Mahipal, Amit

This series of nine articles (three original articles, six reviews) is presented by international leaders in biliary tract cancers (BTC) [...]

Abstract Background: Critically shortened telomeres contribute to chromosomal instability and neoplastic transformation and are associated with early death of patients with certain cancer types. Shorter leukocyte telomere length (LTL) has been associated with higher risk for pancreatic ductal adenocarcinoma (PDAC) and might be associated also with survival of patients with PDAC. We investigated the association between treatment-naïve LTL and overall survival of patients with incident PDAC. Methods: The study included 642 consecutively enrolled PDAC patients in the Mayo Clinic Biospecimen Resource for Pancreas Research. Blood samples were obtained at the time of diagnosis, before the start of cancer treatment, from which LTL was assayed by qRT-PCR. LTL was first modeled as a continuous variable (per-interquartile range decrease in LTL) and then as a categorized variable (short, medium, long). Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated for overall mortality using Cox proportional hazard models. Results: Shorter treatment-naïve LTL was associated with higher mortality among patients with PDAC (HRcontinuous = 1.13, 95% CI: 1.01–1.28, P = 0.03; HRshortest vs. longest LTL = 1.29, 95% CI: 1.05–1.59, Ptrend = 0.01). There was a difference in the association between LTL and overall mortality by tumor stage at diagnosis; resectable tumors (HRcontinuous = 0.91; 95% CI: 0.73–1.12), locally advanced tumors (HRcontinuous = 1.29; 95% CI: 1.07–1.56), and metastatic tumors (HRcontinuous = 1.17; 95% CI: 0.96–1.42), Pinteraction = 0.04. Conclusion: Shorter treatment-naïve LTL is associated with poorer overall survival of patients with incident PDAC. Impact: Peripheral blood LTL might be a prognostic marker for PDAC.

The current standard treatment for patients with early-stage colon cancer consists of surgical resection, followed by adjuvant therapy in a select group of patients deemed at risk of cancer recurrence. The decision to administer adjuvant therapy, intended to eradicate the clinically inapparent minimal residual disease (MRD) to achieve a cure, is guided by clinicopathologic characteristics of the tumor. However, the risk stratification based on clinicopathologic characteristics is imprecise and results in under or overtreatment in a substantial number of patients. Emerging research indicates that the circulating tumor DNA (ctDNA), a fraction of cell-free DNA (cfDNA) in the bloodstream that originates from the neoplastic cells and carry tumor-specific genomic alterations, is a promising surrogate marker of MRD. Several recent studies suggest that ctDNA-guided risk stratification for adjuvant therapy outperforms existing clinicopathologic prognostic indicators. Preliminary data also indicate that, aside from being a prognostic indicator, ctDNA can inform on the efficacy of adjuvant therapy, which is the underlying scientific rationale for several ongoing clinical trials evaluating ctDNA-guided therapy escalation or de-escalation. Furthermore, serial monitoring of ctDNA after completion of definitive therapy can potentially detect cancer recurrence much earlier than conventional surveillance methods that may provide a critical window of opportunity for additional curative-intent therapeutic interventions. This article presents a critical overview of published studies that evaluated the clinical utility of ctDNA in the management of patients with early-stage colon cancer, and discusses the potential of ctDNA to transform the adjuvant therapy strategies.

Biliary tract cancers (BTCs) are a heterogeneous group of adenocarcinomas that originate from the epithelial lining of the biliary tree. BTCs are characterized by presentation with advanced disease precluding curative surgery, rising global incidence, and a poor prognosis. Chemotherapy is the mainstay of the current treatment, which results in a median overall survival of less than one year, underscoring the need for novel therapeutic agents and strategies. Next-generation sequencing-based molecular profiling has shed light on the underpinnings of the complex pathophysiology of BTC and has uncovered numerous actionable targets, leading to the discovery of new therapies tailored to the molecular targets. Therapies targeting fibroblast growth factor receptor (FGFR) fusion, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and BRAF mutations have produced early encouraging results in selected patients. Current clinical trials evaluating targeted therapies, as monotherapies and in combination with other agents, are paving the way for novel treatment options. Genomic profiling of cell-free circulating tumor DNA that can assist in the identification of an actionable target is another exciting area of development. In this review, we provide a contemporaneous appraisal of the evolving targeted therapies and the ongoing clinical trials that will likely transform the therapeutic paradigm of BTC.

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models. Experimental Design: We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial. Results: SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin–bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor–GEM–nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months. Conclusions: Our preclinical and ongoing clinical study lends support to the use of selinexor–GEM–nab-paclitaxel as an effective therapy for metastatic PDAC.

AbstractTrial InformationClick here to access other published clinical trials.Lessons LearnedTrifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy.BackgroundPatients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.MethodsPatients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity.ResultsOf 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.ConclusionFTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with dismal prognosis when diagnosed at advanced stages. Surgical resection of the primary tumor or orthotropic liver transplantation serves as a potential curative option. However, this approach is highly dependent on the hepatic reserve and baseline functional status of the patient. Liver directed therapies such as portal vein embolization (PVE), trans-arterial chemoembolization (TACE), and systemic chemotherapy are employed in non-surgical candidates. Sorafenib was the only approved systemic therapeutic agent for almost a decade until the recent approval of lenvatinib by the United States Food and Drug Administration (FDA) as an alternate first-line agent. Regorafenib, nivolumab, pembrolizumab and cabozantinib are approved by the FDA as second-line agents in patients who failed or could not tolerate sorafenib. Ramucirumab was recently FDA approved for the subset of patients that have high alfa-fetoprotein levels (>400 ng/mL). A better understanding of tumorigenesis and encouraging clinical trial results that evaluated immune-checkpoint inhibitors opened doors for immunotherapy in HCC. Immune checkpoint inhibitors have demonstrated a prolonged median overall and progression-free survival in a subset of patients with HCC. On-going translational and clinical research will hopefully provide us with a better understanding of tumor markers, genetic aberrations and other factors that determine the immunotherapy response in HCC. In this review, we sought to summarize the potential role and future directions of immunotherapy in the management of HCC.

Objectives Prognostic factors for solid pseudopapillary neoplasms (SPN) of the pancreas have been incompletely defined in the literature. We aimed to use the National Cancer Database to describe survival and characterize prognostic factors in patients with pancreatic pseudopapillary neoplasms. Methods We identified 304 patients with pancreatic SPN diagnosed between 2004 and 2012 using the National Cancer Database. All patients were included in the survival analysis. Kaplan-Meier method, χ 2 , and log-rank tests were used for statistical analysis. Cox proportional hazard regression model was used for multivariate analysis. Results The median age at diagnosis was 36.5 years. Eighty-five percent of patients were female, 69% were white, and 25% were black. Metastases were observed in 5% of patients. Median tumor size was 5.1 cm. Ninety-two percent of patients underwent primary tumor resection. At 60 months, 98% of patients who underwent resection were alive, and 40% who did not undergo resection were alive. On multivariate analysis, female sex, resection of primary tumor, and absence of metastasis were correlated with improved survival. Conclusions Patients with SPN who undergo resection have an excellent survival at 5 years. Surgery should be considered in all patients with this diagnosis.