with previous reports. TMA data indicated that 60% of patients displayed potentially actionable alterations. Furthermore, 20.5% were categorized as having a high tumor mutational burden, and 13% possessed micro-satellite instability (MSI). Results also confirmed previous studies reporting high Epstein-Barr virus (EBV) positivity (13%) in Chilean-derived GC samples suggesting a high proportion of patients could benefit from immunotherapy. As expected, TP53 and PIK3CA were the most frequently altered genes. However, NGS demonstrated the presence of TP53, NRAS, and BRAF variants previously unreported in current GC databases. Finally, using the Kendall method, we report a significant correlation between EBV+ status and programmed death ligand-1 (PDL1)+ and an inverse correlation between p53 mutational status and MSI. Our results suggest that in this Chilean cohort, a high proportion of patients are potential candidates for immunotherapy treatment. To the best of our knowledge, this study is the first in South America to assess the prevalence of actionable targets and to examine a molecular profile of GC patients.

Biliary tract cancer (BTC) is comprised of intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (EHC) and gallbladder cancer (GBC). These tumors arise in the biliary epithelium, share histological characteristics and are associated with grim prognosis even when diagnosed at early stages. Moreover, its relatively low incidence in developed countries has precluded the development of clinical trials addressing specific differences among BTC subgroups in terms of their biology, treatment response and clinical outcomes. In this scenario, the development of effective treatment strategies for patients has been rather modest. To date, the combination of cisplatin plus gemcitabine remains as the standard first line therapy in advanced disease and after progression to this regimen there are limited treatment options. Next generation sequencing (NGS) studies have assessed the distribution of driver genes and potentially actionable genomic alterations among ICC, EHC and GBC. Here, we outline genomic differences among these subsets and describe key milestones in order to develop novel targeted drugs against BTCs. Although the early results of several studies are promising, international collaboration is critical to conduct adequately-powered trials, enrolling patients from high-incidence countries.

Rectal cancer accounts for one-third of newly diagnosed colorectal cancer cases. Given its anatomical location and risk for local recurrence, a multidisciplinary treatment program including surgery, radiation therapy, and chemotherapy has demonstrated improved outcomes in localized disease. Genetic analysis has become part of the standard approach for management of advanced disease and new trials are considering tailored therapies for locally advanced disease. This review describes molecular subsets of colorectal cancer; implications for clinical management, including patterns of metastatic spread and response to therapies; and emerging matched therapies. During the last decade, significant biological differences have been noted based on colorectal cancer primary location and here we focus on rectal cancers and relevant markers for this disease. As more treatment for localized rectal cancer is shifted to the neoadjuvant setting and more targeted regimens are developed for metastatic disease, radiologists will increasingly see patients defined by molecular subsets and their awareness of the genetics of rectal cancer will help further refine our understanding of this disease.

Background: Plasma cfDNA evaluation at acquired resistance to targeted therapies in lung cancer is routine, however, reports of extended clinical application and pitfalls in laboratory practice are still limited. In this study we describe our experience with cfDNA testing using EGFR T790M as a prototype. Methods: Patients with metastatic EGFR-mutant NSCLC patients who underwent plasma EGFR T790M testing at acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) from January 2016 through August 2017 were identified. Molecular laboratory records were reviewed to assess performance of testing by digital PCR, concordance between plasma and tissue testing, turnaround time (TAT), plasma T790M variant allele frequency (VAF), and its correlations with metastatic sites and clinical outcomes. Results: 177 patients underwent T790M cfDNA testing during this period. Plasma T790M was positive in 32% of patients. The median TAT was shorter for plasma T790M compared to tissue PCR (9 vs. 15 days, p p = .4). Plasma T790M status correlated with a higher number of metastatic sites (4 vs. 3, p p = .0002). Conclusion: Plasma EGFR T790M testing had shorter TAT compared to tissue testing, however, it was longer than anticipated. Test sensitivity is higher in patients with osseous metastases and with higher metastatic burden suggesting a more limited role for early detection. T790M VAF was not associated with clinical outcomes.

