Abstract PL01-03: The landscape of cancer prevention: Personalized approach in lung cancer
Authors: Hong Waun Ki , Kim Edward S. , Jack Lee J. , Wistuba Ignacio , Lippman Scott 
Published: July 2012

Recent data indicate that lung cancer causes over 1.3 million deaths worldwide each year, over 157,000 deaths in the U.S. alone. Although the overall incidence of cancer in the U.S. has decreased (1.3 % for men; 0.5% for women) largely because of declines in breast, prostate, lung, and colon cancer, lung cancer in women is increasing.

Tobacco causes more than 30% of cancer, not just of the lung but in at least 12 other cancers, including the head and neck, esophagus, pancreas, stomach, and bladder. Smoking cessation is an important approach for decreasing cancer risk but is not sufficient because 50% of new lung cancers arise in former smokers. The molecular mechanisms of lung-cancer pathogenesis in former smokers are under intense investigation.

Cancer screening and early detection have made substantial progress in cervical, colorectal, breast, prostate, and lung cancers. Very recently, the National Lung Screening Trial (NLST) demonstrated that spiral chest CT scanning reduced lung-cancer mortality by 20% in heavy smokers. This finding is extremely important and should be capitalized on by complementary targeted lung-cancer chemoprevention strategies that could further improve public health.

The fundamental concept of cancer chemoprevention, defined by Sporn as the use of pharmacologic agents to impede, arrest, or reverse carcinogenesis at earlier, preinvasive stages, was based on the biological understanding that genetic and epigenetic alterations through multistep carcinogenesis and field effects of carcinogen exposure lead to cancer. These biologic processes comprise the hallmarks of cancer development that were well described by Hanahan and Weinberg – evasion of apoptosis, self sufficiency of growth signals, insensitivity to antigrowth signals, strong replication potential, and sustained angiogenesis.

Cancer prevention trials of single or combined molecular-targeted agents in the breast, prostate, and colorectum and of vaccines in cervical cancer have met with very positive results. Several agents are currently approved by the Food and Drug Administration (FDA) for treating precancerous lesions or reducing the risk of cancer. These agents include bacillus Calmette-Guérin (BCG) in the bladder, hormone-related modulators to prevent breast cancer, nonsteroidal anti-inflammatory drugs to prevent colorectal and skin cancers, and human papillomavirus vaccines to prevent cervical cancer. Other agents, not FDA approved, also are established for reducing cancer risk in definitive phase III prevention trials.

Despite the availability of these agents to reduce some cancer risks, many are not accepted for cancer prevention by the public because of concerns over their toxicity and the need for long-term treatment. These agents can have paradoxical biologic effects; e.g., tamoxifen reduces estrogen-receptor-positive breast cancer but increases endometrial cancer, and finasteride reduces prostate cancer incidence but appeared in initial reports to induce high-grade prostate cancer. Therefore, cancer chemoprevention, in contrast to chemoprevention of cardiovascular disease with statins or antihypertensive agents, is highly controversial even in the setting of high-risk individuals. This controversy should be openly debated in regard to agent risk versus prevented-cancer risk and agent benefit versus agent risk in the primary, secondary, and tertiary prevention settings.

Lung cancer is the most lethal major cancer, with a 16% 5-year survival rate despite aggressive combined-modality treatment. This grim statistic has provided a strong rationale for conducting lung cancer chemoprevention trials over the last two decades and for the extraordinary efforts to prevent smoking and treat smoking addiction. Many chemopreventive agents (e.g., beta-carotene and vitamin A and E) were selected for clinical trials based largely on epidemiologic data; many were tested in large randomized controlled trials that produced quite disappointing results. Major reasons for the negative findings of these trials were a lack of understanding of the molecular underpinnings, heterogeneity of the targeted carcinogenesis and insufficient identification of the drivers of cancer development that could serve as molecular targets.

