Jawaher Ansari

Role of tyrosine kinase inhibitors in lung cancer.

Protein tyrosine kinases are enzymes which catalyze the phosphorylation of tyrosine residues and activate a downstream cascade of cellular signalling pathways which regulate cell proliferation, differentiation and apoptosis and a wide variety of cellular functions. Clinical developments over the past decade have identified several novel therapeutic agents which inhibit tyrosine kinase activity, either by direct receptor inhibition or indirect inhibition of tyrosine kinase controlled pathways. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), such as gefitinib and erlotinib have been studied extensively in patients with refractory non-small cell lung cancer (NSCLC). Early studies with gefitinib showed undoubted clinical activity but failed to show a survival benefit, whereas studies with erlotinib showed a small but statistically significant benefit in overall survival. Subsequent studies explored the possibility of synergistic activity between targeted agents (gefitinib or erlotinib) and conventional chemotherapy drugs reporting disappointing results. Clinical trial results with gefitinib and erlotinib, either as monotherapy or in combination with chemotherapy, have failed to match the encouraging results noted in the pre-clinical setting. It is now increasingly recognised that clinical exploration of molecular targeted agents may not conform well to traditional phase I/II/III drug trial designs. Therapeutic responses may be limited to a small subpopulation of patients, therefore diluting the overall therapeutic effect. Hypothesising a genetic basis for the heterogeneity in trial results, biomarkers (such as EGFR gene mutation analysis, EGFR protein expression, and increased EGFR gene copy number) have been studied with a view to identifying a target population most likely to benefit from these drugs. Future clinical trials with targeted agents need to be carefully designed to incorporate correlative translational research elements that will allow selection of appropriate treatment strategies for individual patients. For assessment of phase III trial results in advanced disease, progression free survival may serve as a more appropriate end-point than response rate in an adequately designed trial in the appropriately selected population, although there should be no substitute for the overall survival and quality of life end points. The role of EFGR TKI in NSCLC will be discussed in detail and data from these studies will be used to illustrate the challenges in designing clinical trials and interpreting outcomes.

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.Case presentationHere, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.ConclusionConducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.

Evolution of the Treatment Paradigm for Patients with Metastatic Castration-Resistant Prostate Cancer

As recently as 2004, treatment options for men with metastatic castration-resistant prostate cancer (mCRPC) were limited, with docetaxel the only approved agent conferring a survival benefit. The therapeutic landscape is now very different, with several agents demonstrating prolonged survival since 2010. New agents for the treatment of mCRPC include sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide and radium-223. All are now approved for use in this patient group, although the specific licensing terms vary between agents. In addition, denosumab may have utility in patients with bone metastases. A number of novel agents are also in development with promising initial results. However, because these treatment options have proliferated rapidly, there is currently a paucity of clinical evidence regarding their optimal sequencing. Selection of an appropriate treatment option should take into consideration disease characteristics, drug availability and patient choice. In summary, we discuss several new treatment options available for mCRPC and their integration into the current treatment paradigm.

Fatal Clostridium difficile infection associated with vinorelbine chemotherapy: case report and literature review

Differentiating between chemotherapy-related diarrhoea and Clostridium difficile-associated diarrhoea (CDAD) can be extremely difficult. There is increasing evidence that CDAD can be seen in patients on chemotherapy without prior antibiotic usage. We report the first case of CDAD secondary to vinorelbine chemotherapy and review the literature.

Role of second-line systemic treatment post-docetaxel in metastatic castrate resistant prostate cancer- current strategies and future directions.

Treatment of metastatic castrate resistant prostate cancer (mCRPC) after progression on docetaxel chemotherapy is a challenging clinical scenario with limited availability of treatment options. Re-treatment with docetaxel, either as monotherapy or in combination with other cytotoxics or targeted agents has shown durable responses. However, most docetaxel re-treatment studies have been either retrospective or early phase non-randomised studies which have not formally assessed Quality of life or survival gain with re-treatment. Despite limited evidence for efficacy of mitoxantrone in the second-line, it continues to remain widely used, largely due to lack of available suitable alternatives. Cabazitaxel in combination with prednisolone is the only chemotherapy to have shown a significant survival benefit and receive approval by the U.S. Food and Drug Administration for patients with mCRPC previously treated with a docetaxel-based regimen. Abiraterone acetate has recently demonstrated a significant improvement in survival when compared to placebo in patients with docetaxel-treated mCRPC. This review aims to summarize the current evidence and discuss future strategies for treatment of mCRPC patients following failure of docetaxel chemotherapy.

