Keratin 17 is a prognostic and predictive biomarker in pancreatic ductal adenocarcinoma.

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses. RESULTS: Patients with advanced-stage, low K17 PDACs treated using 5-fluorouracil (5-FU)-based chemotherapeutic regimens had 3-fold longer survival than corresponding cases treated with gemcitabine-based chemotherapy. By contrast, PDACs with high K17 did not respond to either regimen. The predictive value of K17 was independent of tumor mutation status and other clinicopathologic variables. CONCLUSIONS: The detection of K17 in 10% or greater of PDAC cells identified patients with shortest survival. Among patients with low K17 PDACs, 5-FU-based treatment was more likely than gemcitabine-based therapies to extend survival.

A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease.

BACKGROUND: Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. METHODS: Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. RESULTS: The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. CONCLUSIONS: In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.

Perioperative chemotherapy versus adjuvant chemotherapy strategies in resectable gastric and gastroesophageal cancer: A Markov decision analysis.

BACKGROUND: Perioperative chemotherapy has been shown to improve overall survival (OS) for operable gastric and gastroesophageal cancer. However, optimal sequence of surgery and chemotherapy has not been clearly identified. Markov models are useful for analyzing the outcomes of different treatment strategies in the absence of adequately powered randomized clinical trials. In this study, we use Markov decision analysis models to compare median OS (mOS), quality-adjusted mOS, life expectancy (LE), and quality-adjusted life expectancy (QALE) of perioperative chemotherapy with adjuvant chemotherapy strategies in resectable gastric and gastroesophageal cancer patients. METHODS: Markov models are constructed to compare two strategies: adjuvant chemotherapy after surgery and preoperative chemotherapy followed by cancer resection and postoperative chemotherapy. LE and QALE are calculated analytically, and mOS are obtained by simulation. Parameters used in the models are computed from prospective clinical trial data published in PUBMED from January 2000 to July 2020. RESULTS: Total of 8088 patients from 25 prospective studies were included in this analysis. Regardless of R0 resection ratio, the analyses of the models show a higher mOS for patients in the perioperative therapy arm compared to adjuvant chemotherapy. For R0 resected patients, the perioperative therapy arm provided an additional 11.0 mOS months (61.3 months vs. 50.3 months). For R1 resected patients, the perioperative therapy arm had mOS of 17.0 months vs. 10.7 months in adjuvant therapy. CONCLUSIONS: The Markov models indicate that perioperative chemotherapy improves mOS, quality-adjusted mOS, LE, and QALE for resectable gastric and gastroesophageal cancer patients compared to adjuvant chemotherapy strategies.

Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients.

Purpose This was a phase I/II adoptive T cell trial in 7 locally advanced and metastatic pancreatic cancer patients using 3-8 infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (BATs) to determine safety, the maximum tolerated dose (MTD), immune responses, time to progression (TTP), and overall survival (OS). Study Design: T cells obtained by apheresis were expanded and armed with EGFRBi, cryopreserved for infusions. In a phase I dose escalation, five patients received three weekly infusions of 10-40 × 109 BATs/infusion followed by a booster infusion 3 months later, and 2 patients received 8 infusions twice weekly for 4 weeks in a phase II. The trials were registered at http://www.clinicaltrials.gov, NCT01420874 and NCT02620865. Results: There were no dose-limiting toxicities (DLTs), and the targeted dose of 80 × 109 BATs was met. The median TTP is 7 months, and the median OS is 31 months. Two patients had stable disease for 6.5 and 25+ months, and two patients developed complete responses (CRs) after restarting chemotherapy. Infusions of BATs induced anti-pancreatic cancer cytotoxicity, innate immune responses, cytokine responses (IL-12, IP-10), and shifts in CD4 and CD8 Vß repertoire with enhanced cytoplasmic IFN-γ staining in the Vß repertoire of the CD8 subset that suggest specific clonal TCR responses. Conclusions: Infusions of BATs are safe, induce endogenous adaptive anti-tumor responses, and may have a potential to improve overall survival.

Correction: Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comparative single-cell RNA sequencing (scRNA-seq) reveals liver metastasis-specific targets in a patient with small intestinal neuroendocrine cancer.

Genomic analysis of a patient's tumor is the cornerstone of precision oncology, but it does not address whether metastases should be treated differently. Here we tested whether comparative single-cell RNA sequencing (scRNA-seq) of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide the treatment of a patient's metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on Sandostatin, and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases that had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated.

