Malinda Itchins

A multireferral centre retrospective cohort analysis on the experience in treatment of metastatic uveal melanoma and utilization of sequential liver-directed treatment and immunotherapy

Metastatic uveal melanoma is a rare malignancy with a poor prognosis. To date, systemic therapy has been ineffective; however, there are few data on the benefits of anti-CTLA4 or anti-PD-1 antibodies in sequence with liver-directed therapy. A retrospective cohort analysis was carried out on 37 consecutive patients managed in a tertiary referral centre examining the safety and efficacy of treatment; patterns of care; and impact on survival. The sequential treatment with transarterial chemotherapy (TAC), systemic immunotherapy (IT) and systemic chemotherapy was reviewed. In all, 18 patients in the series received sequential therapy. The median overall survival (OS) was 17 months (n=37), which compared favourably with previously reported series. Patients treated with TAC first or second line had an overall progression-free survival (PFS) of 9 months (n=29) and IT PFS 7 months (n=26). The overall response rate (ORR) for TAC first line was 26% and the disease control rate (DCR) was 65% (n=23). ORR for IT first line was 7%, DCR 77% (n=14). Second-line (cross-over) IT ORR was 16%, DCR 58% (n=12). For second-line (cross-over) TAC, ORR was 50% and DCR was 66% (n=6). Toxicity was manageable. There were no cases of autoimmune hepatitis. In this retrospective small series analysis in uveal melanoma, liver-directed therapy and IT in sequence have shown to be active and reasonably well tolerated. Further prospective clinical trials should clarify the role of these treatments and their potential survival benefit.

Treatment of ALK-rearranged non-small cell lung cancer: A review of the landscape and approach to emerging patterns of treatment resistance in the Australian context

Since the identification of anaplastic lymphoma kinase (ALK) gene rearrangements in non‐small cell lung cancer (NSCLC) in 2005, the treatment of ALK‐rearranged NSCLC (ALK+ NSCLC) has evolved at a rapid pace. This molecularly distinct subset of NSCLC has uniquely important biology, clinicopathologic features and mechanisms of drug resistance which impact on the choice of treatment for a patient with this disease. There are multiple ALK tyrosine kinase inhibitors now available in clinical practice with efficacy data continuing to emerge and guide the optimal treatment algorithm. A detailed search of medical databases and clinical trial registries was conducted to capture all relevant articles on this topic enabling an updated detailed overview of the landscape of management of ALK‐rearranged NSCLC.

Do EGFR tyrosine kinase inhibitors (TKIs) still have a role in EGFR wild-type pre-treated advanced non-small cell lung cancer (NSCLC)?—the shifting paradigm of therapeutics

EGFR mutations are well established as important oncogenic drivers that occur in 10–44% of primary lung adenocarcinomas occurring more frequently in women, Asians and non-smokers (1,2).

ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms accounting for 1% to 2% of all pancreatic tumors. The biological behavior of PanNETs is heterogeneous and unpredictable, adding to the difficulties of clinical management. The DAXX (death domain associated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) genes encode proteins involved in SWI/SNF-like chromatin remodeling. Somatic inactivating mutations in DAXX and ATRX are frequent in PanNETs, mutually exclusive, and associated with telomere dysfunction, resulting in genomic instability and alternate lengthening of telomeres. We sought to assess the clinical significance of the loss of the ATRX and DAXX proteins as determined by immunohistochemistry (IHC) in patients with PanNET. From an unselected cohort of 105 patients, we found ATRX loss in 10 tumors (9.5%) and DAXX loss in 16 (15.2%). DAXX and ATRX losses were confirmed mutually exclusive and associated with other adverse clinicopathological variables and poor survival in univariate analysis. In addition, ATRX loss was also associated with higher AJCC stage and infiltrative tumor borders. However, only ATRX loss, lymphovascular invasion, and perineural spread were independent predictors of poor overall survival in multivariate analysis. In conclusion, loss of expression of ATRX as determined by IHC is a useful independent predictor of poor overall survival in PanNETs. Given its relative availability, ATRX loss as determined by IHC may have a role in routine clinical practice to refine prognostication in patients with PanNET.

