Purpose

Early-stage non–small cell lung cancer (NSCLC) is potentially curable, however, many patients develop recurrent disease. Therefore, identification of biomarkers that can be used to predict patient’s risk of recurrence and survival is critical. Genetic polymorphisms or single-nucleotide polymorphisms (SNP) of DNA- and histone-modifying genes, particularly those of O6-methylguanine DNA-methyltransferase (MGMT), have been linked to an increased risk of lung cancer as well as treatment outcomes in other tumors.

Experimental Design

We assessed the association of 165 SNPs in selected epigenetic enzyme genes, DNA methyltransferases, and methyl-CpG–binding proteins with cancer recurrence in 467 patients with stage I or II NSCLC treated with either surgery alone (N = 340) or surgery plus (neo)-adjuvant chemotherapy (N = 127).

Results

We found several SNPs to be strongly correlated with tumor recurrence. We identified 10 SNPs that correlated with the outcome in patients treated with surgery alone but not in patients treated with surgery and adjuvant chemotherapy, which suggested that the addition of platinum-based chemotherapy could reverse the high genetic risk of recurrence. We also identified 10 SNPs that predicted the risk of recurrence in patients treated with surgery plus adjuvant chemotherapy but not in patients treated with surgery alone. The cumulative effect of these SNPs significantly predicted outcomes with P-values of 10−9and 10−6, respectively.

Conclusions

The first set of genotypes may be used as novel predictive biomarkers to identify patients with stage I NSCLC, who could benefit from adjuvant chemotherapy, and the second set of SNPs might predict response to adjuvant chemotherapy.

Background

Persistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III-N2 non-small cell lung cancer patients. This population has high rates of local-regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients.

Methods

In all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local-regional failure, distant failure, and overall survival.

Results

All patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p = 0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p = 0.003). However, additional postoperative chemotherapy had no affect on local-regional failure.

Conclusions

Aggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery.

Introduction

We evaluated the ability of histopathologic response criteria to predict overall survival (OS) and disease-free survival (DFS) in patients with surgically resected non-small cell lung cancer (NSCLC) treated with or without neoadjuvant chemotherapy.

Methods

Tissue specimens from 358 patients with NSCLC were evaluated by pathologists blinded to the patient treatment and outcome. The surgical specimens were reviewed for various histopathologic features in the tumor including percentage of residual viable tumor cells, necrosis, and fibrosis. The relationship between the histopathologic findings and OS was assessed.

Results

The percentage of residual viable tumor cells and surgical pathologic stage were associated with OS and DFS in 192 patients with NSCLC receiving neoadjuvant chemotherapy in multivariate analysis (p = 0.005 and p = 0.01, respectively). There was no association of OS or DFS with percentage of viable tumor cells in 166 patients with NSCLC who did not receive neoadjuvant chemotherapy (p = 0.31 and p = 0.45, respectively). Long-term OS and DFS were significantly prolonged in patients who had ≤10% viable tumor compared with patients with >10% viable tumor cells (5 years OS, 85% versus 40%, p < 0.0001 and 5 years DFS, 78% versus 35%, p < 0.001).

Conclusion

The percentages of residual viable tumor cells predict OS and DFS in patients with resected NSCLC after neoadjuvant chemotherapy even when controlled for pathologic stage. Histopathologic assessment of resected specimens after neoadjuvant chemotherapy could potentially have a role in addition to pathologic stage in assessing prognosis, chemotherapy response, and the need for additional adjuvant therapies.

Background

Clinical factors predicting pulmonary complications after lung resection have been well described, whereas the role of genetics is unknown. The vascular endothelial growth factor (VEGF) signaling pathway has been linked to acute lung injury. We hypothesized that genetic variations in this pathway may be associated with postoperative pulmonary complications after lung resection.

Methods

One hundred ninety-six single nucleotide polymorphisms (SNPs) in 17 genes in the VEGF pathway were genotyped in a discovery set of 264 patients and a replication set of 264 patients who underwent lobectomy for lung cancer. Multivariable analysis adjusting for baseline clinical factors was used to identify SNPs associated with pulmonary complications. Cumulative and classification and regression tree (CART) analyses were used to further stratify risk groups.

Results

The overall number of pulmonary complications was 164/528 (31%). The effects of 6 SNPs were consistent in the discovery and replication sets (pooled p value < 0.05). The rs9319425 SNP in the VEGF receptor gene FLT1 resulted in a 1.50-fold increased risk (1.15–1.96; p = 0.003). A cumulative effect for the number of risk genotypes and complications was also evident (p < 0.01). Patients carrying 5 risk genotypes had a 5.76-fold increase in risk (2.73–12.16; p = 4.44 × 10−6). Regression tree analysis identified potential gene-gene interactions between FLT1:rs9319425 and RAF1:rs713178. The addition of the 6 SNPs to the clinical model increased the area under the receiver operating characteristic curve by 6.8%.

Conclusions

Genetic variations in the VEGF pathway are associated with risk of pulmonary complications after lobectomy. This may offer insight into the underlying biological mechanisms of pulmonary complications.

