EDITORIAL

For Whom the Bell Tolls: Susceptibility to Common Adult Cancers in Retinoblastoma Survivors

Frederic J. Kaye, J. William Harbour

Affiliations of authors: Genetics Branch, Center for Cancer Research, National Cancer Institute, and the National Naval Medical Center, Bethesda, MD (FJK); Ocular Oncology Service, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO (JWH).

Correspondence to: Frederic J. Kaye, MD, Bldg. 8, Rm. 5101, National Naval Medical Center, 8901 Wisconsin Ave., Bethesda, MD 20889 (e-mail: fkaye{at}helix.nih.gov)

A priority in the management of patients with potentially curable or indolent cancers is to maximize tumor control while minimizing the iatrogenic complications that may occur many years later. A balance between these short-term and long-term goals can sometimes be elusive, as seen in the ongoing controversy over the role of external beam radiation therapy (EBRT) in the initial treatment of patients with early-stage Hodgkin's disease (1). In the case of hereditary retinoblastoma, where more patients in the United States die of second primary cancers (many induced by EBRT) than from their initial eye tumor (2), the treatment for intraocular disease has recently undergone dramatic changes to minimize the delayed tumorigenic potential of EBRT. These changes focus on the substitution of EBRT with chemotherapy, followed by local consolidative modalities such as laser hyperthermia and cryotherapy. However, some patients are not responsive to chemotherapy and may still require EBRT in an attempt to avoid enucleation and blindness. In addition, there is increasing recognition that hereditary retinoblastoma patients who have never received EBRT also have an increased risk of second primary cancers (3). Therefore, a thorough understanding of treatment-related cancer incidence and mortality in retinoblastoma survivors is essential for the counseling of patients and their families.

To understand the risk estimates in retinoblastoma survivors, it is worth making several observations. First, an increased risk for second cancers has been substantiated only for retinoblastoma patients who carry a constitutive RB1 mutation (2). It would be more accurate to refer to these patients as "germline" or "hereditary" retinoblastoma patients, of whom 90% will develop the disease on a sporadic basis (i.e., with no family history). In addition, at least 10%–15% of patients with non-hereditary unilateral retinoblastoma carry a mutant RB1 allele but manifest unilateral disease as a result of mosaicism or a distinctive, low-penetrant RB1 allele (46). Consequently, databases of non-hereditary retinoblastoma survivors will have some degree of contamination with hereditary retinoblastoma survivors, which may explain the modest increased risk of nonocular cancers that has been observed for this group. Second, the quantitative risk estimates for these second cancers must be interpreted with caution because they are based on retrospective analyses that may not control adequately for EBRT and may likely contain incomplete demographic and outcome data. Finally, it is reasonable to speculate that the homozygous loss of RB gene function is necessary and sufficient for the clinical manifestation of retinoblastoma, whereas the second primary cancers in these patients are likely to require additional mutations, the number of which may correspond roughly to the latency duration and the carcinogen exposure requirements for that cancer. This simplistic model proposes that the increased probability for second cancers observed in patients with germline RB1 mutations arises because the number of sequential "hits" required for clonal expansion of a malignancy would have been reduced by one. Accordingly, early-onset second cancers, such as midline intracranial primitive neuroectodermal tumors, generally arise months to years after the diagnosis of hereditary retinoblastoma, osteosarcomas and soft tissue sarcomas usually arise during the adolescent years, and melanomas tend to occur in patients in their twenties or older (3).

By contrast, the link between hereditary retinoblastoma and late-onset adult epithelial tumors has been less clearly established and, remarkably, was first highlighted by molecular genetic findings rather than by results of clinical epidemiologic studies. For example, small-cell lung cancer is the first and only adult cancer to be associated with a high (>90% of cases) frequency of RB1 gene mutations (7,8), yet there was no obvious clinical relationship between hereditary retinoblastoma survivors and this type of lung tumor in many case series (913). However, results of more recent studies that included a larger subset of patients older than 40 years (14,15) have now suggested that these patients may have an increased risk for lung cancer. One study (15) reported a standardized mortality ratio (SMR) of 15.2 for lung cancer among 964 survivors of hereditary retinoblastoma (five cases of lung cancer) but no statistically significant increase in lung cancer mortality among 640 survivors of non-hereditary retinoblastoma (no cases of lung cancer). Importantly, three of the five patients who developed lung cancer did so before the age of 40 years, suggesting that they had a genetic predisposition for this disease. In several other studies [(14), and those cited in (15)], nine (90%) of 10 hereditary retinoblastoma survivors who developed lung cancer with a known pathology subtype were diagnosed with a small-cell histology, which is substantially greater than the expected proportion of only 20%–25%.

