Act Local, Think Global: IR and Its Role in Immuno-Oncology in Hepatocellular Carcinoma.

Interventional oncology (IO) is evolving rapidly. The treatment landscape of liver cancer is changing rapidly, and immunotherapy combinations have become the standard of care for most patients with advanced hepatocellular carcinoma (HCC). The higher response rates and improved outcomes observed with these agents are leading to initiatives for their earlier incorporation in the course of the disease, including in combination with ablative and transarterial treatment options. The intersectionality of systemic therapies and liver-directed approaches has allowed IO to be at the center stage of a rapidly evolving dynamic field across all stages of HCC. This review article will address the current state of treatment for advanced HCC and the incorporation of these options in both localized and advanced stages along with IO to further enhance the observed benefits.

Targeting Fibroblast Growth Factor Receptor Pathway: Precision Medicine for Biliary Cancer and Beyond.

Fibroblast growth factor receptor 2 (FGFR2) inhibitors are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma (CCA). Activation of the FGF-FGFR pathway is related to proliferation and tumor progression. Targeting the FGF-FGFR pathway is effective and can yield durable responses in patients with CCA harboring FGFR2 fusions or rearrangements. In this review article, we address molecules and clinical trials evaluating FGFR inhibitors in advanced CCA. We will further discuss identified mechanisms of resistance and the strategies to overcome it. The incorporation of next-generation sequencing in advanced CCA and circulating tumor DNA on disease progression will unveil mechanisms of resistance and improve the development of future clinical trials and more selective drugs and combinations.

Response to Abemaciclib and Immunotherapy Rechallenge with Nivolumab and Ipilimumab in a Heavily Pretreated TMB-H Metastatic Squamous Cell Lung Cancer with CDKN2A Mutation, PIK3CA Amplification and TPS 80%: A Case Report.

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

FGFR2-IIIb Expression by Immunohistochemistry Has High Specificity in Cholangiocarcinoma with FGFR2 Genomic Alterations.

BACKGROUND: FGFR2 genomic alterations are observed in 10-20% of cholangiocarcinoma (CCA). Although FGFR2 fusions are an important actionable target, FGFR2 protein expression has not been thoroughly characterized. AIMS: To evaluate FGFR2 protein expression in cholangiocarcinoma harboring FGFR2 genomic alterations. METHODS: FGFR2 protein expression was evaluated in 99 CCA cases with two different antibodies. FGFR2 genomic alterations were confirmed via next-generating sequencing (NGS) or FISH. Primary objective was to determine the specificity and sensitivity of FGFR2 immunohistochemistry staining for detecting FGFR2 genomic alterations. Secondary objectives included overall FGFR2 immunohistochemistry staining in CCA patients, and evaluation of whether FGFR2 expression correlates with clinical outcomes including overall survival (OS), progression-free survival (PFS), and time-to-tumor recurrence (TTR). RESULTS: Immunohistochemistry staining with two antibodies against FGFR2, FPR2-D, and clone 98706 showed high accuracy (78.7% and 91.9%) and specificity (82.9% and 97.7%), and moderate sensitivity (53.9% and 57.1%), respectively, when compared with the standard methods for detecting FGFR2 genomic alterations. In a median follow-up of 72 months, there were no statistically significant differences in OS, PFS, and TTR, for patients with positive or negative FGFR2 staining. CONCLUSION: FGFR2 protein expression by immunohistochemistry has high specificity and therefore could be used to imply the presence of FGFR2 genomic alterations in the context of a positive test. In the case of a negative test, NGS or FISH would be necessary to ascertain cases with FGFR2 genomic alterations.

Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR).

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1α, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death.

Combination Immunotherapy for Hepatocellular Carcinoma: Where Are We Currently?