Identification of targetable BRAF ΔN486_P490 variant by whole-genome sequencing leading to dabrafenib-induced remission of a BRAF-mutant pancreatic adenocarcinoma.

The tumor genome of a patient with advanced pancreatic cancer was sequenced to identify potential therapeutic targetable mutations after standard of care failed to produce any significant overall response. Matched tumor-normal whole-genome sequencing revealed somatic mutations in BRAF, TP53, CDKN2A, and a focal deletion of SMAD4 The BRAF variant was an in-frame deletion mutation (ΔN486_P490), which had been previously demonstrated to be a kinase-activating alteration in the BRAF kinase domain. Working with the Novartis patient assistance program allowed us to treat the patient with the BRAF inhibitor, dabrafenib. The patient's overall clinical condition improved dramatically with dabrafenib. Levels of serum tumor marker dropped immediately after treatment, and a subsequent CT scan revealed a significant decrease in the size of both primary and metastatic lesions. The dabrafenib-induced remission lasted for 6 mo. Preclinical studies published concurrently with the patient's treatment showed that the BRAF in-frame mutation (ΔNVTAP) induces oncogenic activation by a mechanism distinct from that induced by V600E, and that this difference dictates the responsiveness to different BRAF inhibitors. This study describes a dramatic instance of how high-level genomic technology and analysis was necessary and sufficient to identify a clinically logical treatment option that was then utilized and shown to be of clinical value for this individual.

Spotlight on liposomal irinotecan for metastatic pancreatic cancer: patient selection and perspectives.

Pancreatic cancer is a highly lethal disease, where the mortality closely matches increasing incidence. Pancreatic ductal adenocarcinoma (PDAC) is the most common histologic type that tends to metastasize early in tumor progression. For metastatic PDAC, gemcitabine had been the mainstay treatment for the past three decades. The treatment landscape has changed since 2010, and current first-line chemotherapy includes triplet drugs like FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and oxaliplatin), and doublet agents like nab-paclitaxel and gemcitabine. Nanoliposomal encapsulated irinotecan (nal-IRI) was developed as a novel formulation to improve drug delivery, effectiveness, and limit toxicities. Nal-IRI, in combination with leucovorin-modulated fluorouracil (5-FU/LV), was found in a large randomized phase III clinical trial (NAPOLI-1) to significantly improve overall survival in patients who progressed on gemcitabine-based therapy. This review will focus on the value of using nal-IRI, toxicities, recent clinical experiences, and tools to improve patient outcomes in this setting.

Challenges in Ras therapeutics in pancreatic cancer.

Pancreatic cancer is considered among the most aggressive and the least curable of all human malignancies. It is usually characterized by multiple aberrations in tumor suppressor genes and oncogenes, most notably activating mutations in KRAS. This review examines the various attempts that have been made to inhibit Kras and its downstream signaling pathways in pancreatic cancer with an emphasis on challenges related to clinical trials. Attempts include preventing the localization of Ras protein to the plasma membrane, inhibiting downstream oncogenic signaling by targeting Kras effectors such as MEK1/2, Erk1/2 or Akt singly or in combination, and directly inhibiting Kras protein. Most clinical trials have focused on inhibiting downstream effector pathways and clinical benefit has been limited due to compensatory mechanisms and toxicity associated with small therapeutic windows. Additionally, genetic screens have been conducted to identify gene or genes that could provide therapeutic vulnerabilities in mutant KRAS cells and provide a way to target mutant Kras protein only. We also discuss how potentially transforming clinical trials have failed in the past and what new strategies are on-going in clinical trials for pancreas cancer. For long-term success in targeting Kras, future efforts should focus on combinatorial strategies to more effectively block Kras pathways at multiple points, and improve translational application of pre-clinical data to the clinic.

Fluoridation and county-level secondary bone cancer among cancer patients 18 years or older in New York State.