Gastric cancer (GC) is the fourth most common neoplasm and the second leading cause of cancer-related death worldwide. In Latin America (LA), the burden of this disease is higher and is the leading cause of cancer death in some countries. Chemotherapy is the standard treatment for advanced-stage GC. However, the best regimen for specific populations, such as LA, is as yet unknown. Cisplatin and fluoropyrimidine continue to be the standard of care in light of the findings of phase III studies, while docetaxel, cisplatin, and 5-fluorouracil (5-FU) are alternatives for patients with suitable overall health. Oxaliplatin or irinotecan with fluoropyrimidine can also be used in elderly patients who are not candidates for cisplatin, or have a limited performance status. This review examines studies conducted in LA. Patients from LA are under-represented in multicenter trials of chemotherapy and targeted therapies. The major challenges currently lie in implementing strategies in which patients are selected on the basis of regional, racial or molecular characteristics, to consider the molecular subtype of GC for enrolment, and in selecting patients according to prognostic factors to optimize the benefits of chemotherapy.

e16717 Background: Human gallbladder cancer research lacks in vitro models that can recapitulate the pathophysiology of the original tumor and normal epithelia. Organoids cultures emulate the tumor heterogeneity and have been successively used as translational models to evaluate clinical response to anticancer drug. Here, we established and characterized patients derived organoids culture (PDOs) from human gallbladder cancer patients. Methods: Fresh tissues obtained from gallbladder cancer patients who underwent cholecystectomy were digested with Collagenase/Dispase, filtered and then suspension cells were mixed with Matrigel (1:1) for organoids establishment. Cultures were maintained at 37°C and 5% CO2. The organoids were characterized through histopathology evaluation, immunohistochemistry, and ultra-deed targeted sequencing (TruSeq protocol, Illumina, TSACP; 25 genes). In addition, we evaluated the response of organoids to gemcitabine, cisplatin and Fluorouracil (5-FU), using the CellTiter-Glo 3D luminescence assay. Results: We have successfully established PDOs cultures from six patients with gallbladder adenocarcinoma with a 60% efficiency (6/10). The PDOs recapitulated the histological features and maintained the expression of CK19, Ki67, P53 as compared with the epithelia of primary tumors. Moreover, the PDOs maintained the mutational status of major driver genes, including TP53 and PIK3CA. Finally, tumor organoids showed differential response to standard chemotherapy treatment. GBC-PDO2 and GBC-PDO4 showed high resistant to gemcitabine (IC50 > 10μM), which suggests that the personalized treatment is necessary for generate better response. Conclusions: the established gallbladder tumor organoids exhibited similar histological and genomic features in relation to their original epithelia. PDOs can be considered a valuable tool for future research aimed to understand gallbladder cancer biology and for developing personalized-medicine approaches for advanced gallbladder cancer patients. (Funding Source: FONDECYT #1171463, FONDECYT #1170893 and Fondef IT16I10051).

Neuroendocrine tumors (NETs) are relatively rare and highly heterogeneous neoplasms. Despite this, recent studies from North America and Central Europe have suggested an increase in incidence. In Latin America, NET data are scarce and scattered with only a few studies reporting registries. Our goal was to establish a NET registry in Chile. Here, we report the establishment and our first 166 NET patients. We observed a slight preponderance of males, a median age at diagnosis of 53 years and a median overall survival of 110 months. As anticipated, most tumors were gastroenteropancreatic (GEP). Survival analyses demonstrated that non-GEP or stage IV tumors presented significantly lower overall survival (OS). Similarly, patients with surgery classified as R0 had better OS compared to R1, R2, or no surgery. Furthermore, patients with elevated chromogranin A (CgA) or high Ki67 showed a trend to poorer OS; however, these differences did not reach statistical significance (log-rank test p = 0.07). To the best of our knowledge, this is the first report of a NET registry in Chile. Median OS in our registry (110 months) is in line with other registries from Argentina and Spain. Other variables including age at diagnosis and gender were similar to previous studies; however, our data indicate a high proportion of small-bowel NETs compared to other cohorts, reflecting the need for NET regional registries. Indeed, these registries may explain regional discrepancies in incidence and distribution, adding to our knowledge on this seemingly rare, highly heterogeneous disease. Electronic supplementary material The online version of this article (10.1007/s12672-018-0354-5) contains supplementary material, which is available to authorized users.

Background Regorafenib is a therapeutic alternative for patients with metastatic colorectal cancer (MCRC) resistant to conventional therapies. The reported toxicity is relevant and there is no data on Latin American patients. The objective was to evaluate the overall survival (OS), progression-free survival (PFS) and quality of life (QoL) in a prospective cohort of Latin American patients treated with an adjusted dose of regorafenib. Methods We prospectively recruited patients with MCRC that progressed to standard therapy. A dose escalation algorithm was used. OS, PFS, response rate and QoL were evaluated. Results We recruited 13 patients between June and November 2015. The median age was 60 years. Median OS was 8.6 months and median PFS was 2.2 months. The response rate was 8%. Grade 3-4 toxicities included grade 3 palmoplantar erythrodysesthesia in 23% and grade 3 fatigue in 12% of patients. Conclusion Regorafenib treatment is effective in Latin American patients with conventional therapy resistant MCRC.