The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanisms; therefore, therapeutic strategies aiming at disrupting tumor immune tolerance are becoming attractive curative options in HCC. Immune checkpoint inhibitors have demonstrated impressive effectiveness in HCC, including in sorafenib-unresponsive patients. Synergistic approaches with checkpoint inhibitors (anti-PD-1/PD-L1 and CTLA-4) and antiangiogenic drugs are burgeoning as first-line treatment therapeutic modalities in HCC.

Circulating Tumor DNA-Based Testing and Actionable Findings in Patients with Advanced and Metastatic Pancreatic Adenocarcinoma.

PURPOSE: Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. MATERIALS AND METHODS: From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. RESULTS: All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. CONCLUSION: Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. IMPLICATIONS FOR PRACTICE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.

Signet ring cell component, not the Lauren subtype, predicts poor survival: an analysis of 198 cases of gastric cancer.

AIM: Prognostic differences between major histologic gastric cancer groups, intestinal and diffuse are uncertain, since cellular components in each of them possibly have different behaviors. MATERIALS & METHODS: We reviewed 198 gastric cancer patients charts diagnosed from January 2003 to December 2015 in a tertiary hospital. Multivariate Cox proportional survival models were used to evaluate the impact of histologic groups on overall survival. RESULTS: About a third had the signet-ring cell carcinoma (SRCC). In a comparison of the different histologic subtypes, SRCC had the worst prognosis of all. The median durations of survival for patients with stage III and stage IV were 19.7 and 7.7 months, respectively. CONCLUSION: Signet-ring cell component seem to have a relevant role in defining prognosis for gastric cancer.

Continuous palliative sedation for patients with advanced cancer at a tertiary care cancer center.

BACKGROUND: Palliative sedation (PS) is an intervention to treat refractory symptoms and to relieve suffering at the end of life. Its prevalence and practice patterns vary widely worldwide. The aim of our study was to evaluate the frequency, clinical indications and outcomes of PS in advanced cancer patients admitted to our tertiary comprehensive cancer center. METHODS: We retrospectively studied the use of PS in advanced cancer patients who died between March 1st, 2012 and December 31st, 2014. PS was defined as the use of continuous infusion of midazolam or neuroleptics for refractory symptoms in the end of life. This study was approved by the Research Ethics Committee of our institution (project number 2481-15). RESULTS: During the study period, 552 cancer patients died at the institution and 374 met the inclusion criteria for this study. Main reason for exclusion was death in the Intensive Care Unit. Among all included patients, 54.2% (n = 203) received PS. Patients who received PS as compared to those not sedated were younger (67.8 vs. 76.4 years-old, p < 0.001) and more likely to have a diagnosis of lung cancer (23% vs. 14%, p = 0.028). The most common indications for sedation were dyspnea (55%) and delirium (19.7%) and the most common drugs used were midazolam (52.7%) or midazolam and a neuroleptic (39.4%). Median initial midazolam infusion rate was 0.75 mg/h (interquartile range - IQR - 0.6-1.5) and final rate was 1.5 mg/h (IQR 0.9-3.0). Patient survival (length of hospital stay from admission to death) of those who had PS was more than the double of those who did not (33.6 days vs 16 days, p < 0.001). The palliative care team was involved in the care of 12% (n = 25) of sedated patients. CONCLUSIONS: PS is a relatively common practice in the end-of-life of cancer patients at our hospital and it is not associated with shortening of hospital stay. Involvement of a dedicated palliative care team is strongly recommended if this procedure is being considered. Further research is needed to identify factors that may affect the frequency and outcomes associated with PS.

