Linda Coate

Molecular predictive and prognostic markers in non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer death in the developed world. Platinum-based chemotherapy is the therapeutic foundation of treatment both in the metastatic and adjuvant setting and targeted therapies are entering standard treatment paradigms. However, many patients do not obtain benefit from cytotoxic agents or newer targeted therapies, but are still exposed to their toxic effects. Reliable biomarkers to select treatments for patients most likely to obtain benefit have, therefore, been an important focus for many research groups. In this paper, we review current predictive and prognostic biomarkers in NSCLC. We assess their potential clinical use and explore recent data pertaining to genome-wide approaches for treatment selection in NSCLC.

Germline Genetic Variation, Cancer Outcome, and Pharmacogenetics

Studies of the role of germline or inherited genetic variation on cancer outcome can fall into three distinct categories. First, the impact of highly penetrant but lowly prevalent mutations of germline DNA on cancer prognosis has been studied extensively for BRCA1 and BRCA2 mutations as well as mutations related to hereditary nonpolyposis colorectal cancer syndrome. These mainly modest-sized analyses have produced conflicting results. Although some associations have been observed, they may not be independent of other known clinical or molecular prognostic factors. Second, the impact of germline polymorphisms on cancer prognosis is a burgeoning field of research. However, a deeper understanding of potentially confounding somatic changes and larger multi-institutional, multistage studies may be needed before consistent results are seen. Third, research examining the impact of germline genetic variation on differential treatment response or toxicity (pharmacogenetics) has produced some proof-of-principle results. Putative germline pharmacogenetic predictors of outcome include DPYD polymorphisms and fluorouracil toxicity, UGT1A1 variation and irinotecan toxicity, and CYP2D6 polymorphisms and tamoxifen efficacy, with emerging data on predictors of molecularly targeted or biologic drugs. Here we review data pertaining to these germline outcome and germline toxicity relationships.

Impact and feasibility of a comprehensive geriatric assessment in the oncology setting: a pilot study.

ObjectivesA comprehensive geriatric assessment (CGA) is an objective means of assessing the global health of older patients. While evidence suggesting its promise in improving outcome prediction in the oncology setting is growing, its benefit in guiding treatment decisions remains uncertain. We sought to determine the feasibility and impact of CGA, from a consultative geriatric-oncology service, on treatment decisions in older cancer patients. MethodsA pilot clinic, where patients underwent CGA with a medical oncologist and geriatrician, was established. Patients ≥70 years, with gastrointestinal or lung cancer were eligible. Following standard assessment by the primary oncologist, a treatment decision was recorded. Patients subsequently underwent a CGA. The final treatment plan was made by the primary oncologist after receipt of findings and recommendations from the CGA. Changes in treatment decisions were recorded. ResultsThe study enrolled from January to October 2009. Of 168 eligible patients, 120 (71%) were not referred for assessment. Thirty of 48 patients approached underwent CGA. In six patients the treatment plan was undecided at time of referral. In five of these, CGA impacted the ultimate decision (83%). Where the management plan was decided at time of referral (n=24), CGA impacted the final decision in only 1 patient (4%). Previously unidentified medical problems were identified in 70% of patients. ConclusionsSeveral factors limited the feasibility of a consultation-type geriatric-oncology service to assess older cancer patients. The impact of CGA in informing treatment decisions was modest but may be of value when the initial treatment decision is uncertain.

Treatment of the Elderly When Cure is the Goal: The Influence of Age on Treatment Selection and Efficacy for Stage III Non-small Cell Lung Cancer