The widespread use of next generation sequencing (NGS) has led to a refined understanding of the genomics of colorectal cancer (CRC). However, progress in the use of molecular biomarkers in standard practice has been slow, and there is no approved targeted therapy for CRC based on a positive predictive marker yet. In this review, we will first summarize biomarkers with clinical utility in standard practice or targeted therapy trials and then consider how to rationally design clinical trials to more effectively target CRC. Specifically, we will discuss current clinical applications of genomic information consisting of the use of the MAPK (mitogen-activated protein kinase) pathway genes KRAS, NRAS, and BRAF as prognostic and predictive biomarkers for standard treatment, risk stratification by primary tumor site and consideration of tumor laterality in patient selection for epidermal growth factor receptor (EGFR) antibody treatment, and the evaluation for genomic biomarkers, including BRAF V600E, HER2 amplification, and gene rearrangements, for targeted therapies in clinical trials. Applying lessons from targeted therapy trials in CRC, we now appreciate that both tumor genomics and tissue of origin affect targeted therapy response and that the development of resistance to targeted therapies is dynamic and often subclonal. Based on these understandings, we propose the design of adaptive clinical trials that evaluate real-time pharmacodynamic markers and monitor tumor subpopulations during the course of treatment to overcome challenges targeting genetic drivers in CRC.

Supplemental Digital Content is available in the text, Gastric cancer (GC) is the world's second-leading cause of neoplastic mortality. Genetic alterations, response to treatments, and mortality rates are highly heterogeneous across different regions. Within Latin America, GC is the leading cause of cancer death in Chile, affecting 17.6 per 100,000 people and causing >3000 deaths/y. Clinical outcomes and response to “one size fits all” therapies are highly heterogeneous and thus a better stratification of patients may aid cancer treatment and response. The Gastric Cancer Task Force is a Chilean collaborative, noninterventional study that seeks to stratify gastric adenocarcinomas using clinical outcomes and genomic, epigenomic, and protein alterations in a cohort of 200 patients. Tumor samples from the Pathology Department and the Cancer Center at UC-Christus healthcare network, Pontificia Universidad Católica de Chile will be analyzed using a panel of 143 known cancer genes (Oncomine Comprehensive Assay) at the Center of Excellence in Precision Medicine in Santiago, Chile. In addition, promoter methylation for selected genes will be performed along with tissue microarray for clinically relevant proteins (e.g., PD-L1, Erb-2, VEGFR2, among others) and Helicobacter pylori and Epstein–Barr virus status. Obtained data will be correlated to 120 clinical parameters retrieve from medical records, including general patient information, cancer history, laboratory studies, comorbidity index, chemotherapy, targeted therapies, efficacy, and follow-up. The development of a clinically meaningful classification that encompasses comprehensive clinical and molecular parameters may improve patient treatment, predict clinical outcomes, aid patient selection/stratification for clinical trials and may offer insights into future preventive and/or therapeutic strategies in patients from Latin America region. Trial registration: ClinicalTrials.gov Identifier: NCT03158571, Registered on May 18, 2017.

3585 Background: We assembled a large series of consecutive patients with unresectable metastatic colorectal cancer (mCRC) to identify genomic biomarkers of response and survival. Methods: Patients with unresectable mCRC treated at Memorial Sloan Kettering with genomic tumor profiling between 2014 and 2017 were included. Patients who underwent upfront metastasectomy or received neoadjuvant/conversion chemotherapy were excluded. Clinical information was retrieved from electronic medical records, and we evaluated associations between genomic profiles with progression free survival (PFS) on first-line chemotherapy and overall survival (OS). Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: Of 1453 mCRCs profiled in this period, 471 patients met the study criteria. Median age was 59 years (range, 18 to 95), and 73% of patients were stage IV at diagnosis. Most tumors (91%) were microsatellite stable (MSS). The most frequent first-line regimen was FOLFOX +/- bevacizumab (66%). Among MSS patients treated with oxaliplatin-containing regimens (n = 305), 7% harbored alterations in genes associated with DNA damage response (DDR) (BRCA1, BRCA2, ATM, PALB2). DDR gene alterations were not associated with PFS (P = 0.94) nor were different quartiles of large-state transitions (P = 0.54). Genomic alterations that significantly varied by duration of response included BRAF (16%, 10%, and 5% for PFS < 6 months, 6-12 months, and > 12 months, respectively) and APC (62%, 74%, and 80% for PFS < 6 months, 6-12 months, and > 12 months, respectively). APC mutation, single or dual, was associated with significantly longer PFS (HR 0.67) and OS (HR 0.59) in multivariate analysis versus no WNT pathway alteration or alterations in other WNT pathway genes (RNF43, AXIN2, CTNNB1). Conclusions: In unresectable mCRC patients, mutations in APC were associated with better outcomes; absence of an APC alteration or the occurrence of other WNT pathway alterations was associated with shorter survival. Somatic alterations in DDR genes were not associated with outcomes in mCRC patients receiving oxaliplatin-containing regimen.