The decision whether to fluoridate drinking water continues to be controversial in some communities. Dental and skeletal fluorosis in response to chronic fluoride overexposure are cited as reasons to avoid community water fluoridation in spite of evidence of the oral and skeletal health benefits fluoridation confers. Community fluoridation of ~ 1 mg/L fluoride has not been found to be associated with primary bone cancer but is associated with improved bone strength. No studies have examined fluoride exposure and secondary bone cancer, a common metastasis with significant morbidity. We hypothesize that fluoridation could diminish the likelihood of secondary bone cancer due to its role in bone fortification. We examined the association between community water fluoridation category and prevalence of secondary bone cancer from 2008 to 2010 among cancer patients of 18 years of age or older in counties in New York State. Relative to counties with less than 25% of the water supply fluoridated, we report no association between secondary bone cancer among cancer patients in counties with 25-75% of the water supply fluoridated (ß = 0.02, p = 0.96) and among those in counties with > 75% fluoridated (ß = 0.02, p = 0.97). We found no evidence of an association between community water fluoridation category and secondary bone cancer from 2008 to 2010 at the county level in New York State.

Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) hijacks innate cellular processes to promote cancer growth. We hypothesized that PC exploits PD-1/PD-L1 not only to avoid immune responses, but to directly enhance growth. We also hypothesized that immune checkpoint inhibitors (ICIs) have direct cytotoxicity in PC. We sought to elucidate therapeutic targeting of PD-1/PD-L1. METHODS: PD-1 was assessed in PC cells, patient-derived organoids (PDOs), and clinical tissues. Then, PC cells were exposed to PD-L1 to evaluate proliferation. To test PD-1/PD-L1 signaling, cells were exposed to PD-L1 and MAPK was examined. Radio-immunoconjugates with anti-PD-1 drugs were developed to test uptake in patient-derived tumor xenografts (PDTXs). Next, PD-1 function was assessed by xenografting PD-1-knockdown cells. Finally, PC models were exposed to ICIs. RESULTS: PD-1 expression was demonstrated in PCs. PD-L1 exposure increased proliferation and activated MAPK. Imaging PDTXs revealed uptake of radio-immunoconjugates. PD-1 knockdown in vivo revealed 67% smaller volumes than controls. Finally, ICI treatment of both PDOs/PDTXs demonstrated cytotoxicity and anti-MEK1/2 combined with anti-PD-1 drugs produced highest cytotoxicity in PDOs/PDTXs. CONCLUSIONS: Our data reveal PCs innately express PD-1 and activate druggable oncogenic pathways supporting PDAC growth. Strategies directly targeting PC with novel ICI regimens may work with adaptive immune responses for optimal cytotoxicity.

Multiregion Comprehensive Genomic Profiling of a Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm with Trilineage Differentiation.

Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) are a group of rare tumors previously known as mixed adenoneuroendocrine carcinomas (MANECs). The neuroendocrine component is high-grade and may consist of small-cell carcinoma or large-cell neuroendocrine carcinoma. The nonneuroendocrine component may consist of adenocarcinoma or squamous cell carcinoma. We report a unique case of a MiNEN with trilineage differentiation: large-cell neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma. The reported patient presented with symptoms of an upper gastrointestinal bleed and was ultimately diagnosed with a MiNEN with trilineage differentiation. This is the first report of this exceedingly rare tumor type to include next-generation sequencing of the 3 separate tumor entities. In addition, we review the current literature and discuss the role of next-generation sequencing in classifying and treating MiNEN tumors.

Development of Patient-Derived Gastric Cancer Organoids from Endoscopic Biopsies and Surgical Tissues.

BACKGROUND: Organoids are three-dimensional in vitro models of human disease developed from benign and malignant gastrointestinal tissues with tremendous potential for personalized medicine applications. We sought to determine whether gastric cancer patient-derived organoids (PDOs) could be safely established from endoscopic biopsies for rapid drug screening. METHODS: Patients underwent esophagogastroduodenoscopy (EGD) for surveillance or staging and had additional forceps biopsies taken for PDO creation. Cancer tissues from operative specimens were also used to create PDOs. To address potential tumor heterogeneity, we performed low-coverage whole-genome sequencing of endoscopic-derived PDOs with paired surgical PDOs and whole-tumor lysates. The stability of genomic alterations in endoscopic organoids was assessed by next-generation sequencing and nested polymerase chain reaction (PCR) assay. The feasibility and potential accuracy of drug sensitivity screening with endoscopic-derived PDOs were also evaluated. RESULTS: Gastric cancer PDOs (n = 15) were successfully established from EGD forceps biopsies (n = 8) and surgical tissues (n = 7) from five patients with gastric adenocarcinoma. Low-coverage whole-genomic profiling of paired EGD and surgical PDOs along with whole-tumor lysates demonstrated absence of tumor heterogeneity. Nested PCR assay identified similar KRAS alterations in primary tumor and paired organoids. Drug sensitivity testing of endoscopic-derived PDOs displayed standard dose-response curves to current gastric cancer cytotoxic therapies. CONCLUSIONS: Our study results demonstrate the feasibility of developing gastric cancer PDOs from EGD biopsies. These results also indicate that endoscopic-derived PDOs are accurate surrogates of the primary tumor and have the potential for drug sensitivity screening and personalized medicine applications.

