Boone Goodgame

MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer

About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. MicroRNAs (miRNAs) are a class of small non-coding RNAs of 19-25 nt and play important roles in gene regulation in human cancers. The purpose of this study is to identify miRNA expression profiles that would better predict prognosis of stage I NSCLC. MiRNAs extracted from 527 stage I NSCLC patients were profiled on the human miRNA expression profiling v2 panel (Illumina). The expression profiles were analyzed for their association with cancer subtypes, lung cancer brain metastasis and recurrence/relapse free survival (RFS). MiRNA expression patterns between lung adenocarcinoma and squamous cell carcinoma differed significantly with 171 miRNAs, including Let-7 family members and miR-205. Ten miRNAs associated with brain metastasis were identified including miR-145*, which inhibit cell invasion and metastasis. Two miRNA signatures that are highly predictive of RFS were identified. The first contained 34 miRNAs derived from 357 stage I NSCLC patients independent of cancer subtype, whereas the second containing 27 miRNAs was adenocarcinoma specific. Both signatures were validated using formalin-fixed paraffin embedded and/or fresh frozen tissues in independent data set with 170 stage I patients. Our findings have important prognostic or therapeutic implications for the management of stage I lung cancer patients. The identified miRNAs hold great potential as targets for histology-specific treatment or prevention and treatment of recurrent disease.

Prognostic Value of Preoperative Positron Emission Tomography in Resected Stage I Non-small Cell Lung Cancer

Purpose: Approximately 20 to 40% of patients with surgically resected stage I non-small cell lung cancer (NSCLC) will develop recurrent disease. Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG) is used often in staging NSCLC. We conducted this study to determine whether the preoperative maximum tumor standardized uptake value (SUVmax) was associated with recurrence in patients with resected stage I NSCLC. Patients and Methods: We identified consecutive patients who underwent curative surgical resection for stage I NSCLC between 1999 and 2003 who had preoperative FDG-PET imaging. Patients were divided into two cohorts based on SUVmax above or below the median for the group. Recurrence rates were estimated by the Kaplan-Meier method and overall survival was analyzed as a secondary end point. Results: Of 136 patients who met inclusion criteria, 77 (57%) had T1 and 59 (43%) had T2 tumors. The median follow-up time was 46 months and 32 patients had a disease recurrence. The median SUVmax was 5.5. The 5-year estimates of recurrence rates for patients with low and high SUVmax were 14% and 37%, respectively (p = 0.002), with 5-year overall survivals of 74% and 53%, respectively (p = 0.006). In multivariate analyses based on SUVmax, T-classification, age, and histology, high SUVmax was independently associated with recurrence (p = 0.002) and mortality (p = 0.041). Conclusion: High SUVmax (≥5.5) on preoperative FDG-PET is an independent predictor of relapse and death in resected stage I NSCLC. Prospective trials of adjuvant chemotherapy in patients with stage I NSCLC and high SUVmax should be considered.

Distinctive Characteristics of Non-small Cell Lung Cancer (NSCLC) in the Young: A Surveillance, Epidemiology, and End Results (SEER) Analysis

Background: The median age of patients with newly diagnosed non-small cell lung cancer (NSCLC) at presentation is 71 years. We conducted an analysis of Surveillance, Epidemiology, and End Results data to assess whether the presentation and outcomes of NSCLC in younger patients (age ≤40 years) are different from that in older patients (age >40 years). Methods: We obtained the demographic, clinical, and outcomes data for all patients diagnosed with NSCLC from 1988 to 2003 in the Surveillance, Epidemiology, and End Results registry. Patients were grouped by age at diagnosis into younger than or equal to 40 years (younger cohort) or older than 40 years (older cohort). Results: During the period analyzed, we identified 2775 patients with NSCLC in the younger cohort and 236,313 patients in the older cohort. Compared with the older group, the younger group had greater proportion of African Americans (19.2% versus 10.9%; p < 0.0001), Asian or Pacific Islander (10.3% versus 5.9%; p < 0.0001), women (48.7% versus 41.9%; p < 0.0001), and patients with stage IV disease (57.4% versus 43.0%; p < 0.0001). Adenocarcinoma was more common in younger patients than in the older patients (57.5% versus 45.2%; p < 0.0001). Squamous cell carcinoma was less prevalent in the younger cohort than in older cohort (12.5% versus 26.4%; p < 0.0001). Five-year overall survival and cancer specific survival were significantly better for younger patients than for older patients across all stages. Conclusions: There is a greater representation of African Americans, Asians or Pacific Islanders, women, and adenocarcinoma histology in the younger cohort of patients with NSCLC compared with the older cohort. Despite presenting with stage IV disease more often, the overall and cancer-specific survivals are better in younger cohort than in the older cohort.

Use of microRNA expression levels to predict outcomes in resected stage I non-small cell lung cancer.