659 Background: BRAF non-V600 mutations occur in 2-3% of colorectal cancer. These mutants can be classified as RAS independent (class 2) or RAS dependent (class 3). We reported BRAF non-V600 mutations could be a negative predictive factor for anti-EGFR therapy in patients (pts) with pretreated metastatic colorectal cancer (mCRC), while mCRC pts with class 3 BRAF mutations could respond to anti-EGFR therapy because of its dependency on receptors and RAS. Methods: This study evaluates the efficacy to anti-EGFR therapy in a large cohort of pts with BRAF non-V600 mutated mCRC. Pts with mCRC referred to the participating centers from 2010 to 2017 were included. Clinicopathological features, efficacy of anti-EGFR therapy, and survival outcomes were stratified by BRAF mutational class. Results: One hundred seventeen pts with BRAF non-V600 mutated mCRC were identified. Median age was 58 years (range, 27-83), 68 pts (58%) were male, and 38 pts (33%) had right-sided tumors. Mucinous histology was seen in 11 cases (9%); concurrent RAS mutations occurred in 31 cases (27%), and 3 cases (3%) were MSI-H. Also, TP53 mutations were detected in 74 pts among 90 analyzed cases (82%). Regarding BRAF mutation subtype, 25/63/29 pts were classified as class 2/3/not reported (NR), respectively. Median OS in RAS wild-type/mutant were 44.8/34.6 months, respectively (p=0.082). The median OS in RAS wild-type pts with BRAF non-V600 mutations for class 2, 3, and NR were 25.7, 44.2, and 79.1 months, respectively (class 2 vs. 3, p=0.219). Among 40 pts treated with anti-EGFR therapy, response rates were 14%, 44%, and 40% for class 2, 3, and NR, respectively. Median PFS was 4.4, 8.3, 4.0 months for class 2, 3, and NR, respectively. Moreover, in 25 pts receiving anti-EGFR therapy as third or later line, response rate was 0%, 27%, and 50% in class 2, 3, and NR, and median PFS was 2.8, 3.7, and 4.0 months (p=0.762), respectively. Conclusions: Pts with class 2 BRAF mutations tend to have a poor prognosis compared to those with class 3 mutations. While almost half of pts with class 3 BRAF mutations responded to anti-EGFR therapy, response was rare for pts with class 2 BRAF mutations, and none achieved objective response in the third or later line.

Background: Multiple clinical trials have demonstrated the benefits of adjuvant 5-fluorouracil-based chemotherapy for patients with resectable colon cancer (CC), especially in stage III. Aim: To describe the clinical characteristics of a cohort of CC patients treated at a single university hospital in Chile since 2002, and to investigate if chemotherapy had an effect on survival rates. Material and methods: Review of a tumor registry of the hospital. Medical records of patients with CC treated between 2002 and 2012 were reviewed. Death certificates from the National Identification Service were used to determine mortality. Overall survival was described using the Kaplan-Meier method. A multivariate Cox proportional hazard regression model was also used. Results: A total of 370 patients were treated during the study period (202 in stage II and 168 in stage III). Adjuvant chemotherapy was administered to 22 and 70% of patients in stage II and III respectively. The median follow-up period was 4.6 years. The 5-year survival rate for stage II patients was 79% and there was no benefit observed with adjuvant chemotherapy. For stage III patients, the 5-year survival rate was 81% for patients who received adjuvant chemotherapy, compared to 56% for those who did not receive chemotherapy (hazard ratio (HR): 0.29; 95% confidence interval (CI): 0.15–0.56). The benefit of chemotherapy was found to persist after adjustment for other prognostic variables (HR: 0.47; 95% CI: 0.23–0.94). Conclusions: Patients with colon cancer in stage III who received adjuvant chemotherapy had a better overall survival.

e17081Background: Obesity is a public health problem in most developed countries, with growing incidence in the last decades. Epidemiologic studies associate obesity with increased risk of developi...