Background: Treatment of elderly patients with stage III NSCLC is controversial. Limited data exist, as the elderly are underrepresented in clinical trials. Methods: After ethics approval, we performed a retrospective review of 1372 stage III NSCLC patients treated at our institution during the period 1997–2007. Patients with malignant effusions and microscopic N2 discovered only postoperatively were excluded, leaving 740 who were classified by treatment plan: palliative (palliative chemotherapy or radiation [≤40 Gy]); nonsurgical multimodality (>40 Gy radiation ± chemotherapy); or surgical multimodality (chemotherapy, radiation, and surgery). Demographics, treatment, toxicity, and survival were analyzed by age, 0 to 65 years, n = 384; 66 to 75 years, n = 256; 76+ years, n = 100, and compared using log-rank, univariate, and multivariate statistical tests. Results: Patients older than 65 years were more likely to have poor performance status (p < 0.0001), multiple comorbidities (p < 0.0001), and to receive palliative therapy only (p < 0.0001). Older and younger patients treated with curative intent with nonsurgical bimodality therapy or trimodality therapy including surgery had similar rates of grade 3/4 toxicity (0–65 years, 39%; 66–75 years, 43%; 76+ years, 5%; p = 0.18) and toxic death (0–65 years, 4%; 66–75 years, 4%; 76+ years, 0%; p = 0.76). Survival was worse with increasing age (p < 0.0001), likely due to greater use of palliative treatment in the elderly. When survival was analyzed for patients treated with curative intent, there was no difference between age groups for nonsurgical (p = 0.32) or surgical (p = 0.53) therapy. Conclusion: In select fit elderly patients, combined modality therapy is tolerable and is associated with survival similar to that of younger patients.

Maintenance Therapy in Advanced Non-small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world, and survival rates for advanced disease remain low with standard platinum-based chemotherapy. One treatment strategy that has been investigated extensively in NSCLC is that of “maintenance” therapy. Options for maintenance include maintaining response to initial therapy by continuing the initial combination chemotherapy regimen, continuing only single agent chemotherapy, or by introducing a new agent. Treatments that have been studied in randomized trials to date include chemotherapy, molecularly targeted agents, and immunotherapy approaches. After the development of multiple new agents that show activity in NSCLC and have a tolerable side effect profile, there has been increasing interest recently in this treatment strategy. In this study, we examine the evolution of this strategy by reviewing trials investigating the main treatment paradigms used in maintenance therapy for NSCLC.

Tumour islet Foxp3+ T-cell infiltration predicts poor outcome in nonsmall cell lung cancer.

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis. Tumour- and stroma-infiltrating CD3+, CD8+ and forkhead box P3 (Foxp3)+ T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined. There was a positive association between overall survival and increased CD8+ TI/S ratio (hazard ratio (HR) for death 0.44, p<0.001) but an inverse relationship between Foxp3+ TI/S ratio and overall survival (HR 4.86, p<0.001). Patients with high CD8+ islet (HR 0.48, p<0.001) and Foxp3+ stromal (HR 0.23, p<0.001) counts had better survival, whereas high CD3+ and CD8+ stromal counts and high Foxp3+ islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8+ TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3+ TI/S ratio was associated with worse survival (HR 3.91, p<0.001). Microlocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC. Lymphocyte microlocalisation strongly influences survival in lung cancer patients undergoing curative-intent surgery http://ow.ly/QUwbD

Maintenance therapy in advanced non-small cell lung cancer: evolution, tolerability and outcomes.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world. Despite significant progress in early stage disease, survival rates for advanced disease remain low. Maintenance therapy is a treatment strategy that has been investigated extensively in NSCLC and has been the subject of considerable recent debate. Options for maintenance include continuing the initial combination chemotherapy regimen, continuing only single agent chemotherapy (‘continuation maintenance’) or introducing a new agent (‘switch’ maintenance therapy). Therapies that have been studied in this setting in randomized trials to date include chemotherapy, molecularly targeted agents and immunotherapy approaches. Following the development of multiple new agents that show activity in NSCLC, and have a tolerable side-effect profile, there has been increasing interest in utilizing them to maintain response to initial therapy after treatment with platinum-based doublets. Despite considerable controversy, it has become an acceptable treatment paradigm. Here, we briefly outline the evolution of this treatment paradigm and examine which subgroups of patients are most likely to benefit.

How Affordable are Targeted Therapies in Non-Small Cell Lung Cancer?

