U.S. Department of health and human services National Institutes of Health

1. U.S. Department of health and human services National Institutes of Health Second Tumors in Retinoblastoma Survivors National Cancer Institute Ruth A Kleinerman, Margaret A Tucker, Lindsay M Morton Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD Celebrating 100 years of Our Retinoblastoma Center in New York, September 18-19, 2014

2. Aims • Importance of second cancers • Spectrum of second cancers in retinoblastoma survivors • Survivors at highest risk of second cancers • Treatment-related risk • Pattern of risk over time

3. Outline • Epidemiology of retinoblastoma • Second cancers • Treatment-related risk for sarcomas • Implications

4. Retinoblastoma • Rare childhood cancer: 3% of pediatric cancers • Approximately 300 cases/yr in US • Incidence rates stable over past 3 decades • 5-year survival: 96.5% US SEER Data, 2004-2010

5. Hereditary RB1 Germline mutation Age at diagnosis:0-12 months Bilateral disease (85%)or Unilateral + family history of Rb (15%) 40% of RB Non-hereditary RB1 Somatic mutation Age at diagnosis: 2-5 years of age Unilateral disease, no family history of Rb 60% of RB U Retinoblastoma

6. Why study second cancers? • RB1is a high risk cancer susceptibility gene • Somatic mutations in the RB1gene: sarcomas and epithelial cancers (lung, bladder, breast, ovary) • Treatments: radiotherapy and chemotherapy have been linked to second cancers

7. Second cancers • Retinoblastoma is rare but informative • Second cancers are rare • Large number of survivors • Many years of follow up needed • Ideal childhood cancer population – excellent survival and long-term follow-up

8. Causes of second cancers Medical, lifestyle, environment Genetic Susceptibility Second cancer Cancer Treatment

9. Second cancers after Retinoblastoma Second Cancers after Retinoblastoma * P<0.05 ¶compared to the general population Kleinerman et al, JCO, 2005; Reulen et al, JAMA 2011; Maress et al, JNCI, 2008 *p<0.05

10. NCI Retinoblastoma Cohort Study • Purpose: To evaluate the risk of second cancers in relation to treatment in a cohort of 1854 1-year survivors of retinoblastoma • Diagnosed 1914-1996 at two medical centers (New York and Boston) • 1092 hereditary subjects; 762 non-hereditary subjects

11. Second Cancers after Retinoblastoma Second Cancers after retinoblastoma * P<0.05 Kleinerman et al, JCO, 2005 *p<0.05

12. Second Cancers after Retinoblastoma Second cancers after retinoblastoma * P<0.05 Kleinerman et al, JCO, 2005 *p<0.05

13. 36.0% 95% CI = (30.9% – 41.1%) 5.69% 95% CI = (2.4% – 11.1%) Hereditary 963 760 615 401 147 30 Non-Hereditary 638 570 500 317 134 46 Number of Patients at Risk Cumulative risk of a second cancer Hereditary Retinoblastoma Non-Hereditary Retinoblastoma Kleinerman et al. J ClinOncol 2005

14. Cumulative mortality from second cancers Cumulative mortality 25.5% (21%-30%) 1.0% (0.2%-1.8%) Time since Rb diagnosis, yrs Yu et al, JNCI, 2009

15. Cumulative incidence of second cancers by family history and laterality Kleinerman et al., JCO, 2012

16. Causes of second cancers Genetic susceptibility Cancer treatments Second cancer Medical, lifestyle, environment

17. External beam radiotherapy for retinoblastoma; 48 Gy (15-115 Gy) to affected eye GH Fletcher, Textbook of Radiotherapy, 2nd ed. 1973

18. Risk for soft tissue sarcoma and bone cancer after retinoblastoma Radiation dose-response for soft tissue sarcoma Wong et al, JAMA, 1997

19. Risk for soft tissue sarcoma by histology Kleinerman et al. JNCI 2007

20. Risks of Soft Tissue Sarcomas by Years Since of RB Diagnosis Risks of soft tissue sarcomas by time since Rbdiagnosis Kleinerman et al. JNCI, 2007

21. Cumulative incidence of soft tissue sarcoma after radiotherapy 7.9% (5.5%-10.2%) In-field Cumulative incidence % 5.1% (2.8%-7.3%) Out of field Time since Rb diagnosis, yrs

22. Risk of leiomyosarcoma by treatment for hereditary retinoblastoma Wong et al, JCO, in press

23. Risk for soft tissue sarcoma and bone cancer after retinoblastoma Radiation dose-response for soft tissue and bone sarcoma Wong et al, JAMA, 1997

24. Age at bone sarcoma by proximity to radiation field

25. Cumulative incidence of bone sarcoma after radiotherapy In-field 7.9% (5.8%-10.0%) Out of field Cumulative incidence % 3.8% (2.4%-5.2%) Time since Rb diagnosis, yrs

26. Risk of bone sarcoma by treatment for hereditary retinoblastoma Wong et al, JCO, in press

27. Discussion • Second cancer in hereditary >>>non-hereditary survivors • Chemotherapy and radiation increased risk of bone sarcomas and leiomyosarcoma • Radiation-dose response for bone and soft tissue sarcoma • Sarcoma risk higher in radiation field >>> out of field • Sarcoma risk begins earlyand persists for decades • Second cancers higher in bilateral patients + family history of Rb

28. Conclusion • Increasing occurrence of second cancers in hereditary survivors • Major cause of morbidity and mortality • Treatments contribute substantially to risks in addition to genetic predisposition • Risks persist for decades

29. Future • Continue to follow survivors • Inform re: risk of second cancers

30. Second cancer genetic pilot study • Objective: Identify molecular changes that characterize specific second cancers in relation to radiotherapy and chemotherapy • Study design: Tumor and normal tissue from second cancers in hereditary patients • Method: Whole genome sequencing and RNA-Seq • Contact: Ruth.Kleinerman@nih.gov

31. Acknowledgements • National Cancer Institute • Lindsay Morton, Margaret Tucker, Jeannette Wong, Mark Little, Chu-ling Yu, Sara Schonfeld, Josh Sampson • Memorial Sloan Kettering Cancer Center • David Abramson, Jasmine Francis • Tufts New England Medical Center • Johanna Seddon • M.D. Anderson Cancer Center • Marilyn Stovall, Susan Smith, Rita Weathers Original Cohort Study: John D Boice, Jr, NCRP; CharisEng (Cleveland Clinic); Fred Li, Dana Farber Cancer Institute (retired); Robert Tarone (IEI): Lennie Wong (City of Hope)