1. Risk for Second Cancers in Survivors of Childhood Cancer
M. Monica Gramatges, MD, PhD
June 25, 2015

2. Outline of presentation
General overview of second cancers
Research related to predicting risks for second cancers

3. With modern therapy, survival for all childhood cancers now exceeds 80%
Childhood leukemia outcomes
Hunger et al, J Clin Oncol, 2012

4. Second cancers are a well-recognized late effect of cancer therapy
Most common cause of treatment-related deaths in cancer survivors
About 8% of childhood cancer survivors will develop a second malignant neoplasm (SMN)
3-6 fold increased risk
Armstrong et al, J of Clin Oncol, 2009
Friedman et al, J Natl Cancer Inst, 2010
Olsen et al, J Natl Cancer Inst, 2009
Reulen et al, JAMA, 2011

5. The number of second cancers in childhood cancer survivors is increasing
Friedman et al, J Natl Cancer Inst, 2010

6. What are the most common second malignant cancers we see in survivors?
Breast cancer
After Hodgkin lymphoma or neuroblastoma
Thyroid cancer
After any therapy that included radiation to the head/neck or chest
Sarcomas (bone and muscle tumors)
After CNS tumors, Hodgkin lymphoma, Wilms tumor, kidney tumors, and sarcomas
Also common: head and neck cancers, CNS tumors
Morton et al, ASCO Educational Book, 2014

7. Which primary diagnoses are associated with the greatest risk for second cancers?
Hodgkins lymphoma
Ewing sarcoma
Friedman et al, J Natl Cancer Inst, 2010

8. What are the other risk factors for second cancers?
Female sex
Age at the time of the primary diagnosis
Younger age: CNS tumors, thyroid cancers, sarcomas
Older age: breast cancer
Any exposure to radiation therapy
Friedman et al, J Natl Cancer Inst, 2010

9. What about genetic risk?
One out of three survivors who get a second cancer go on to develop a third, fourth cancer
Siblings and family members of survivors with second cancers have an increased cancer risk
Armstrong et al, J of Clin Oncol, 2011
Friedman et al, Cancer Epidemiol Biomarkers Prev 2005
Strong et al, J Natl Cancer Inst,1987

10. Short telomeres are a genetic factor that may contribute to cancer risk
Telomeres are repetitive DNA-protein structures at chromosome ends
Protect chromosome ends from the DNA damage response

11. Telomeres naturally shorten with aging
Telomere length
Age in years
Modified from Aubert, Phys Rev, 2008

12. Telomere length is largely determined by hereditary factors
Environmental factors may also accelerate rates of attrition
Stress, anxiety, psychological stressors
Smoking
Exposures to DNA-damaging agents, such as chemotherapy or radiation
Kananen, PLoS One, 2010
Parks, Cancer Epidemiol Cancer Prev, 2009
Valdes, Lancet, 2005
Broer, EJHG, 2103
De Meyer, EJHG, 2014

13. Shorter telomeres are associated with risk for various cancers
Modified from Willeit et al, JAMA, 2010
Follow up time, months
Cumulative hazard for cancer
p <0.001
Longest TL tertile
Shortest TL tertile
Middle TL tertile

14. Are short telomeres associated with risk for subsequent cancers in childhood cancer survivors?

15. Nested case-control study
Childhood Cancer Survivor Study
Survivors without SMN
Survivors with SMN
Primary diagnosis
Age when sample collected
Length of time between primary diagnosis and sample collection
Chemo/radiation exposures
Gramatges et al, Clin Cancer Res, 2014

16. Results
*Adjusted for sex, race, family history, smoking status, and age at the time of diagnosis of primary disease
Gramatges et al, Clin Cancer Res, 2014

17. Conclusions
Telomere length appears to be associated with SMN in cancer survivors
Primarily driven by effect of thyroid cancer SMN
Effect not seen in secondary breast cancer or sarcomas
First investigation of the relationship between telomere length and risk for cancer in childhood cancer survivors
Gramatges et al, Clin Cancer Res, 2014

18. Limitations Relatively small sample size
Unable to determine if shortened telomeres were inherited or if they resulted from cancer therapy
The CCSS survivor cohort is relatively young, and incidence of second, third, or additional neoplasms is expected to increase as the population ages

19. Future Directions – predicting thyroid second cancers
Thyroid SMN: prevalent disease in survivor populations who received head/neck radiation
Failure to detect thyroid cancer early may lead to significant morbidities with advanced disease
Current practice: surveillance with palpation
relatively high failure rate for detecting a nodule

20. Building a thyroid cancer risk prediction model
The existing model for predicting thyroid cancer risk is based upon clinical factors
Incorporation of genetic risk factors into this model may further refine the existing model and narrow the population of survivors at highest risk
Goal to facilitate early detection
Kovalchik et al, J Clin Oncol, 2012

21. Funding Sources
Texas Children’s Cancer Center (TXCH) NIH K12 Faculty Fellowship in Pediatric Oncology Clinical Research
NIH NCI K23 Career Development Award
Alex’s Lemonade Stand Young Investigator Award
St. Baldrick’s Foundation Scholar Award
Baylor College of Medicine Chao Physician Scientist Award
TXCH Scholar of Excellence Award