Background
Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) play a critical role in cancer cell growth and resistance to therapy. Most mutations occur at codons 12 and 13. ...In colorectal cancer, the presence of any mutant KRas amino acid substitution is a negative predictor of patient response to targeted therapy. However, in non-small cell lung cancer (NSCLC), the evidence that KRAS mutation is a predictive factor is conflicting.
Methods
We used data from a molecularly targeted clinical trial for 215 patients with tissues available out of 268 evaluable patients with refractory NSCLC to examine associations between specific mutant KRas proteins and progression-free survival and tumor gene expression. Transcriptome microarray studies of patient tumor samples and reverse-phase protein array studies of a panel of 67 NSCLC cell lines with known substitutions in KRas and in immortalized human bronchial epithelial cells stably expressing different mutant KRas proteins were used to investigate signaling pathway activation. Molecular modeling was used to study the conformations of wild-type and mutant KRas proteins. Kaplan-Meier curves and Cox regression were used to analyze survival data. All statistical tests were two-sided.
Results
Patients whose tumors had either mutant KRas-Gly12Cys or mutant KRas-Gly12Val had worse progression-free survival compared with patients whose tumors had other mutant KRas proteins or wild-type KRas (P = .046, median survival = 1.84 months) compared with all other mutant KRas (median survival = 3.35 months) or wild-type KRas (median survival = 1.95 months). NSCLC cell lines with mutant KRas-Gly12Asp had activated phosphatidylinositol 3-kinase (PI-3-K) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) signaling, whereas those with mutant KRas-Gly12Cys or mutant KRas-Gly12Val had activated Ral signaling and decreased growth factor-dependent Akt activation. Molecular modeling studies showed that different conformations imposed by mutant KRas may lead to altered association with downstream signaling transducers.
Conclusions
Not all mutant KRas proteins affect patient survival or downstream signaling in a similar way. The heterogeneous behavior of mutant KRas proteins implies that therapeutic interventions may need to take into account the specific mutant KRas expressed by the tumor.
The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized ...study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non-small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials.
The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with "real-time" biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment.
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic ...data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP), and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further revealed biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules, and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant lung adenocarcinoma with distinct biology and therapeutic vulnerabilities.
Co-occurring genetic alterations in STK11/LKB1, TP53, and CDKN2A/B-the latter coupled with low TTF1 expression-define three major subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities.
Epithelial-mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene ...expression profiles from four platforms using non-small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study.
We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified.
Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies.
We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype.
PURPOSE To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) ...consisting of six weekly cycles of paclitaxel 135 mg/m(2) and carboplatin (area under the curve = 2) with cetuximab 400 mg/m(2) in week 1 and then 250 mg/m(2) (PCC). PATIENTS AND METHODS Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis. Results After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046). CONCLUSION ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.
Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI ...Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC).
A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months.
Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.
As therapy for non–small-cell lung cancer (NSCLC) patients becomes more personalized, additional tissue in the form of core-needle biopsies (CNBs) for biomarker analysis is increasingly required for ...determining appropriate treatment and for enrollment into clinical trials. We report our experience with small-caliber percutaneous transthoracic (PT) CNBs for the evaluation of multiple molecular biomarkers in BATTLE (biomarker-integrated approaches of targeted therapy for lung cancer elimination), a personalized, targeted therapy NSCLC clinical trial.
The medical records of patients who underwent PTCNB for consideration of enrollment in BATTLE were reviewed for diagnostic yield of 11 predetermined molecular markers and procedural complications. Univariate and multivariate analyses of factors related to patient and lesion characteristics were performed to determine possible influences on diagnostic yield.
One hundred and seventy PTCNBs were performed using 20-gauge biopsy needles in 151 NSCLC patients screened for the trial. The biopsy specimens of 82.9% of the patients were found to have adequate tumor tissue for analysis of the required biomarkers. On multivariate analysis, metastatic lesions were 5.4 times more likely to yield diagnostic tissue as compared with primary tumors (p = 0.0079). Pneumothorax and chest tube insertion rates were 15.3% and 9.4%, respectively.
Image-guided 20-gauge PTCNB is safe and provides adequate tissue for analysis of multiple biomarkers in the majority of patients being considered for enrollment into a personalized, targeted therapy NSCLC clinical trial. Metastatic lesions are more likely to yield diagnostic tissue as compared with primary tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The decision by journals to append protocols to published reports of randomized trials was a landmark event in clinical trial reporting. However, limited information is available on how this ...initiative effected transparency and selective reporting of clinical trial data.
We analyzed 74 oncology-based randomized trials published in Journal of Clinical Oncology, the New England Journal of Medicine, and The Lancet in 2012. To ascertain integrity of reporting, we compared published reports with their respective appended protocols with regard to primary end points, nonprimary end points, unplanned end points, and unplanned analyses.
A total of 86 primary end points were reported in 74 randomized trials; nine trials had greater than one primary end point. Nine trials (12.2%) had some discrepancy between their planned and published primary end points. A total of 579 nonprimary end points (median, seven per trial) were planned, of which 373 (64.4%; median, five per trial) were reported. A significant positive correlation was found between the number of planned and nonreported nonprimary end points (Spearman r = 0.66; P < .001). Twenty-eight studies (37.8%) reported a total of 65 unplanned end points; 52 (80.0%) of which were not identified as unplanned. Thirty-one (41.9%) and 19 (25.7%) of 74 trials reported a total of 52 unplanned analyses involving primary end points and 33 unplanned analyses involving nonprimary end points, respectively. Studies reported positive unplanned end points and unplanned analyses more frequently than negative outcomes in abstracts (unplanned end points odds ratio, 6.8; P = .002; unplanned analyses odd ratio, 8.4; P = .007).
Despite public and reviewer access to protocols, selective outcome reporting persists and is a major concern in the reporting of randomized clinical trials. To foster credible evidence-based medicine, additional initiatives are needed to minimize selective reporting.
Epidemiologic and preclinical data support the oral cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPL) to receive GTE ...at 500, 750, or 1,000 mg/m(2) or placebo thrice daily for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n = 28; 50%) versus placebo (n = 11; 18.2%; P = 0.09) but did not reach statistical significance. However, the two higher-dose GTE arms 58.8% (750 and 1,000 mg/m(2)), 36.4% (500 mg/m(2)), and 18.2% (placebo); P = 0.03 had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%; P = 0.65), although not statistically significant. GTE was well tolerated, although higher doses increased insomnia/nervousness but produced no grade 4 toxicity. Higher mean baseline stromal vascular endothelial growth factor (VEGF) correlated with a clinical (P = 0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n = 5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in nonresponsive patients at 12 weeks (versus at baseline). An extended (median, 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12-week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.
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