Assessing Clinical Outcomes in Colorectal Cancer with Assays for Invasive Circulating Tumor Cells.

Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality. The goals of this study are to evaluate the association between levels of invasive circulating tumor cells (iCTCs) with CRC outcomes and to explore the molecular characteristics of iCTCs. Peripheral blood from 93 patients with Stage I⁻IV CRC was obtained and assessed for the detection and characterization of iCTCs using a functional collagen-based adhesion matrix (CAM) invasion assay. Patients were followed and assessed for overall survival. Tumor cells isolated by CAM were characterized using cell culture and microarray analyses. Of 93 patients, 88 (95%) had detectable iCTCs, ranging over 0⁻470 iCTCs/mL. Patients with Stage I⁻IV disease exhibited median counts of 0.0 iCTCs/mL (n = 6), 13.0 iCTCs/mL (n = 12), 41.0 iCTCs/mL (n = 12), and 133.0 iCTCs/mL (n = 58), respectively (p < 0.001). Kaplan⁻Meier curve analysis demonstrated a significant survival benefit in patients with low iCTC counts compared with in patients with high iCTC counts (log-rank p < 0.001). Multivariable Cox model analysis revealed that iCTC count was an independent prognostic factor of overall survival (p = 0.009). Disease stage (p = 0.01, hazard ratio 1.66; 95% confidence interval: 1.12⁻2.47) and surgical intervention (p = 0.03, HR 0.37; 95% CI: 0.15⁻0.92) were also independent prognostic factors. Gene expression analysis demonstrated the expression of both endothelial and tumor progenitor cell biomarkers in iCTCs. CAM-based invasion assay shows a high detection sensitivity of iCTCs that inversely correlated with overall survival in CRC patients. Functional and gene expression analyses showed the phenotypic mosaics of iCTCs, mimicking the survival capability of circulating endothelial cells in the blood stream.

Clinical Utility of Positron Emission Tomography Magnetic Resonance Imaging (PET-MRI) in Gastrointestinal Cancers.

Anatomic imaging utilizing both CT (computed tomography) and MRI (magnetic resonance imaging) limits the assessment of cancer metastases in lymph nodes and distant organs while functional imaging like PET (positron emission tomography) scan has its limitation in spatial resolution capacity. Hybrid imaging utilizing PET-CT and PET-MRI are novel imaging modalities that are changing the current landscape in cancer diagnosis, staging, and treatment response. MRI has shown to have higher sensitivity in soft tissue, head and neck pathology, and pelvic disease, as well as, detecting small metastases in the liver and bone compared to CT. Combining MRI with PET allows for detection of metastases that may have been missed with current imaging modalities. In this review, we will examine the clinical utility of FDG PET-MRI in the diagnosis and staging of gastrointestinal cancers with focus on esophageal, stomach, colorectal, and pancreatic cancers. We will also explore its role in treatment response and future directions associated with it.

Liposomal Irinotecan in the Treatment of Refractory Pancreatic Cancer.

Effective therapies against metastatic pancreatic cancer remain limited, and despite treatment, many will ultimately progress. Previously, few options were available for second line therapy in metastatic pancreatic cancer. Liposomal encapsulated irinotecan, in combination with leucovorin-modulated fluorouracil, was found to significantly increase overall survival in patients who have progressed after gemcitabine- based therapy in a large, international, randomized clinical trial (NAPOLI-1). We reviewed the background of systemic therapy for metastatic pancreatic cancer, examined putative mechanisms for the success of encapsulated drugs, and identified recent patent applications on the use of liposomal irinotecan in pancreatic cancer. The landmark NAPOLI-1 trial established a second-line option for those with metastatic pancreatic cancer refractory to gemcitabine chemotherapy, but effective therapies with long duration of response are still lacking. Alternative techniques targeting key driver genes in pancreatic cancer and novel methods of early detection and targeting drugs are currently being explored. How liposomal irinotecan can be integrated into chemotherapy regimens, including neoadjuvant or first line combinations, are currently being tested in clinical trials and covered by several new patent applications.