An overview of up-and-coming immune checkpoint inhibitors for pancreatic cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1/PD-L1) pathway as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have demonstrated substantial potential in several malignancies. Pancreatic adenocarcinoma (PC) still carries a high mortality despite tremendous advances in the anti-cancer arsenal. AREAS COVERED: In this review, we discuss completed and ongoing studies on various ICIs in PC. ICIs have not yielded significant benefits as monotherapy. However, the combination with currently utilized therapies as well as with several other newer forms of therapy has delineated encouraging results. Larger trials are currently underway to definitively characterize the utility of ICIs in the treatment algorithm of PC. ICIs are approved for cancers with mismatch repair deficiency (dMMR) or microsatellite instability-high tumors (MSI-H) as a tumor-agnostic treatment strategy usually referred to as hot tumors. EXPERT OPINION: Studies evaluating different drugs to transform the tumor microenvironment (TME) from 'cold' to 'hot' have not shown promise in PC. There still needs to be more prospective trials evaluating the efficacy of the combination of ICIs with different therapeutic modalities in PC that can augment the immunogenic potential of those 'cold' tumors. Exploratory biomarker analysis may help us identify those subsets of PC patients who may particularly benefit from ICIs.

Disparities in esophageal cancer care: a population-based study.

BACKGROUND: Vulnerable populations potentially have a worse prognosis for cancer. The present study aimed to identify individual and municipal characteristics of access to health, including education, use of health insurance, gross domestic product per capita (GDPpc), and urban aspects, which could impact the prognosis of patients with esophageal cancer. METHODS: Data on urban concentration, administrative hierarchy, GDPpc, individual patient characteristics, and access to healthcare were collected from national and state public databases spanning between 2013 and 2022. The study included cities in the state of Sao Paulo, Brazil. Independent variables such as GDPpc, urban concentration, municipal administrative hierarchy, health insurance status, education level, and individual cancer and patient characteristics were evaluated against the outcomes of overall survival (OS), likelihood of undergoing surgical treatment, and time-to-treatment initiation. RESULTS: A total of 9280 patients with esophageal cancer (85% squamous cell carcinoma and 15% adenocarcinoma) treated in 42 cities were included in the study. In univariate analysis, higher education (hazard ratio [HR] = 0.6; P < .001), female gender (HR = 0.85; P < .001), and having private health insurance (HR = 0.65; P < .001) were identified as protective factors for OS in esophageal cancer. After adjusting for other variables in multivariate analysis, higher education (HR = 0.77; P = .009), female gender (HR = 0.82; P < .001), and private insurance (HR = 0.65; P < .001) remained protective factors. GDPpc was not associated with OS. Urban concentration and hierarchy influenced the likelihood of receiving surgical treatment. Patients from high urban concentrations had shorter time-to-treatment initiation intervals. CONCLUSION: Populations at risk, particularly those with limited access to education and healthcare, face a worse prognosis for esophageal cancer.

Prognostic value of programmed cell death ligand 1 (PD-L1) expression in patients with stage III non-small cell lung cancer under different treatment types: a retrospective study.

OBJECTIVE: Currently programmed cell death protein 1 (PD-1) inhibitors in combination with other therapies are being evaluated to determine their efficacy in cancer treatment. However, the effect of PD-ligand (L) 1 expression on disease outcomes in stage III (EC III) non-small cell lung cancer is not completely understood. Therefore, this study aimed to assess the influence of PD-L1 expression on the outcomes of EC III non-small cell lung cancer. METHODS: This study was conducted on patients diagnosed with EC III non-small cell lung cancer who underwent treatment at a tertiary care hospital. PD-L1 expression was determined using immunohistochemical staining, all patients expressed PD-L1. Survival was estimated using the Kaplan-Meier method. Relationships between variables were assessed using Cox proportional regression models. RESULTS: A total of 49 patients (median age=69 years) with EC III non-small cell lung cancer and PD-L1 expression were evaluated. More than half of the patients were men, and most were regular smokers. The patients were treated with neoadjuvant chemotherapy, surgery, or sequential or combined chemotherapy and radiotherapy. The median progression-free survival of the entire cohort was 14.2 months, and the median overall survival was 20 months. There was no significant association between PD-L1 expression and disease progression, clinical characteristics, or overall survival. CONCLUSIONS: PD-L1 expression was not correlated with EC III non-small cell lung cancer outcomes. Whether these findings differ from the association with immune checkpoint inhibitors remains to be addressed in future studies.

