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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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