Background

We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small-cell lung cancer (NSCLC).

Methods

This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative therapy at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time polymerase chain reaction. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model.

Results

Median duration of follow-up was 61 months, and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared with those without recurrence (1.13 versus 1.07, p = 0.046). A subgroup analysis indicates that women had longer RTL compared with men (1.12 versus 1.06, p = 0.025), and the patients with adenocarcinoma demonstrated longer RTL compared with those with other histologic types (1.11 versus 1.05, p = 0.042). To determine whether longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, sex, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in women (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.02-4.96, p = 0.044) and adenocarcinoma subgroups (HR, 2.19; 95% CI, 1.05-4.55, p = 0.036). The increased risk of recurrence due to long RTL was more apparent in women with adenocarcinoma (HR, 2.67; 95% CI, 1.19-6.03, p = 0.018).

Conclusions

This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma seem to be special subgroups in which telomere biology may play an important role.

Background

Population studies suggest that high body mass index (BMI) correlates with a reduced risk for death from lung cancer. The aim of our study was to evaluate definitively the influence of BMI on long-term overall survival (OS) in surgical patients with NSCLC.

Methods

The study population consisted of 1935 patients who underwent surgical resection for lung cancer at M. D. Anderson Cancer Center (2000-2014). Study variables included both patient- and treatment-related characteristics. Univariate and multivariate Cox regression analyses were performed to identify variables associated with OS.

Results

On univariate analysis, significant predictors of improved survival were higher BMI, pathologic tumor stage (stage I versus stage II, III, or IV), type of surgical procedure (lobectomy/pneumonectomy versus wedge resection/segmentectomy), younger age, female sex, and adenocarcinoma histologic subtype (versus squamous) (all p < 0.05). Morbidly obese patients (BMI ≥ 35) demonstrated a trend toward better outcomes than those classified as obese (BMI ≥30 and <35 kg/m²) (p = 0.05), overweight (BMI ≥ 25 and <30 kg/m²) (p = 0.13), or healthy weight (BMI <25 kg/m²) (p = 0.37) (hazard ratio = 0.727, 0.848, 0.926, and 1, respectively). On multivariate analysis, BMI remained an independent predictor of survival (p = 0.02). Propensity matching analysis demonstrated significantly better OS (p = 0.003) in patients with a BMI of 30 kg/m² or higher as compared with a BMI of 25 kg/m².

Conclusions

In this large, retrospective, single-center series, after control for disease stage and other variables, higher BMI was associated with improved OS after surgical resection of NSCLC. Further studies are necessary to elucidate the precise relationship between BMI and treatment outcomes.

Background

Data from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib.

Methods

Patients with resectable stage I to III NSCLCs received cisplatin 80 mg/m², docetaxel 75 mg/m² every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384).

Results

Forty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival.

Conclusions

Induction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies.

UNLABELLED: Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.