BCL-2 Expression is Prognostic for Improved Survival in Non-small Cell Lung Cancer

ObjectiveWe used a large patient population to identify immunohistochemical biomarkers to enable improved prognostication in patients with non-small cell lung carcinoma (NSCLC).MethodsA tissue microarray was constructed using duplicate 0.6 mm cores of formalin-fixed paraffin-embedded tissue blocks from 609 patients with NSCLC. Immunohistochemical was used to detect 11 biomarkers including epidermal growth factor receptor, Her2, Her3, p53, p63, bcl-1, bcl-2, Thyroid transcription factor, carcinoembryonic antigen, chromogranin, and synaptophysin. A clinical database was generated prospectively at the time of tissue collection. Survival outcomes were obtained from a Provincial Cancer Registry database. Univariate and multivariate analyses were performed to look for a relationship between biomarker expression, smoking history, and survival.ResultsSurvival data for 535 cases were available. As of June 2005, 429 patients (80%) had died; of these 286 (54%) died of lung cancer, 117 (22%) died of other known causes, and for 26 (5%) the cause of death was not available. Univariate analysis revealed that bcl-2 (p = 0.007) was the only biomarker prognostic for improved overall survival (OS). bcl-2 (p = 0.021) and p63 (p = 0.025) were both found to be prognostic for improved disease-specific survival (DSS). Multivariate analysis (using age and biomarker expression) revealed that bcl-2 expression is prognostic for improved OS (p = 0.005) and DSS (p = 0.021).ConclusionsOur results suggest that bcl-2 expression is prognostic for improved OS and DSS in NSCLC. Testing for bcl-2 expression in a prospective study will help to determine its clinical relevance in prognostication

Brief Report: A Phase II Study of Sunitinib in Malignant Pleural Mesothelioma. The NCIC Clinical Trials Group

IntroductionMalignant pleural mesothelioma (MPM) is an aggressive malignancy that most often presents at an advanced, incurable stage. After the failure of standard first-line cisplatin/antifolate chemotherapy, there is no accepted treatment. The vascular endothelial growth factor pathway may be a relevant therapeutic target in MPM.MethodsThis open-labeled phase II trial evaluated single-agent sunitinib, an inhibitor of multiple receptor tyrosine kinases including the vascular endothelial growth factor receptors, given at 50 mg daily orally for 4 weeks followed by a 2-week rest, in patients with advanced MPM. Two cohorts were studied: cohort 1, in which patients had previously received cisplatin-based chemotherapy, and cohort 2, consisting of previously untreated patients. A two-stage design was used for both cohorts; the primary outcome was objective response rate as determined by the RECIST criteria modified for MPM. Secondary outcomes included rates and duration of disease control, progression-free survival and overall survival, and safety and tolerability.ResultsA total of 35 eligible patients were enrolled (17 to cohort 1 and 18 to cohort 2). Neither cohort met the criteria for continuing to the second stage of accrual; only one objective response, confirmed by independent review, was observed in a previously untreated patient. Median progression-free and overall survivals were 2.8 and 8.3 months in cohort 1, and 2.7 and 6.7 months in cohort 2, respectively. Observed toxicity was within that expected for sunitinib.ConclusionsSunitinib, similar to other angiogenesis inhibitors, has limited activity in MPM. Future trials of angiogenesis inhibitors given as single agents in unselected patients with MPM are not warranted

American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer

The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non–small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis.Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points.A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3,1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm.In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib.ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981

Correlations of EGFR mutations and increases in EGFR and HER2 copy number to gefitinib response in a retrospective analysis of lung cancer patients

<p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, <it>EGFR </it>and <it>HER2</it>, in 39 patients treated with gefitinib at the BC Cancer Agency.</p> <p>Methods</p> <p>Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of <it>EGFR</it>, were amplified by PCR and sequenced. <it>EGFR </it>and <it>HER2 </it>copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.</p> <p>Results</p> <p>Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with <it>EGFR </it>amplification, three with <it>HER2 </it>amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and <it>EGFR </it>mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in <it>EGFR </it>or <it>HER2 </it>copy number (p = 0.552 and 0.437, respectively).</p> <p>Conclusion</p> <p>Neither mutation of <it>EGFR </it>nor increased copy number of <it>EGFR </it>or <it>HER2 </it>was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond <it>EGFR </it>status may be necessary to accurately predict treatment outcome.</p

A retrospective review of the multidisciplinary management of medullary thyroid cancer: eligibility for systemic therapy

Abstract Background Medullary thyroid carcinoma (MTC) accounts for 1-2% of all thyroid cancers. The clinical course of metastatic disease can be indolent. Our aim was to characterize the natural history of disease to evaluate the true proportion of patients who would be eligible for the currently available systemic therapies. Methods The British Columbia Cancer Agency (BCCA) provides cancer care to a population of 4.6 million. A retrospective chart review was conducted of all patients with MTC referred to the BCCA from 1991 to 2013. Clinical characteristics, pathology, treatment and outcome data were collected. Relapse free survival and overall survival was determined for patients based on staging at the time of diagnosis. Results Of the 98 patients referred to the BCCA during the study period, inherited mutations were found in 6% though 60% did not undergo genetic testing. Based on clinical SEER staging at diagnosis 50% had localized disease, 38% regional, and 12% had distant metastasis. 77% had complete surgical resection of which 25% received adjuvant radiation therapy. Five year relapse free survival (RFS) for localized and regional disease was 75% and 66%, respectively (p = 0.006). Initial treatment of 23 patients with locally unresectable and metastatic disease predominantly involved multiple modalities. Of the 37 patients with relapsed or metastatic MTC only 7 (19%) patients received one or more course of chemotherapy for metastatic disease: 1 temsirolimus, 2 adriamycin, 3 sunitinib, 3 sorafenib, and 3 vandetanib. Five year OS based on clinical SEER stage: localized 93%, regional 72% and distant 33% (p < 0.001). Conclusion Localized and regional MTC treatment patterns reflect multidisciplinary management based on disease characteristics. Patients with distant disease had poor outcomes with 28% of patients dying from disease. In our cohort the minority of patients ultimately received systemic therapy due to timing and lack of TKI availability