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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1349-1350 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.309
In Reply:
Hôpital Tenon, Paris, France We read with interest the letter from Pantanowitz et al in response to our recent article published1 in the September 15 issue of the Journal of Clinical Oncology. These authors disagree with our hypothesis of underreporting or possible competing mortality to explain the deficit of breast cancer observed in the studied female HIV population as compared with the French general population of the same age and sex. While we still believe that underreporting and competing risk play a role in our results, we do not exclude the possibility that other factors may also be involved. Indeed, it is possible that either HIV infection or immunodeficiency may protect from developing breast cancer. However, this last hypothesis is still debated among transplanted women.2-5 Moreover, it is not obvious that results observed among transplanted women should be transposed to HIV women since populations, treatments, care, and major clinical concerns are quite different in these two populations. We also read with interest the letter from Powles et al in response to ours. These authors speculate on the reasons for the increasing incidence of lung cancer (LC) in HIV-infected patients. Smoking is the most plausible explanation because of the higher proportion of smokers among HIV-infected patients than in the general population.6 The higher standardized incidence ratio of LC that we observed among injecting drug users compared with the other HIV transmission groups probably reflected the higher tobacco consumption among drug users.7 In contrast, HIV-seropositive and HIV-seronegative patients with LC do not differ in terms of smoking habits.8,9 It is difficult to determine the role of chronic immunodeficiency in the increasing incidence of LC among HIV-infected patients. HIV-infected patients are not particularly severely immunodeficient at LC diagnosis. In case-control studies, the median CD4+ lymphocyte count at LC diagnosis was 250/µL; 50% of patients had counts above 200/µL, and approximately 60% had not yet developed AIDS. Moreover, CD4+ lymphocyte counts tend to be higher in the highly active antiretroviral therapy (HAART) era—the period during which the increasing incidence of LC was noted.10,11 As suggested by Powles et al, the duration of chronic immunodeficiency, as reflected by the duration of HIV infection, might explain the increasing risk of LC. However, we think that smoking remains a key factor. Indeed, in the transplant setting, the risk of LC is not increased after several years of therapeutic immunosuppression, except in heart transplant recipients, 70% of whom are smokers.12 Regarding other potential causes, the viral hypothesis of human LC has never been proven. Human papillomavirus can cause invasive cervical cancer, but human papillomavirus sequences are not detected in lung tumors from HIV-infected patients.13 Although some antiretroviral nucleoside analogues are carcinogenic in mice, there is no firm evidence that this is also the case in humans.14 Together, smoking, chronic immunodeficiency, and antiretroviral therapy could promote LC by increasing genomic instability in normal epithelial cells, as shown by the higher frequency of microsatellite alterations in lung tumors from HIV-infected patients, compared to their HIV-seronegative counterparts.13 The markedly improved patient survival in the HAART era is the most obvious explanation for the increased incidence of LC in this era. AIDS-related deaths declined from 52% in the pre-HAART era to 23% currently, leading to a corresponding increase in deaths from other causes, including LC.15,16 Thus, as suggested by Powles et al, smoking alone cannot account for the excess of LC observed during the HAART era. The high frequency of adenocarcinoma subtype LC in HIV-infected patients does not reflect a weaker association between LC and cigarette smoking in this population. Indeed, the adenocarcinoma subtype is over-represented among elderly women who never smoked, but also among young heavy smokers, in whom adenocarcinoma is now more frequent than squamous cell carcinoma.17-19 One possible explanation for the larger increase in the incidence of LC since the advent of HAART is that there are currently more patients living longer with HIV/AIDS, exposed both to chronic smoking and chronic immunodeficiency (2 to 10 years).8 Did