Clinical Utility of Ivosidenib in the Treatment of IDH1-Mutant Cholangiocarcinoma: Evidence To Date.

Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p < 0.0001) and overall survival (OS), median OS was 10.8 months for ivosidenib and 9.7 months for the placebo arm (p = 0.06) for patients with previously treated and IDH1 mutated cholangiocarcinoma. In this review article, we will address the mechanism of action of ivosidenib and data from early trials and safety from the randomized trial in cholangiocarcinoma. As a conclusion, future perspectives of IDH1 inhibition in IDH1 mutated tumors and possible strategies of sequencing and combinations will be reviewed and discussed.

Novel precision therapies for cholangiocarcinoma: an overview of clinical trials.

INTRODUCTION: The treatment landscape of biliary cancers is rapidly changing. Inhibitors against the actionable targets FGFR and IDH1 are now being included in the treatment guidelines of multiple countries for patients with advanced cholangiocarcinoma. However, there remains an unmet need in identifying the mechanisms of resistance and treatment strategies involving possible tumor sequencing. AREAS COVERED: In this review article, we address clinical trials evaluating FGFR, IDH, BRAF and HER2 inhibitors in advanced cholangiocarcinoma. We also review the mechanisms of resistance described thus far and approaches to overcome them. Articles selected for this review were based on reported studies indexed in PubMed (2010-2022). EXPERT OPINION: Precision medicine in biliary cancers has already been incorporated into the treatment landscape of the disease in many countries. Fusions of FGFR2 and mutations in IDH1 are the first drivers with targetable treatments approved in these cancers. HER2 and BRAF would be the next drivers with possible tumor-agnostic or cholangiocarcinoma-specific approvals. The advent of ctDNA could improve the accessibility of sequencing and recruitment in these clinical trials. However, limitations of detecting fusions should be considered and addressed in these platforms.

Immunotherapy in biliary tract cancers: Current evidence and future perspectives.

Bile duct tumors are comprised of tumors that originate from both intrahepatic and extrahepatic bile ducts and gallbladder tumors. These are aggressive tumors and chemotherapy is still the main treatment for advanced-stage disease and most of these cases have a poor overall survival. Strategies are aimed at treatments with better outcomes and less toxicity which makes immunotherapy an area of ​​significant importance. Recent Food and Drug Administration approvals of immune checkpoint inhibitors (ICI) for agnostic tumors based on biomarkers such as microsatellite instability-high and tumor mutation burden-high are important steps in the treatment of patients with advanced bile duct tumors. Despite limited responses with isolated checkpoint inhibitors in later lines of systemic treatment in advanced disease, drug combination strategies have been demonstrating encouraging results to enhance ICI efficacy.

Precision approaches for cholangiocarcinoma: progress in clinical trials and beyond.

INTRODUCTION: Although a relatively uncommon tumor, the incidence of intrahepatic cholangiocarcinoma is rising globally. Unfortunately, most patients are diagnosed with locally advanced or metastatic disease with poor prognosis. Strategies targeting genomic alterations and incorporation of precision medicine will represent a new therapeutic avenue for these patients. AREAS COVERED: In this review article, we addressed clinical trials in cholangiocarcinoma with FGFR, IDH, BRAF, and ErbB2 targeted therapies. We also reviewed mechanisms of resistance to precision medicine and possible future strategies to overcome clonal evolution. Articles selected for this review were based on reported studies indexed in PubMed (2010-2021). EXPERT OPINION: Pemigatinib, infigratinib and futibatinib could eventually be incorporated in the landscape of first-line systemic treatment for advanced cholangiocarcinoma with FGFR2 fusions or rearrangements after the ongoing phase III trials. Circulating tumor DNA could be used as a dynamic tool for evaluating mechanisms of resistance and prediction of response in patients treated with directed therapy.