Biomarker panel predicts survival after resection in pancreatic ductal adenocarcinoma: A multi-institutional cohort study

BACKGROUND Up to 60% of patients who undergo curative-intent pancreatic ductal adenocarcinoma (PDAC) resection experience disease recurrence within six months. We recently published a systematic review of prognostic immunohistochemical biomarkers in PDAC and shortlisted a panel of those reported with the highest level of evidence, including p53, p16, Ca-125, S100A4, FOXC1, EGFR, mesothelin, CD24 and UPAR. This study aims to discover and validate the prognostic significance of a combinatorial panel of tumor biomarkers in patients with resected PDAC. METHODS Patients who underwent PDAC resection were included from a single institution discovery cohort and a multi-institutional validation cohort. Tumors in the discovery cohort were stained immunohistochemically for all nine shortlisted biomarkers. Biomarkers significantly associated with overall survival (OS) were reevaluated as a combinatorial panel in both discovery and validation cohorts for its prognostic significance. RESULTS 224 and 191 patients were included in the discovery and validation cohorts, respectively. In both cohorts, S100A4, Ca-125 and mesothelin expression were associated with shorter OS. In both cohorts, the number of these biomarkers expressed was significantly associated with OS (discovery cohort 36.8 vs. 26.4 vs 16.3 vs 12.8 months, P < 0.001; validation cohort 25.2 vs 18.3 vs 13.6 vs 11.9 months, P = 0.008 for expression of zero, one, two and three biomarkers, respectively). On multivariable analysis, expression of at least one of three biomarkers was independently associated with shorter OS. CONCLUSION Combinations of S100A4, Ca-125 and mesothelin expression stratify survival after resection of localized PDAC. Co-expression of all three biomarkers is associated with the poorest prognostic outcome.

ROS1-Rearranged Non–Small-Cell Lung Cancer, Factor V Leiden, and Recurrent Venous Thromboses

Cancer-related venous thromboembolic events are a significant morbidity and mortality burden. The risks of venous thromboembolic events vary with cancer location, stage, preexisting thrombophilia conditions, and possibly with driver mutations. In combination, these risks may be synergistic despite each factor being a minor risk independently. Despite the availability of targeted therapy for ROS1rearranged nonesmall-cell lung cancer, there is increasing evidence of a poorer outcome group with rapid decline and progression of disease; the mechanisms are still unknown, and interaction with coagulation system may be a potential factor. Thromboprophylaxis for increasedor multiple-risk patients needs to be individually tailored and closely monitored.

Pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+ NSCLC) in an Australian Metropolitan Tertiary Referral Centre: A retrospective cohort analysis

To report on the pattern of care and survival of anaplastic lymphoma kinase rearranged non–small cell lung cancer (ALK+NSCLC) in a real‐world retrospective cohort from an Australian tertiary referral center.

The evolving landscape of treatment for advanced gastric cancer and the role of anti-angiogenic therapy: implications from results of the INTEGRATE study

Gastric cancer (GC) is the fifth most common malignancy worldwide. Nearly 2/3 of all cases are in developing countries in Eastern Europe, South America, and Asia, 42% of all new cases are in China (1). Empiric chemotherapy has been the mainstay of treatment for patients presenting with advanced/metastatic disease, to help reduce symptoms and prolong survival. In the first line setting a fluoropyrimidine backbone is utilized (5-FU, capecitabine, S1), in combination with a platinum agent (cisplatin, oxaliplatin) or a taxane (2). Therapy has evolved in a stepwise fashion, with incremental gains with each additional agent to this backbone, with doublet then triplet chemotherapy leading to improvements in median overall survival (OS), but at the expense of greater toxicity. Randomised controlled trials have further confirmed the benefit of chemotherapy in the second line setting with paclitaxel, docetaxel and irinotecan (3,4). The next key evolution of therapy has been the addition of a biologic agent to chemotherapy and the use anti-angiogenic therapy in refractory disease.