Risk for Second Cancers in Survivors of Childhood Cancer

M. Monica Gramatges, MD, PhDJune 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%

0 1 2 3 4 5 6 7 8 9 100

10

20

30

40

50

60

70

80

90

100

2000-2005 (7171)

1995-1999 (7180)

1989-1998 (5121)

1983-1988 (3711)

1978-1983 (2984)

1975-1977 (1313)

1972-1975 (936)

1970-1972 (499)

1968-1970 (402)

Years

Su

rviv

al (

%)

Hunger et al, J Clin Oncol, 2012

Childhood leukemia outcomes

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 Friedman et al, J Natl Cancer Inst,

2010Olsen et al, J Natl Cancer Inst, 2009Reulen et al, JAMA, 2011

Armstrong et al, J of Clin Oncol, 2009

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 2005Strong 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

Modified from Aubert, Phys Rev, 2008

Telo

mer

e le

ngth

Age in years

Telomeres naturally shorten with aging

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, 2010Parks, Cancer Epidemiol Cancer Prev, 2009Valdes, Lancet, 2005Broer, EJHG, 2103De Meyer, EJHG, 2014

Shorter telomeres are associated with risk for various cancers

Modified from Willeit et al, JAMA, 2010

Follow up time, months

Cum

ulat

ive

ha

zard

for

canc

er

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

Survivors without SMN

Survivors with SMN

Childhood Cancer Survivor Study

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