BACKGROUND

The double-strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and the Ku heterodimeric regulatory complex 86-kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.

METHODS

mRNA expression levels of ATM, DNA-PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real-time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan-Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.

RESULTS

mRNA expression of ATM and DNA-PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA-PKcs were associated significantly with a 1.82-fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13-fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan-Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA-PKcs had notably shorter median survival than patients with low ratios.

CONCLUSIONS

The current findings suggested that the T/N expression ratios of ATM and DNA-PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy.

Detection of lung cancer by sputum cytology has low sensitivity but is noninvasive and, if improved, could be a powerful tool for early lung cancer detection. To evaluate whether the accuracy of diagnosing lung cancer by evaluating sputa for cytologic atypia and genetic abnormalities is greater than that of conventional cytology alone, automated scoring of genetic abnormalities for 3p22.1 and 10q22.3 (SP-A) by fluorescence in situ hybridization (FISH) and conventional cytology was done on sputa from 35 subjects with lung cancer, 25 high-risk smokers, and 6 healthy control subjects. Multivariate analysis was performed to select variables that most accurately predicted lung cancer. A model of probability for the presence of lung cancer was derived for each subject. Cells exfoliated from patients with lung cancer contained genetic aberrations and cytologic atypias at significantly higher levels than in those from control subjects. When combined with cytologic atypia, a model of risk for lung cancer was derived that had 74% sensitivity and 82% specificity to predict the presence of lung cancer, whereas conventional cytology achieved only 37% sensitivity and 87% specificity. For diagnosing lung cancer in sputum, a combination of molecular and cytologic variables was superior to using conventional cytology alone.

Background

Our objective was to study the feasibility of detecting chromosomal deletions at 3p22.1 and 10q22.3 by fluorescent in situ hybridization (FISH) and to examine their distribution in different areas of the airway in patients with non-small cell lung cancer.

Methods

Brush biopsies from the mainstem bronchus on the normal side contralateral to the tumor (NBB) and mainstem bronchus on the tumor side (TBB) were obtained from 122 patients who underwent surgical resection. Touch preparations from the tumor (TTP), normal lung parenchyma, and bronchi adjacent to the tumor were also obtained. Two FISH assays using probes complementary to 3p22.1 and 10q22.3 were used to detect deletions.

Results

NBB showed a relatively low deletion rate of 3p22.1 and 10q22.3 compared with TTP (p < 0.0001). TBB showed a significantly higher rate of deletions compared with NBB but lower than TTP from the tumor (p < 0.05) for both 3p22.1 and 10q22.3. A significantly higher deletion rate was seen at TTP compared with normal lung parenchyma at both the 3p22.1 and 10 q22.3 (p < 0.0001). Correlations were seen between the deletion rates of TTP and TBB at 3p22.1 (ρ = 0.61, p < 0.0001) and between TTP and bronchi adjacent to the tumor at 10q22.3 (ρ = 0.64, p < 0.0001).

Conclusion

Deletions of the 3p22.1 and 10q22.3 regions can be reliably detected by FISH. As one progresses from the contralateral normal bronchus to the bronchus on the side of tumor and the tumor itself, the percentage of chromosomal deletions increases in a statistically significant fashion. This suggests that, FISH analysis of bronchoscopic brushes may be useful for identifying patients at high risk for developing non-small cell lung cancer.

Purpose

Patients receiving cancer-related thoracotomy are highly symptomatic in the first weeks after surgery. This study examined whether at-home symptom monitoring plus feedback to clinicians about severe symptoms contributes to more effective postoperative symptom control.

Patients and Methods

We enrolled 100 patients receiving thoracotomy for lung cancer or lung metastasis in a two-arm randomized controlled trial; 79 patients completed the study. After hospital discharge, patients rated symptoms twice weekly for 4 weeks via automated telephone calls. For intervention group patients, an e-mail alert was forwarded to the patient's clinical team for response if any of a subset of symptoms (pain, disturbed sleep, distress, shortness of breath, or constipation) reached a predetermined severity threshold. No alerts were generated for controls. Group differences in symptom threshold events were examined by generalized estimating equation modeling.

Results

The intervention group experienced greater reduction in symptom threshold events than did controls (19% v 8%, respectively) and a more rapid decline in symptom threshold events. The difference in average reduction in symptom interference between groups was −0.36 (SE, 0.078; P = .02). Clinicians responded to 84% of e-mail alerts. Both groups reported equally high satisfaction with the automated system and with postoperative symptom control.

Conclusion

Frequent symptom monitoring with alerts to clinicians when symptoms became moderate or severe reduced symptom severity during the 4 weeks after thoracic surgery. Methods of automated symptom monitoring and triage may improve symptom control after major cancer surgery. These results should be confirmed in a larger study.

Background:

Obesity, which is one of the most serious health problems in United States, is considered a risk factor for lower esophageal and gastric cardia adenocarcinoma. However, the influence of obesity on esophageal cancer survival has not been determined. The aim of this study is to examine the impact of obesity on the long-term mortality outcomes for patients with esophageal cancer after surgery.