Recent Advances and Future Directions in the Management of Metastatic Renal Cell Carcinoma

A better understanding of the molecular biology of renal cell carcinoma (RCC) and the emergence of tyrosine kinase inhibitors (TKIs) have revolutionized the treatment for patients with metastatic RCC (mRCC). Multikinase inhibitors (sunitinib and sorafenib) and the inhibitors of mammalian target of rapamycin (temsirolimus and everolimus) have recently shown superiority over IFN-alpha or placebo; and bevacizumab + IFN-alpha have demonstrated improved activity when compared to IFN-alpha alone in patients with mRCC. Newer anti-vascular endothelial growth factor (VEGF) agents such as axitinib, pazopanib and cediranib are currently under investigation to expand and elucidate future treatment options. Several studies have investigated the synergistic potential of TKIs with a view to blocking multiple signalling pathways simultaneously, but this approach has resulted in a significant increase in toxicity. Sequential TKI administration has demonstrated encouraging results but the optimal sequence of TKIs is yet to be determined. Studies combining TKIs with immunotherapy have resulted in varying degrees of success; with bevacizumab + IFN-alpha being the only studies with positive outcomes. The purpose of this review is to summarize the current evidence supporting the role of TKIs and to discuss potential future directions in the management of mRCC. The role of TKIs as monotherapy, in combination with immunotherapy or other TKIs (combined or sequential approach) will be discussed.

Triple Negative Breast Cancer: A Tale of Two Decades

Triple negative breast cancer (TNBC) is a heterogeneous disease entity constituting about 15% of breast cancer cases worldwide. TNBC is associated with poor prognosis and lack of sustained response to conventional chemotherapeutic agents. Tumoral heterogeneity and the presence of several subtypes of TNBC such as Basal like (BL)-1, BL-2, immune-modulatory, luminal androgen receptor, mesenchymal, and mesenchymal/stem like subtype and claudin low subtype, may explain some of the difficulties faced in managing this challenging disease subgroups. Although no approved targeted therapy is available for TNBCs, molecular-profiling efforts have revealed promising molecular targets such as the vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), polyadenosine ribose polymerase inhibitors (PARPi) and DNA repair pathway, androgen pathway, and NOTCH pathway. TNBC is subject to intense research activities aiming at dissecting potential pathways, identifying potential molecular signatures and biomarkers in order to properly develop new targeted biologic modifiers. Despite this, there is a lack of approved predictive and prognostic biomarkers, and keeping in view the complexity of TNBC biology, research should be targeted towards identifying multi-factorial signatures rather than single markers. This review aims to summarize the current evidence, ongoing research and discuss future strategies for the treatment of patients with TNBC. In addition we have reviewed the recent advances in detecting predictive and prognostic biomarkers and identifying surrogate markers for early identification of potential responders to the new therapies.

Critical appraisal of axitinib in the treatment of advanced renal cell carcinoma

A growing understanding of the biology of renal cell carcinoma (RCC) has led to the development and US Food and Drug Administration approval of seven new molecular targeted agents over the past 7 years. Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors and the latest to join the armamentarium of drugs available for the treatment of metastatic RCC. Despite recent advances in the development of molecular targeted agents for metastatic RCC, the ideal sequencing of these agents remains unclear.

Gene expression profiling in bladder cancer identifies potential therapeutic targets

Despite advances in management, bladder cancer remains a major cause of cancer related complications. Characterisation of gene expression patterns in bladder cancer allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Hypergeometric analysis was used to identify canonical pathways and curated networks having statistically significant enrichment of differentially expressed genes. Osteopontin (OPN) expression was validated by immunohistochemistry. Hierarchical clustering defined signatures, which differentiated between cancer and healthy tissue, muscle-invasive or non-muscle invasive cancer and healthy tissue, grade 1 and grade 3. Pathways associated with cell cycle and proliferation were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer compared to healthy tissue. The present study contributes to a growing body of work on gene expression signatures in bladder cancer. The data support an important role for osteopontin in bladder cancer, and identify several pathways worthy of further investigation.

Atypical diffuse bilateral cystic lung changes secondary to erlotinib treatment in a patient with metastatic non‑small cell lung carcinoma: A case report and literature review

Erlotinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) mutations. The response rate to erlotinib is ~60% and the incidence of erlotinib-induced interstitial lung disease (ILD) is ~1-4%. The Response Evaluation Criteria in Solid Tumours (RECIST) tool is commonly used to assess response to erlotinib; however, evaluation of response and subsequent progression in the presence of atypical cystic lung changes may be challenging. We herein present a rare case of diffuse cystic lung changes secondary to erlotinib treatment in a patient with EGFR mutation-positive metastatic NSCLC. Challenges in assessing atypical tumour response to erlotinib, pitfalls in using RECIST and differential diagnosis of TKI-related ILD are discussed in detail.