Opinion statementAs the treatment of non-small cell lung cancer (NSCLC) evolves to include more targeted therapies, costs of treatment have increased significantly. Advances in NSCLC treatment include longer survival duration, and in some cases, better progression-free survival and quality of life, and the potential for decreased toxicity. Through pharmacoeconomic analyses, payors seek to value the improvements in outcomes from novel therapies, and relate these improvements to their costs. In NSCLC, three categories of novel agents have been introduced into clinical practice: (1) agents targeting the epidermal growth factor receptor (EGFR); (2) agents targeting the vascular endothelial growth factor (VEGF) and (3) novel chemotherapy agents, specifically pemetrexed. Here we review published economic analyses for these agents in lung cancer, and their potential impact on treatment decisions.

Glioblastoma treatment in the elderly in the temozolomide therapy era

BACKGROUND optimal treatment of glioblastoma (gBM) in the elderly remains unclear. the impact of age on treatment planning, toxicity, and efficacy at a Canadian Cancer Centre was retrospectively reviewed. METHODS glioblastoma patients treated consecutively between 2004 and 2008 were reviewed. utilizing 70 years as the threshold for definition of an elderly patient, treatments and outcome were compared in younger and elderly populations. RESULTS four hundred and twenty one patients were included in this analysis and median overall survival (oS) for the entire cohort was 9.8 months. 290 patients were aged <70 (median age 57, range 17- 69) and 131 were aged ≥ 70 (median age 76, range 70-93). patients ≥ 70 were more likely to receive best supportive care (BSC) and all patients >70 who were treated with radiotherapy received <60 gy (P<0.001), except one. patients aged >70 demonstrated inferior survival (one year oS 16% versus 54% for those <70, hr 3.46, P<0.001). in patients treated with BSC only, age had no impact on survival (median survival two months in both groups, hr 0.89, P=0.75). for those treated with higher doses of radiotherapy (>30 gy to <60 gy), one year survival was 19% versus 24% in patients aged >70 versus <70 (hr 1.47, P=0.02) respectively. CONCLUSION in this retrospective single institution series, elderly patients were more likely to be treated with BSC or palliative doses of radiotherapy. randomized phase iii study results are required for guidance in treatment of this population of patients.

Early adulthood body mass index, cumulative smoking, and esophageal adenocarcinoma survival

BACKGROUND Smoking and obesity are esophageal adenocarcinoma (EAC) risk factors. However, the same risk factors may also affect biological aggressiveness and cancer outcomes. Our study evaluated the combined effects of early-adulthood obesity and cumulative smoking on the EAC survival. PATIENTS AND METHODS In two EAC cohorts, Toronto (TO; N=235) and Boston (BO; N=329), associations between early adulthood body mass index (EA-BMI), BMI at 1year prior to diagnosis (BMI-1), and smoking with overall survival (OS) were assessed using Cox proportional hazard models, adjusted for relevant covariates. RESULTS Both cohorts were predominantly Caucasian (89%), male (88%), ever-smokers (73%) with locally advanced/metastatic EAC (78%), and good ECOG performance status (90%); median packyears was 34; median EA-BMI, 24; median BMI-1, 25. No relationships with survival were found with BMI-1. For smoking and EA-BMI, TO, BO, and combined TO-BO analyses showed similar associations: smoking conferred worse OS in the combined TO-BO cohort, with adjusted hazard ratios (aHR) of 1.22 (95%CI: 1.15-1.43;p<0.0001) for each 20 pack-year increase. Likewise, EA-BMI ≥25 was associated with worse OS (EA-BMI of 25-<30, aHR=1.84,95%CI: 1.37-2.48; and EA-BMI>30, aHR=2.78, 95%CI: 1.94-3.99). Risk of death was also increased in remotely underweight patients with EA-BMI<18.5 (aHR=2.03,95%CI: 1.27-3.24), when compared to normal-EA-BMI (18≤EA-BMI<25). CONCLUSIONS Two key modifiable behaviors, elevated BMI in early adulthood and heavy cumulative smoking history are independently associated with increased mortality risk in two North American cohorts of EAC patients.