Neoadjuvant vs. adjuvant treatment of Siewert type II gastroesophageal junction cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry.

BACKGROUND: Cancer of the gastroesophageal junction (GEJ) has been rising in incidence in recent years. The role of radiation therapy (RT) in the treatment of GEJ cancer remains unclear, as the largest prospective trials advocating for either adjuvant or neoadjuvant chemoradiotherapy (CRT) combine GEJ cancer with either gastric or esophageal cancer. The aim of the present study is to examine the association of neoadjuvant versus adjuvant treatment with overall and disease-specific survival (DSS) for patients with surgically resected cancer of the true GEJ (Siewert type II). METHODS: The surveillance, epidemiology, and end results (SEER) registry database (2001-2011) was queried for cases of surgically resected Siewert type II GEJ cancer. A total of 1,497 patients with resectable GEJ cancer were identified, with 746 receiving adjuvant RT and 751 receiving neoadjuvant RT. Retrospective analysis was performed with the endpoints of overall and DSS. RESULTS: Using cox regression and controlling for independent covariates (age, sex, race, stage, grade, histology, and year of diagnosis), we showed that adjuvant RT was associated with a significantly lower death risk [hazard ratio (HR), 0.84; 95% confidence interval 0.73-0.97; P value=0.0168] and significantly lower disease-specific death risk (HR, 0.84; 95% confidence interval, 0.72-0.97; P value=0.0211) as compared to neoadjuvant RT. CONCLUSIONS: This analysis of SEER data showed that adjuvant RT was associated with a survival benefit as compared to neoadjuvant RT for the treatment of Siewert type II GEJ cancer. We suggest future prospective studies to compare outcomes of adjuvant versus neoadjuvant treatment for true GEJ cancer.

A Randomized, Phase II Trial of Cetuximab With or Without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients With Metastatic Colorectal Carcinoma.

BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in colorectal cancer (CRC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. This randomized phase II study evaluated cetuximab with or without PX-866 in patients with metastatic, anti-epidermal growth factor receptor-naive, KRAS codon 12 and 13 wild-type CRC. PATIENTS AND METHODS: Patients with metastatic CRC who had received both oxaliplatin and irinotecan were randomized (1:1) to cetuximab (400 mg/m2 loading then 250 mg/m2 weekly) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival (OS), toxicity, and correlation of relevant biomarkers with efficacy outcomes. RESULTS: A total of 85 patients were enrolled. The median PFS was 59 days versus 104 days for arms A (cetuximab + PX-866) and B (cetuximab alone), respectively (P = .77). OS between the 2 arms (266 vs. 333 days for arm A vs. B) were similar (P = .83). Overall toxicity, including treatment-related toxicity, was higher in arm A compared with arm B, especially in terms of all-grade nausea (66% vs. 37%), vomiting (50% vs. 29%), diarrhea (64% vs. 18%), and rash (66% vs. 37%). Grade 3 diarrhea occurred in 19% of patients in Arm A and 0% in Arm B. PIK3CA mutations and PTEN loss by immunohistochemistry were infrequently seen. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, objective response rate, or OS in patients with metastatic CRC. The combination arm had greater toxicity and may have been harmful in this study.

Second-Line Treatment of Advanced Gastric Cancer: Where Do We Stand?

Gastric cancer is a leading cause of cancer death and is associated with poor prognosis. The treatment of advanced gastric cancer is changing with the development of novel agents. Until recently, no standard treatment was available for patients with advanced gastric cancer in the second-line setting. Single-agent chemotherapy with docetaxel or irinotecan has been shown to improve survival and quality of life in patients whose disease has progressed while on prior chemotherapy. Combination chemotherapy is associated with a modest benefit at the expense of increased toxicity. Recently, ramucirumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF) receptor-2, has been approved for the treatment of refractory advanced gastric cancer as a single agent or in combination with paclitaxel. Apatinib, a small molecule tyrosine kinase inhibitor targeting VEGF, has demonstrated activity in Asian populations whose disease has progressed on 2 lines of therapy. However, much work is still needed, including the development of biomarkers that could predict response to therapy.