we underestimate the importance of LC in HIV-infected women? It was not our intention to underestimate the marked increase in the number of cases of LC among HIV-infected women. Furthermore, the risk of LC is higher among women than among men, at all levels of tobacco exposure,18 and particularly among young women.17 Between 1985 and 1995, the incidence of LC increased by 56% among French women younger than 65 years.20 It is likely that the LC incidence rate continued to increase from 1995 to 1999 in the general population of women, leading to a underestimation of the expected number of cases of LC in this population and, consequently, to a slight overestimation of the standardized incidence ratio for LC (based on 1995 data) among HIV-infected women in the HAART period. In conclusion, the incidence of LC in the HIV-infected population has shown a worrying increase over the last decade. The higher proportion of smokers, the increased risk of LC, and the predominance of the adenocarcinoma subtype (with peripheral onset) call for prospective evaluations of low-dose computed tomography for LC screening in this population. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Herida M, Mary-Krause M, Kaphan R, et al: Incidence of Non–AIDS-Defining Cancers Before and During the Highly Active Antiretroviral Therapy Era in a Cohort of Human Immunodeficiency Virus-Infected Patients. J Clin Oncol 21:3447-3453, 2003 2. Stewart T, Tsai SC, Grayson H, et al: Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 346:796-798, 1995[CrossRef][Medline] 3. Weiss NS: Risk of breast cancer after renal or cardiac transplantation. Lancet 346:1422, 1995[CrossRef] 4. N'zi K, Asquier E, Fauchier F, et al: Does renal transplantation increase the risk of breast diseases? J Radiol 82:469-472, 2001[Medline] 5. Adami J, Gäbel H, Lindelöf B, et al: Cancer risk following organ transplantation: A nationwide cohort study in Sweden. Br J Cancer 89:1221-1227, 2003[CrossRef][Medline] 6. Saves M, Chene G, Ducimetiere P, et al: Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis 37:292-298, 2003[CrossRef][Medline] 7. Rosen MJ, Lou Y, Kvale PA, et al: Pulmonary function tests in HIV-infected patients without AIDS. Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med 152:738-745, 1995[Abstract] 8. Bower M, Powles T, Nelson M, et al: HIV-related lung cancer in the era of highly active antiretroviral therapy. AIDS 17:371-375, 2003[CrossRef][Medline] 9. Lavole A, Massiani MA, Chouaid C, et al: Lung cancer in Human Immuno deficiency virus (HIV) infected patients in the era of highly active antiretroviral therapy (HAART): a case control study. Lung Cancer 41:S110, 2003 (suppl 2) 10. Tirelli U, Spina M, Sandri S, et al: Lung carcinoma in 36 patients with human immunodeficiency virus infection. The Italian Cooperative Group on AIDS and Tumors. Cancer 88:563-569, 2000[CrossRef][Medline]
11. Sridhar KS, Flores MR, Raub WA Jr, et al: Lung cancer in patients with human immunodeficiency virus infection compared with historic control subjects. Chest 102:1704-1708, 1992 12. Cadranel J, Naccache J, Wislez M, et al: Pulmonary malignancies in the immunocompromised patient. Respiration 66:289-309, 1999[CrossRef][Medline]
13. Wistuba II, Behrens C, Milchgrub S, et al: Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects. JAMA 279:1554-1559, 1998 14. Wutzler P, Thust R: Genetic risks of antiviral nucleoside analogues–a survey. Antiviral Res 49:55-74, 2001[CrossRef][Medline] 15. Mocroft A, Brettle R, Kirk O, et al: Changes in the cause of death among HIV positive subjects across Europe: Results from the EuroSIDA study. AIDS 16:1663-1671, 2002[CrossRef][Medline] 16. Louie JK, Hsu LC, Osmond DH, et al: Trends in causes of death among persons with acquired immunodeficiency syndrome in the era of highly active antiretroviral therapy, San Francisco, 1994-1998. J Infect Dis 186:1023-1027, 2002[CrossRef][Medline] 17. Ramalingam S, Pawlish K, Gadgeel S, et al: Lung cancer in young patients: Analysis of a Surveillance, Epidemiology, and End Results database. J Clin Oncol 16:651-657, 1998[Abstract] 18. Zang EA, Wynder EL: Differences in lung cancer risk between men and women: Examination of the evidence. J Natl Cancer Inst 88:183-192, 1996 19. Alberg AJ, Samet JM: Epidemiology of lung cancer. Chest 123:21S–49S, 2003 (suppl 1) 20. Francim R: Le cancer en France: Incidence et mortalité. Paris, France, La documentation française, 1998
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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