Abstract PL01-02: Smoking, molecular markers, and the risk of second cancers in cancer patients

Abstract

Abstract Chemoprevention entails the reversal, prevention, abrogation or delay of carcinogenic progression to cancer (1). A number of successful trials have been conducted in the reversal of premalignancy in breast (2,3), prostate (4,5), and colorectal (6,7) cancer. In tobacco-related cancers, compelling evidence has suggested that ongoing tobacco smoking is able to prevent the reversal of premalignant lesions (8-10). The first such evidence was demonstrated by Lee et al. who noted that only those patients who ceased smoking saw meaningful improvement in their premalignancy in a randomized trial of 13-cis-retinoic acid in reversal of premalignancy (11). This built on the seminal work by Hong et al. who were able to show that high doses of vitamin A derivatives, specifically, 13-cis-retinoic acid, were able to reverse premalignancy in head and neck cancer (12), and perhaps more importantly, prevent or delay the development of second primary tumors while patients were on high dose 13-cis-retinoic acid (13). Unfortunately, the vast majority of patients on high dose 13-CRA or isotretinoin failed to tolerate this dose and required dose reduction or dose interruption (12,13). Subsequent randomized trials of 13-CRA in prevention of second primary tumors of the lung (14) and head and neck failed (15) to show the same promise as the higher dose, but one message was clearly consistent. Those patients who stopped smoking had considerably lower rates of second primary tumors and a trend toward a lower rate of primary lung or head and neck tumor recurrence (14, 15). Similar data emerged from the selenium trial, where the agent itself was ineffective in preventing second primary tumors of the lung, but those patients who were able to cease smoking had consistently lower rates of development of second primary tumors (16). A series of recent studies have indicated that genomic testing of patients on the 13-CRA head and neck second primary tumor prevention trial can select those patients who appear to derive the greatest benefit from chemopreventive approaches with natural compounds and their derivatives (17,18). These data suggest that patients with activation of the PI3-kinase/mTOR pathway are more likely to develop second primary cancers (18), consistent with data implicating this pathway demonstrated by Spira et al (19). Similarly, the Retinoid Head and Neck Second Primary Prevention Trial has shown data that certain patient populations on the head and neck second primary trial were more likely to benefit than others, based on genomic background, and that of their tumor (17,18). Thus, a strategy emerges whereby specific molecular markers, which are likely to predict benefit from second primary tumors, will be used to select future populations who are placed on chemopreventive approaches (20). However, one lesson must remain clear, and it must impact the future of all chemoprevention trials. Since smoking cessation, generally initiated by the patient, was the single most important factor in reducing secondary primary tumor risk, on these trials (14, 15, 21), all future such trials will require active smoking cessation efforts in these patient populations in order to achieve effective and active chemoprevention approaches. Such trials are planned and are necessary to undertake. The next generation of chemoprevention trials will involve CT screening studies, now the standard for those patients deemed at high risk for developing lung cancer (22, 23), and whether using inhibitors targeting inflammation (8-10) or metabolism (24), the inclusion of effective smoking cessation strategies in these chemopreventive trials is now a must. The overwhelming weight of the evidence therefore shows that effective development of approaches that integrate smoking cessation into biomarker-based chemoprevention of tobacco-driven cancers is no longer optional.