Methods:

A retrospective review was performed of 243 consecutive esophageal cancer patients undergoing surgery who did not receive neoadjuvant therapy. Patients were grouped according to pretreatment body mass index, as normal/underweight (<25 kg/m2) and overweight (≥25 kg/m2). Overall and recurrence-free survivals were investigated using Kaplan-Meier method, and Cox regression model was used to determine the significant prognostic factors on univariate and multivariate analysis.

Results:

There were 67 patients (28%) who were classified as normal/underweight and 176 patients (72%) as overweight. In the overweight group, the numbers of patients who were male (P < .001), with adenocarcinoma (P < .001), and pathologic stage I (p=0.003) were significantly higher than in the normal/underweight group. There was no significant difference in postoperative morbidity rates between the two groups. Both local/regional and distant recurrence rates were significantly higher in the normal/underweight group (P = .027 and P = .039, respectively). The 5-year overall survival rates were 41% in the normal/underweight group, and 67% in the overweight group (P = .002). The 5-year disease free survival rates were 37% in the normal/underweight group, and 65% in the overweight group (P = .001). In univariate analysis, BMI ≥25 and lower esophagus tumor were factors associated with longer survival. Factors including older age, weight loss before treatment, smoking history, squamous cell carcinoma, tumor size>3 cm, pathologic stage III, and poorly differentiated carcinoma were significantly associated with shorter patient survival. In multivariate analysis, age, pathologic stage and tumor location ultimately remained as prognostic factors. Lower esophageal tumor (P = .015; HR, 0.386; 95% CI, 0.179–0.833) was related with better survival, and older age (P = .014; HR, 1.032; 95% CI, 1.006–1.057) and stage III disease (P = .015; HR, 6.162; 95% CI, 1.744–21.766) were related with poor survival.

Conclusions:

Pretreatment BMI cannot be recognized as an independent predictor of long-term prognosis in esophageal cancer patients after surgery. However, high BMI tends to be associated with better prognosis.

This work was supported in part by grants from UT M. D. Anderson Cancer Center, Dallas, Park, Cantu, Smith, and Myers families and by the River Creek Foundation.

Objective

The International Association for the Study of Lung Cancer (IASLC) proposed a revision to the Union Internationale Contre le Cancer (UICC-6) staging system for non–small cell lung cancer. The goal of our study was to compare these systems in patients undergoing surgery for non–small cell lung cancer to determine whether one system is superior in staging operable disease.

Methods

Pathologic stages in 1154 patients undergoing complete resection over a 9-year period were analyzed. Patients were assigned a stage based on both IASLC and UICC-6 systems. We tested for statistically meaningful differences between the two staging systems using the Wilcoxon signed rank test and the permutation test.

Results

The IASLC system is more effective than the UICC-6 system at ordering and differentiating patients (P = .009). Application of the IASLC system resulted in 202 (17.5%) patients being reassigned to a different stage (P = .012), with the most common shifts occurring from IB to IIA and IIIB to IIIA. The 5-year and median survivals of the IASLC IIIA patients including those shifted from the UICC-6 IIIB were 37% and 35 months, respectively. Reclassifying UICC-6 IIIB to IASLC IIIA did not reduce survival for the newly characterized IIIA cohort.

Conclusion

Our data confirm that the proposed IASLC staging system is more effective at differentiating stage than the UICC-6 system. Reclassifying patients from UICC-6 IIIB to IASLC IIIA will shift some patients from a stage previously considered unresectable to a stage frequently offered surgical resection. Further study and validation of the IASLC system are warranted.

Malignant or complex benign tumors of the left heart can present a formidable challenge for complete resection, due to anatomic inaccessibility. Cardiac autotransplantation (cardiac explantation, ex-vivo tumor resection, reconstruction, and reimplantation) was introduced for complex benign primary left-heart cardiac tumors by Cooley and for malignant left-heart tumors by Reardon. Herein, we update our previously reported experience.

From April 1998 through July 2008, 20 patients underwent 21 cardiac autotransplantations for complex left-sided cardiac tumors that were nonresectable by traditional means. Demographics, tumor histology, operative data, and mortality rates were analyzed. Follow-up was complete in all patients.

Of the 20 patients, 17 had malignant lesions, and 3 had benign disease. Two patients had left ventricular lesions and the rest had left atrial lesions. Histology showed 7 malignant fibrous histiocytomas, 5 undifferentiated sarcomas, 3 leiomyosarcomas, 1 malignant osteosarcoma, 1 myxoid sarcoma, 2 paragangliomas, and 1 myxoma. Fourteen patients had previous resection of their cardiac tumors, and 1 patient had repeat autotransplantation for recurrent disease. There were no operative deaths in patients undergoing autotransplantation alone (0/15), and 3 operative deaths in patients undergoing combined cardiac autotransplantation and pneumonectomy (3/6, 50%). All 3 patients with benign disease survived surgery and are alive without recurrent disease. Local recurrence occurred in 3/18 patients with malignant disease: 1 underwent successful repeat autotransplantation and 2 are receiving chemotherapy. The mean survival for all patients with sarcoma is 22 months.

Cardiac autotransplantation enables complete resection and accurate reconstruction in many primary malignant and complex benign left-heart tumors.