Background: Despite undergoing curative resection, nearly a third of patients with stage I non-small cell lung cancer (NSCLC) die of recurrent disease. There are no reliable clinical or molecular predictors of relapse in patients with resected stage I NSCLC. Identifying patients at risk for relapse after surgical resection is one of the important challenges today. MicroRNAs (miRNAs) regulate hundreds of genes central to maintaining a cancer phenotype. Methods: In an exploratory study, we determined whether expression of six miRNAs (let-7a, miR-7, miR-21, miR-155, miR-210, and miR-221) previously reported to correlate with invasiveness or outcome in various human malignancies were associated with tumor recurrence in patients with resected stage I NSCLC. We measured expression of these miRNAs in formalin-fixed, paraffin-embedded tissue from both tumor and matched normal lung in a set of 46 patients with surgically resected T1 or T2 stage I NSCLC. Results: Averaged triplicate data showed that tumors which recurred had 0.14-fold lower miR-221 expression than those which did not recur (p = 0.0036). In addition, increased miR-221in tumor tissue when compared with adjacent normal appearing lung in the same patient also correlated with nonrecurrence (p = 0.0011). Parallel measurement of expression of selected downstream target genes regulated by miR-221, specifically, CDKN1B, CDKN1C, paralemmin-2, and CXCL12, showed a near significant (p = 0.0522) down-regulation of CDKN1C in tumors of patients with no recurrent disease, consistent with increased miR-221 activity in the same group. Conclusion: If confirmed in prospective studies, miRNA expression in resected NSCLC could potentially identify those at high risk of relapse after surgery.

The Effect of FDG-PET on the Stage Distribution of Non-small Cell Lung Cancer

Purpose: To study the impact of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) on stage distribution and survival for patients with newly diagnosed non-small cell lung cancer (NSCLC). Methods: We searched the Barnes-Jewish Hospital/Washington University School of Medicine database for patients with non-small cell lung cancer (NSCLC) diagnosed between January 1, 1990 and December 31, 2004. Since the use of FDG-PET increased in our institution in the year 2000, patients were subdivided into those diagnosed before or after January 1, 2000. We compared the stage distribution of NSCLC before and after the year 2000. We also compared the survival for patients diagnosed between 2000 and 2004 staged with or without FDG-PET. Results: We identified 6118 patients diagnosed with NSCLC, with 3765 (61%) diagnosed before the year 2000 and 2362 (39%) thereafter. The use of FDG-PET was significantly increased after the year 2000 (37% versus 7%, p < 0.001) and there was a significant increase in the proportion of stage IV patients (30–37%, p < 0.001) with an associated decrease in stages I and III. Median overall survival was increased in all patients with stage IV disease diagnosed after the year 2000 (5.8 months versus 4.5 months). Patients with stage III or IV disease staged with FDG-PET scan also had improved survival compared with those undergoing conventional staging Conclusion: The increased use of FDG-PET was associated with a stage migration in patients with NSCLC, which may partially account for improvements in survival as compared with historical controls.

Risk of Recurrence of Resected Stage I Non-small Cell Lung Cancer in Elderly Patients as Compared with Younger Patients

Purpose: Half of all patients with non-small cell lung cancer (NSCLC) are 70 years or older at the time of diagnosis. Surgery is an option for fit elderly patients with early stage disease, but rates of disease recurrence after surgical resection are not well described. We report the outcomes in elderly patients (70 years or older) with stage I NSCLC after surgical resection. Patients and Methods: We conducted a retrospective study of patients diagnosed with stage I NSCLC after surgical resection at Washington University School of Medicine-Alvin J. Siteman Cancer Center from 1990 to 2000. Demographic, pathologic, treatment, and follow-up data were collected. Recurrence rates and overall survival were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were used to detect associations between potential prognostic factors and survival and recurrence. Results: Of the 715 patients with stage I NSCLC, 286 were 70 years or older at diagnosis. In this elderly cohort, the median age was 74 years (range, 70–89 years) and 140 of them were women (49%). Lobectomy was performed in 237 patients (83%) whereas 43 patients (15%) had a wedge or segmental resection, and six patients (2%) underwent pneumonectomy. Clinical and pathologic characteristics were not statistically different between the elderly and younger cohorts, with the exception that older patients were more likely to be white (90% versus 80%, p = 0.0003) and less likely to be smokers (88% versus 95%, p = 0.019) compared with the younger cohort. With a median follow-up of 4.6 years, the overall 5-year survival rate was 52% with a 5-year recurrence rate of 24%. In comparison, the patients younger than 70 years had a 5-year survival rate of 67% (p < 0.001) and a 5-year recurrence rate of 24%. Conclusions: Although overall survival was worse in elderly patients, estimated disease recurrence rates after resection were identical.

