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

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.

References:

1. Sporn MB, Dunlop NM, Newton DL, et al. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc. 1976;35(6):1332-1338.

2. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97(22):1652-1662.

3. Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295(23):2727-41.

4. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215-224.

5. Thompson IM Jr, Goodman PJ, Tangen CM, et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med. 2013;369(7):603-10.

6. Arber N, Eagle CJ, Spicak J, et al; PreSAP Trial Investigators. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med. 2006;355(9):885-95.

7. Bertagnolli MM, Eagle CJ, Zauber AG, et al; APC Study Investigators. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355(9):873-84.

8. Mao JT, Roth MD, Fishbein MC, et al. Lung cancer chemoprevention with celecoxib in former smokers. Cancer Prev Res (Phila). 2011;4(7):984-93

9. Kim ES, Hong WK, Lee JJ, et al. Biological activity of celecoxib in the bronchial epithelium of current and former smokers. Cancer Prev Res (Phila). 2010;3(2):148-59

10. Keith RL, Blatchford PJ, Kittelson J, et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res (Phila). 2011;4(6):793-802.

11. Lee JS, Lippman SM, Benner SE, et al. Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol. 1994;12:937-945.

12. Hong WK, Endicott J, Itri LM, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med. 1986;315(24):1501-5.

13. Hong WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323(12):795-801.

14. Lippman SM, Lee JJ, Karp DD, et al. Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer. J Natl Cancer Inst. 2001;93(8):605-618.

15. Khuri FR, Lee JJ, Lippman SM, et al. Randomized phase III trial of low dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst. 2006;98: 426-427.

16. Karp DD, Lee SJ, Keller SM, et al. Randomized, Double-Blind, Placebo-Controlled, Phase III Chemoprevention Trial of Selenium Supplementation in Patients With Resected Stage I Non-Small-Cell Lung Cancer: ECOG 5597. J Clin Oncol. 2013 Sep 3. Epub ahead of print.

17. Wang J, Lippman SM, Lee JJ, et al. Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma. Carcinogenesis. 2010;31(10):1755-61.

18. Hildebrandt MA, Lippman SM, Etzel CJ, et al. Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict head and neck cancer patient second primary tumor/recurrence risk and response to retinoid chemoprevention. Clin Cancer Res. 2012;18(13):3705-13.

19. Spira A, Beane JE, Shah V, et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med. 2007;13(3):361-6.

20. Dubinett SM, Spira A. Challenge and Opportunity of Targeted Lung Cancer Chemoprevention. J Clin Oncol. 2013 Sep 3.

21. Khuri FR. The dawn of a revolution in personalized lung cancer prevention. Cancer Prev Res (Phila). 2011;4(7):949-53.

22. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409

23. Aberle DR, DeMello S, Berg CD, et al; National Lung Screening Trial Research Team. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013;369(10):920-31.

24. Memmott RM, Mercado JR, Maier CR, et al. Metformin prevents tobacco carcinogen--induced lung tumorigenesis. Cancer Prev Res (Phila). 2010;3(9):1066-76.

Citation Format: Fadlo R. Khuri. Smoking, molecular markers, and the risk of second cancers in cancer patients. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr PL01-02.