Precision Medicine Targeting FGFR2 Genomic Alterations in Advanced Cholangiocarcinoma: Current State and Future Perspectives.

Although a relatively uncommon tumor, cholangiocarcinoma is on the rise globally. Of note, most patients are diagnosed with metastatic disease, and the prognosis is poor with cytotoxic chemotherapy. Strategies targeting specific genomic alterations have demonstrated promising activity in recent years and could represent a new therapeutic avenue for these patients. In this review, we will address the biology and clinical results of FGFR inhibition in intrahepatic cholangiocarcinoma, highlighting limitations associated with treatment and discussing the use of circulating tumor DNA to detect mechanisms of resistance.

Immune Checkpoint Inhibitors as Therapy to Down-Stage Hepatocellular Carcinoma Prior to Liver Transplantation.

Hepatocellular Carcinoma (HCC) is the most common liver malignancy and third leading cause of cancer death worldwide. For early- and intermediate-stage disease, liver-directed therapies for locoregional control, or down-staging prior to definitive surgical therapy with hepatic resection or liver transplantation, have been studied broadly, and are the mainstays of current treatment guidelines. As HCC incidence has continued to grow, and with more patients presenting with advanced disease, our current treatment modalities do not suffice, and better therapies are needed to improve disease-specific and overall survival. Until recently, sorafenib was the only systemic therapy utilized, and was associated with dismal results. The advent of immuno-oncology has been of significant interest, and has changed the paradigm of therapy for HCC. Lately, combination regimens including atezolizumab plus bevacizumab; durvalumab plus tremelimumab; and pembrolizumab plus Lenvatinib have shown impressive responses of between 25-35%; this is much higher than responses observed with single agents. Complete responses with checkpoint inhibitor therapy have been observed in advanced-stage HCC patients. These dramatic results have naturally led to several questions. Can or should checkpoint inhibitors, or other immunotherapy combinations, be used routinely before resection or transplant? Is there a synergistic effect of immunotherapy with locoregional therapy, and will pre-treatment increase disease-free survival after surgical intervention? Is it immunologically safe to use these therapies prior to transplantation? Much is still to be learned in terms of the dosing, timing, and overall utility of the use of immune checkpoint inhibitors for pre-transplant care and down-staging. More studies will be needed to understand the management of adverse events while maximizing the therapeutic window of these agents. In this review, we look at the current data on therapy with immune checkpoint inhibitors in advanced HCC, with a focus on pre-transplant treatment prior to liver transplant.

Laboratory variables as predictors of progression in gastroenteropancreatic neuroendocrine tumors in different lines of antineoplastic treatments.

OBJECTIVE: To determine the association of red cell blood counts, and liver panel tests to predict outcomes in patients with gastroenteropancreatic neuroendocrine tumors who underwent systemic antineoplastic treatments. METHODS: Patients with gastroenteropancreatic neuroendocrine tumors in systemic treatment were assessed according to laboratory tests within the same period. Progression free survival was determined by the period between the beginning of treatment and the date of progression. We used conditional models (PWP model) to verify the association between laboratory tests and tumor progression. The level of significance used was 5%. RESULTS: A total of 30 treatments given to 17 patients in the intention-to-treat population were evaluated. Treatment included octreotide, lanreotide, everolimus, lutetium, and chemotherapy. We had statistically significant results in chromogranin A, neutrophils and platelets-to-lymphocyte ratio. The risk of progression increases by 2% with the addition of 100ng/mL of chromogranin A (p=0.034), 4% with the increase of 100 neutrophil units (p=0.006), and 21% with the addition of 10 units in platelets-to-lymphocyte ratio (p=0.002). CONCLUSION: Chromogranin A, neutrophils and platelets-to-lymphocyte ratio were associated with disease progression during systemic treatment in gastroenteropancreatic neuroendocrine tumors. Further prospective studies with larger cohorts are necessary to validate our findings.