A Clinical Model to Estimate Recurrence Risk in Resected Stage I Non-Small Cell Lung Cancer

Objective:There are no reliable markers to predict recurrence in resected Stage I non-small cell lung cancer (NSCLC). A validated clinical model to estimate the risk of recurrence would help select patients for adjuvant therapy. Methods:We reviewed the medical records of 715 patients who had a potentially curative resection for Stage I NSCLC at our institution from 1990 to 2000. Recurrence rates were estimated by the Kaplan-Meier method. A model to estimate risk of recurrence was developed by combining independent risk factors. Results:With a median follow-up of 4.7 years, the 5-year survival rates for Stages IA and IB were 66% and 55% respectively, and 5-year recurrence rates were 19% and 30%, respectively. Four factors were independently associated with tumor recurrence: tumor size >3 cm (hazard ratio [HR] = 2.4), surgery other than lobectomy (HR = 2.0), nonsquamous histology (HR = 1.4), and high-grade cellular differentiation (HR = 1.4). A scoring system for recurrence was developed by assigning 2 points for each major risk factor (tumor size and surgery) and 1 point for each minor risk factor (histologic subtype and cellular grade). Scores were grouped as low (0–1), intermediate (2–3), and high (>3), yielding 5-year estimates of risk of recurrence of 14%, 27%, and 43%, respectively. Conclusion:This model, based upon readily available clinicopathologic characteristics, can estimate the risk of recurrence in Stage I NSCLC, independent of T classification. This model could be used to select patients for adjuvant therapy if validated in independent data sets.

A phase I study of temsirolimus and thoracic radiation in non-small cell lung cancer

BACKGROUND The addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non-small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer. Inhibition of the mTOR pathway has been found to augment the cytotoxic effect of radiation in preclinical studies. There is scant clinical experience with mTOR inhibitors and radiation. PATIENTS AND METHODS This was a phase I study evaluating the combination of temsirolimus with thoracic radiation in patients with NSCLC. RESULTS Ten patients were enrolled in the study. The dose-limiting toxicities included sudden death, pneumonitis, and pulmonary hemorrhage. The maximum tolerated dose of temsirolimus that could be administered safely with concurrent radiotherapy (35 Gy in 14 daily fractions) was 15 mg intravenously weekly. Of the 8 evaluable patients, 3 had a partial response and 2 had stable disease. CONCLUSION The combination of temsirolimus 15 mg weekly and thoracic radiation is well tolerated and warrants further investigation, perhaps in a molecularly defined subset of patients.

Vaccines and Immunotherapy for Non-small Cell Lung Cancer

Immunotherapy is an attractive therapeutic approach because of its theoretical specificity and the potential for long-term disease control. Nevertheless, despite decades of research, there has been no vaccine or other immune-based therapy approved for non-small cell lung cancer (NSCLC). Some of the main hurdles in the design of these therapies include the complex interaction between the host and the tumor, and the lack of reliable biomarkers for patient selection. Because tumors arise from normal tissues, they are poorly immunogenic. Furthermore, they evade the immune system by down-regulating antigens, decreasing expression of major histocompatibility complex class I, and secretion of cytokines that promote immune tolerance and immunosuppression. The ongoing studies on vaccine immune therapies were discussed at the 10th annual targeted therapies in lung cancer symposium and are summarized later. SUMMARY OF PRESENTATIONS GVAX Granulocyte macrophage colony-stimulating factor (GM-CSF) induces antigen expression and attracts antigenpresenting cells (APCs) to the site of vaccination. This feature was used as the rationale to develop an autologous tumor cell vaccine transfected with an adenovirus containing the GM-CSF gene (GVAX). In a multicenter phase I/II study involving patients with early or advanced stage NSCLC, 1 GVAX was administered every 2 weeks for a total of three to six vaccinations. The most common toxicity was a local injection site reaction. Among the 33 patients with advanced stage, three had durable responses lasting from 6 months to more than 22 months, including two patients with bronchioloalveolar carcinoma. A major drawback of GVAX is that being an autologous vaccine, it requires individual patient tissue and takes a long time to prepare. Among the 83 patients undergoing tumor harvest for the study, only 43 patients received the vaccine, and the median time from tissue collection to vaccine administration was 49 days. Belagenpumatucel-L (Lucanix)

Recent Advances in Lung Cancer: Summary of Presentations from the 45th Annual Meeting of the American Society of Clinical Oncology (2009)

Over the past decade, gradual progress has been made in improving the outcomes of patients with lung cancer. This review summarizes the findings from selected studies presented at the recently concluded 45th annual meeting of the American Society of Clinical Oncology. This report will focus only on findings that are of immediate relevance to clinical practice. The topics discussed here range from the long-term safety of adjuvant chemotherapy and a new systemic chemotherapy regimen for locally advanced non-small cell lung cancer to the emerging issue of maintenance chemotherapy and the use of biomarkers in the treatment of patients with metastatic non-small cell lung cancer.