In this issue of the Journal, Fletcher et al. (16) have extended these observations in a retrospective analysis of patients with hereditary and non-hereditary retinoblastoma born between 1873 and 1950 in the United Kingdom. In this study, 58 cancers were identified among 144 survivors of hereditary retinoblastoma who were between the ages of 25 and 84 years when their second cancers were first diagnosed. Fletcher et al. thought it was unlikely that this cohort of patients had been subjected to EBRT as infants, and they limited their analyses to nonocular tumors that developed at age 25 years or older. Thus, their study focused largely on the incidence and mortality of late-onset, radiation-independent tumors. They observed that, compared with the general population, hereditary retinoblastoma survivors had a higher mortality from all second cancers (SMR = 5.4) and, in particular, from two tobacco-related cancers, bladder cancer (SMR = 26.3) and lung cancer (SMR = 7.0). By contrast, the SMR for all cancers among survivors of sporadic retinoblastoma was 1.23 (95% confidence interval = 0.85 to 1.77). Considering the predicted, low-level contamination of sporadic non-hereditary cases with unilateral hereditary retinoblastoma cases (as discussed above), these findings confirm that sporadic non-hereditary retinoblastoma patients have no increased risk of second cancers compared with the general population. However, because tobacco use is strongly linked to bladder and lung cancers in the general population, it is difficult to quantitate the magnitude of the relative risk for these cancers among the hereditary retinoblastoma survivors in the Fletcher et al. study (16) because of the small number of second tumors detected and the absence of any information on tobacco use in the subject and control populations. Additional support for a link between retinoblastoma and these cancers could be provided by, first, determining whether a reversal of the usually high (75%–80%) ratio of non-small-cell lung cancer to small-cell lung cancer histology is detectable. Three of four lung cancers in the hereditary retinoblastoma patients had small-cell histology, but pathology data for the other lung tumors were not included (16). Second, because patients with a genetic predisposition would be predicted to develop second cancers at a younger age, Fletcher et al. could also examine whether the age at lung cancer diagnosis was statistically significantly higher among the non-hereditary retinoblastoma patients than among survivors of hereditary retinoblastoma.

In summary, the RB1 gene has been the classic paradigm for the concept of a tumor suppressor gene pathway and has provided many insights that apply broadly to the entire field of cancer biology. For many years, the intuitive notion has been that a subset of tobacco users exhibits a genetic susceptibility to developing lung cancer, but there was never evidence to directly link a specific genetic locus to this elevated risk. The RB1 gene may now serve as yet another paradigm for the concept of a genetic susceptibility locus for lung and bladder cancer among tobacco users. Accordingly, Fletcher et al. (16) conclude with the frequently stated advice that hereditary retinoblastoma survivors should avoid tobacco and chronic exposure to all other known carcinogens. However, for the large segment of the population who are not carriers of a germline RB1 mutation, it is worth remembering that many of us, similarly, will carry other genetic loci that are poised to jump-start unintended clonal proliferation in the presence of chronic carcinogen exposures. Tobacco users, therefore, should not idly wonder for whom the bell tolls.

REFERENCES

1 DeVita VT Jr. Hodgkins's disease--clinical trials and travails [published erratum appears in N Engl J Med 2003;349:202]. N Engl J Med 2003;348:2375–6.[Free Full Text]

2 Abramson DH. Second nonocular cancers in retinoblastoma: a unified hypothesis. The Franceschetti Lecture. Ophthalmic Genet 1999;20:193–204.[CrossRef][Medline]

3 Wong FL, Boice JD Jr, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, et al. Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 1997;278:1262–7.[Abstract]

4 Lohmann DR, Gerick M, Brandt B, Oelschlager U, Lorenz B, Passarge E, et al. Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet 1997;61:282–94.[ISI][Medline]

5 Klutz M, Horsthemke B, Lohmann DR. RB1 gene mutations in peripheral blood DNA of patients with isolated unilateral retinoblastoma. Am J Hum Genet 1999;64:667–8.[CrossRef][ISI][Medline]

6 Otterson GA, Modi S, Nguyen K, Coxon AB, Kaye FJ. Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families. Am J Hum Genet 1999;65:1040–6.[CrossRef][ISI][Medline]

7 Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ. Abnormalities in structure and expression of the human retinoblastoma gene in SCLC. Science 1988;241:353–7.[ISI][Medline]

8 Kaye FJ. RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer. Oncogene 2002;21:6908–14.[CrossRef][ISI][Medline]

9 Abramson DH, Ellsworth RM, Kitchin FD, Tung G. Second nonocular tumors in retinoblastoma survivors. Are they radiation-induced? Ophthalmology 1984;91:1351–5.[ISI][Medline]

10 Draper GJ, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986;53:661–71.[ISI][Medline]

11 Lueder GT, Judisch F, O'Gorman TW. Second nonocular tumors in survivors of heritable retinoblastoma. Arch Ophthalmol 1986;104:372–3.[Abstract]

12 Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583–7.[ISI][Medline]

13 Moll AC, Kuik DJ, Bouter LM, Den Otter W, Bezemer PD, Koten JW, et al. Incidence and survival of retinoblastoma in The Netherlands: a register based study 1862-1995. Br J Ophthalmol 1997;81:559–62.[Abstract/Free Full Text]

14 Sanders BM, Jay M, Draper GJ, Roberts EM. Non-ocular cancer in relatives of retinoblastoma patients. Br J Cancer 1989;60:358–65.[ISI][Medline]

15 Kleinerman RA, Tarone RE, Abramson DH, Seddon JM, Li FP, Tucker MA. Hereditary retinoblastoma and risk of lung cancer. J Natl Cancer Inst 2000;92:2037–9.[Free Full Text]

16 Fletcher O, Easton D, Anderson K, Gilham C, Jay M, Peto J. Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 2004;96:357–63.[Abstract/Free Full Text]



             
Copyright © 2004 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement