Andreas Kaubisch

PTEN GENE EXPRESSION AND MUTATIONS IN THE PIK3CA GENE AS PREDICTORS OF CLINICAL BENEFIT TO ANTI EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY THERAPY IN PATIENTS WITH KRAS WILD TYPE METASTATIC COLORECTAL CANCER

PURPOSE To identify novel genetic markers predictive of clinical benefit from epidermal growth factor receptor-directed antibody therapy in patients with metastatic colorectal cancer. PATIENTS AND METHODS Seventy-six consecutive patients who received cetuximab or panitumumab, either alone or in combination with chemotherapy and with available tumor tissue were included. Tumor tissue was tested by pyrosequencing for mutations at known hot spots in the KRAS, BRAF, PIK3CA, PIK3R1, AKT1, and PTEN genes. PTEN promoter methylation status was analyzed by methylation-specific polymerase chain reaction, and expression was determined by immunohistochemistry (IHC). Forty-four patients had 4 weeks of therapy and were considered for clinical correlates. RESULTS Consistent with previous studies, KRAS gene mutations were associated with a shorter progression-free survival (PFS) and overall survival (OS). Among the patients with wild-type KRAS, preservation of PTEN expression and PIK3CA wild-type status was associated with improved OS (median OS, 80.4 vs. 32.5 weeks; hazard ratio, 0.33; P = .0008) and a trend toward improved PFS (median PFS, 24.8 vs. 15.2 weeks; hazard ratio, 0.51; P = .06), compared with PTEN-negative or PIK3CA-mutant tumors. PTEN methylation was more common in the metastatic samples than in the primary samples (P = .02). The simultaneous presence of methylation and mutation in the PTEN gene was associated with IHC negativity (P = .026). CONCLUSION In addition to KRAS mutation, loss of PTEN expression (by IHC) and PIK3CA mutation is likely to be predictive of a lack of benefit to anti-EGFR therapy in metastatic colorectal cancer. PTEN promoter methylation and mutation status was predictive of PTEN expression and may be used as an alternative means of predicting response to EGFR-targeted therapy.

Who Benefits From Adjuvant Radiation Therapy for Gastric Cancer? A Meta-Analysis

PURPOSE Large randomized trials have demonstrated significant survival benefits with the use of adjuvant chemotherapy or chemoradiation therapy for gastric cancer. The importance of adjuvant radiation therapy (RT) remains unclear. We performed an up-to-date meta-analysis of randomized trials testing the use of RT for resectable gastric cancer. METHODS AND MATERIALS We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant (including neoadjuvant) RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine whether the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, or lymph node status. RESULTS Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR = 0.78, 95% CI: 0.70-0.86, P<.001) and DFS (HR = 0.71, 95% CI: 0.63-0.80, P<.001). In the 5 studies that tested adjuvant chemoradiation therapy against adjuvant chemotherapy, similar effects were seen for OS (HR = 0.83, 95% CI: 0.67-1.03, P=.087) and DFS (HR = 0.77, 95% CI: 0.91-0.65, P=.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. CONCLUSION In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regard to patient selection and integration with systemic therapy.

Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET).

260 Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. METHODS We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. RESULTS Confirmed PR was documented in 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%). CONCLUSIONS The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.

Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial

BACKGROUND Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. METHODS KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0-1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with ClinicalTrials.gov number NCT02702414. FINDINGS Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11-26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. INTERPRETATION Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. FUNDING Merck & Co, Inc.

Targeted Therapy for Hepatocellular Carcinoma

Hepatocellular cancer (HCC) is a leading cause of cancer death worldwide, and most patients who are diagnosed with HCC are ineligible for curative local therapy. The targeted agent sorafenib provides modest survival benefits in the setting of advanced disease. Novel systemic treatment options for HCC are sorely needed. In this review, we identify and categorize the drugs and targets that are in various phases of testing for use against HCC. We also focus on the potential for combining these agents with radiotherapy. This would help identify directions for future study that are likely to yield positive findings and improve outcomes for patients with HCC.

Up-regulation of amphotrophic retroviral receptor expression in human peripheral blood CD34+ cells

Retroviral‐mediated gene transfer into hematopoietic stem cells provides the only means of stable transduction of these cells and their progeny for use with a variety of potentially therapeutic genes. Expression of the Moloney amphotropic retroviral receptor—pit‐2 or GLVR‐2—is critical to the recognition and entry of Moloney leukemia virus‐derived viruses into human target cells such as CD34+ hematopoietic cells. GLVR‐2 functions as a sodium‐dependent phosphate transporter as well as a receptor. We have previously shown that the expression of the murine homologue of the amphotropic receptor Ram 1, also a phosphate transporter, is developmentally regulated in murine hematopoietic fetal liver cells. We also demonstrated that culture of murine fetal liver cells in phosphate‐free (PO4‐free) medium increases levels of receptor mRNA and makes murine fetal liver cells susceptible to Moloney amphotropic viral gene transfer. We now examine the effect of culture conditions on the expression of GLVR‐2 in human CD34+ cells. In this report, we demonstrate that there is a 2–3 fold increase in GLVR‐2 mRNA levels in CD34+ cells after 3 days in culture with interleukin 3, interleukin 6, and stem‐cell factor. In addition, the use of PO4‐free medium increases expression of GLVR‐2 an additional 2‐fold in these cells during this time. These results indicate that GLVR‐2 expression can be up‐regulated on these cells, and may permit improved retroviral gene transfer efficiencies. Am. J. Hematol. 61:243–253, 1999.

Survival analysis of Hispanics in a cohort of patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) appears to have worse prognosis among Hispanics and other ethnic minorities in the United States. We investigated the overall survival (OS) of Hispanics with HCC and compared it with non‐Hispanic (NH) whites and NH blacks.

Bridging therapy effectiveness in the treatment of hepatocellular carcinoma prior to orthotopic liver transplantation

Background Orthotopic liver transplantation (OLT) is the most effective treatment for hepatocellular carcinoma (HCC) in patients with underlying cirrhosis and portal hypertension. Availability of OLT is limited by donor-organ shortages, which increase patient waiting time until OLT. A variety of bridging therapies (BT) have been used to halt tumor progression in patients on the OLT waiting list. Despite complete radiologic responses following BT, viable tumor is often present in explants. Methods Treatment outcomes were evaluated in 50 patients who had a total of 125 BT for treatment of 93 nodules. Success of BT was assessed by radiologic response compared to histopathological examination of explanted livers. Results Pre-transplant treatments included: transcatheter arterial chemoembolization (TACE), alcohol ablation (ETOH), radiofrequency ablation (RFA), microwave ablation (MWA), selective internal radiation therapy (SIRT) and stereotactic body radiation therapy (SBRT). Fifty-nine (64%) nodules had a complete radiographic response to therapy; however, only 28 nodules (30%) had complete tumor necrosis (CTN) on explant examination. Ten nodules with CTN were treated with TACE alone. Seven of the 28 nodules with CTN were treated with TACE and RFA. Three of seven nodules treated with TACE and SIRT had CTN. Patients underwent a mean of 2.5 BTs. Six of 50 patients (12%) had no residual HCC in their explants. Five of those six patients (83%) had complete response (CR) on pre-transplant imaging. Conclusions Although favorable radiologic responses are seen following BT, viable HCC is seen in the majority of liver explants and radiographic imaging cannot always accurately predict pathological response. This underscores the need for aggressive treatment of patients who otherwise may not be eligible for OLT.

Inferior vena cava syndrome from pancreatic adenocarcinoma: Successful symptom palliation with endovascular stenting

Dear Editor: A 74-year-old male with unresectable pancreatic adenocarcinoma receiving therapeutic anticoagulation for left femoral deep venous thrombosis presented with extensive nontender bilateral lower extremity edema, in addition to sacral and scrotal edema preventing ambulation. This edema was relatively acute in onset, beginning a few weeks prior to admission, and was associated with an admission serum albumin level of 3.2 g/dL. An abdominal computed tomography scan did not detect propagation of the thrombus into the inferior vena cava (IVC) but did demonstrate significant external IVC compression by tumor (Fig. 1). The compression was just proximal to the right renal vein, resulting in massive dilatation of the IVC distal to the tumor. Palliative IVC stenting with 2 Gianturco self-expanding stents (25 mm 5 cm and 30 mm 5 cm; Cook Medical Inc., Bloomington, IN) was offered, with remarkable results. A venogram performed predeployment (Fig. 2A) and subsequent to the stent placement (Fig. 2B) demonstrates the initial flow obstruction and the immediate restoration of patency of the patient’s IVC. Within 24 hours, the patient had complete resolution of sacral and scrotal edema, with significant decrease in his bilateral lower extremity edema. At 48 hours poststenting, the patient had near-total resolution of edema in the right lower extremity, and nontender 1 pitting edema in his left lower extremity. Palliative diuretics were discontinued, and the patient rapidly resumed ambulation and was discharged home for outpatient management. The palliative results lasted for 5 months until his death from progressive cancer. Palliative management of unresectable pancreatic cancer has traditionally been limited to chemotherapy, radiotherLetters to the Editor

Radiation Recall Dermatitis in Patients Treated with Sorafenib

Introduction Radiation recall dermatitis (RRD) is a phenomenon that occurs in previously irradiated areas shortly after administration of a chemotherapeutic agent. As the use of sorafenib expands, the incidence of radiation recall dermatitis induced by sorafenib will likely increase. Here, we report on a patient who developed RRD and describe his clinical characteristics along with a review of the literature. Case Presentation Our patient was treated with palliative radiation therapy (RT) to a painful metastatic hepatocellular carcinoma lesion in the right forearm. He completed his radiation course with grade 1 dermatitis, which had resolved by the time he was started on sorafenib 400 mg twice daily 7 days afterwards. On the 21st day after RT, he presented with desquamation and erythema in the previously irradiated area of the right forearm, consistent with RRD. The sorafenib was discontinued and his symptoms subsequently resolved with conservative topical management. Conclusions Although the pathophysiologic mechanism of sorafenib-related radiation recall dermatitis remains to be investigated, practitioners should be aware of its presence and management in order to improve clinical outcomes.