Lung cancer incidence by smoking status is as follows: former smokers, 50%; current smokers, 40%; and non-smokers, 10 %. Lung cancer in non- or former smokers is related to EGFR mutations and EML-ALK fusion as major drivers toward lung carcinogenesis. Therefore, the rationale for using EGFR inhibitors as chemopreventive agents in mutated-EGFR lung cancer is strong based on the field effect of mutant EGFR in normal epithelium adjacent to the tumor.

Lung cancer presents one of the biggest challenges and one of the greatest opportunities to make an impact on the global burden of cancer in the future. Our increased understanding of the biology of lung cancer has enabled us to develop biologic risk models and identify new targeted agents for the adjuvant or preventive settings that will enable more personalized chemoprevention.

Recent data provide a proof of principle of the potential of pharmacogenetics to personalize cancer prevention. These data come from genotyping studies in, for example, the head and neck (isotretinoin), colorectum (aspirin, celecoxib, statins), prostate (selenium), and bladder (BCG). Similar personalized genotyping approaches are being applied to research in tobacco dependence and cancer therapy.

We have investigated personalized targeted therapy in advanced lung cancer in our Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. Lessons learned from BATTLE are trickling down in a reverse migration to the development of a BATTLE prevention strategy. We are in the process of developing a biologic risk model for recurrence and second primary tumors (SPTs) through our Department of Defense (DoD)-supported lung cancer prevention programs, with parallel efforts to identify molecular drivers of recurrence as drug targets. The BATTLE program could have several roles in the prevention setting: A model of trial design, with its innovative Bayesian statistical design and emphasis on biomarker discovery; a discovery platform for targets, as provided by its analyses of multiple blood and tissue biomarkers; and a source of experience with targeted agents such as sorafenib. Sorafenib is a well-tolerated oral multi-kinase inhibitor with potent antiangiogenic activity. Studies of biomarkers predicting a benefit from sorafenib in the BATTLE study show a trend towards improved disease control in patients with KDR and PDGFR amplification, and BATTLE evidence also shows that circulating angiogenic factors may predict for efficacy of antiangiogenic agents such as sorafenib. The lessons we have learned from the BATTLE program may help us in studying sorafenib and other agents for cancer chemoprevention.

The first approach toward personalized lung cancer chemoprevention should occur in the tertiary prevention setting of patients with a history of resected lung cancer due to the high risk of these patients and their accessibility for molecular studies in tumor and adjacent tissue. These patients are at high risk for recurrence and SPTs, which can be histologically and molecularly similar or even indistinguishable from one another. Histologically normal tissue near a tumor often has molecular abnormalities due to field “cancerization” and/or clonal spread that may lead to a second cancer. Though predictive and prognostic signatures have been described in patients with, or at a high risk of, lung cancer, none are currently used clinically.

Using all that we have learned from our BATTLE and biological risk-modeling experience, we propose a personalized chemoprevention trial in the tertiary setting of resected lung cancer: Biomarker-integrated Approaches of Targeted Lung-cancer Elimination (BATTLE) Adjuvant and Prevention Trial. Following resection of adenocarcinoma, biomarker analyses would be performed on tumors and adjacent epithelium. Treatment groups would be determined by the molecular drivers of tumorigenesis. Patients whose tumors are driven by EGFR mutations could receive an EGFR inhibitor; KRAS and BRAF mutations, a Ras/Raf inhibitor; EML4-ALK translocation, an ALK inhibitor; VEGFR overexpression, vandetanib or other VEGFR inhibitors. Patients with alterations in the PI3K pathway could receive an Akt inhibitor. Primary endpoints would be recurrence and SPTs. Secondary endpoints would be tolerability, biomarker modulation, and correlation of biomarker modulation with outcome. Issues of dosing and informative biomarkers for patient selection must be optimized before this trial can begin; nevertheless, the basic BATTLE prevention design likely will become more common in the future, as our understanding of the biology of lung cancer tumorigenesis improves.

In this opening plenary session, specific strategic directions of personalized targeted chemoprevention, including study design issues of the use of spiral lung CT screening, targeted agents, and clear endpoints, will be discussed thoroughly.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL01-03. doi:10.1158/1538-7445.AM2011-PL01-03