National Cancer Institute
U.S. Department
of health and human
services
National
Institutes
of Health
Second Tumors in
Retinoblastoma Survivors
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
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
Outline
• Epidemiology of retinoblastoma
• Second cancers
• Treatment-related risk for sarcomas
• Implications
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
Retinoblastoma
U
Hereditary
Non-hereditary
•
RB1 Germline mutation
•
RB1 Somatic mutation
•
Age at diagnosis:
•
Age at diagnosis:
0-12 months
•
Bilateral disease
(85%)or Unilateral +
family history of Rb
(15%)
2-5 years of age
•
•
•
40% of RB
Unilateral disease, no
family history of Rb
60% of RB
Why study second cancers?
• RB1 is a high risk cancer susceptibility gene
• Somatic mutations in the RB1 gene: sarcomas
and epithelial cancers (lung, bladder, breast,
ovary)
• Treatments: radiotherapy and chemotherapy
have been linked to second cancers
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
Causes of second cancers
Medical,
lifestyle,
environment
Cancer
Treatment
Genetic
Susceptibility
Second
cancer
Cancersafter
after Retinoblastoma
SecondSecond
cancers
Retinoblastoma
Cohort
USA (n=1601)
Hereditary
No.
SIR¶
260
19*
Non-hereditary
No.
SIR¶
17
1.2
UK
113
13*
19
1.7*
62
20*
12
1.9
(n=1927)
Netherlands (n=668)
* 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
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
Second
Cancers after
Retinoblastoma
Second
Cancers
after
retinoblastoma
Cancer Site
Hereditary
(n=963)
No.
SIR
Non-hereditary
(n=638)
No.
SIR
Bone
Soft tissue
Nasal cavity
75
34
32
360*
122*
>1000*
0
0
0
0.0
0.0
0.0
Melanoma
Eye/orbit
Brain/CNS
29
17
10
28*
266*
14*
0
0
2
0.0
0.0
3.4
* P<0.05
Kleinerman et al, JCO,
2005
*p<0.05
Second
Cancers after
Retinoblastoma
Second
cancers
after
retinoblastoma
Cancer Site
Hereditary
(n=963)
No.
SIR
Female breast
Lung
Buccal cavity
10
5
7
4.0*
6.0*
20*
7
0
0
2.8*
0.0
0.0
Bladder
Uterus
Thyroid
2
7
2
6.2*
20*
3.3
0
0
0
0.0
0.0
0.0
Leukemia
2
2.3
1
1.5
* P<0.05
Non-hereditary
(n= 638)
No.
SIR
Kleinerman et al, JCO,
2005
*p<0.05
Cumulative risk of a second cancer
Percent Cumulative Incidence, %
40
36.0%
95% CI = (30.9% – 41.1%)
Hereditary Retinoblastoma
30
20
10
5.69%
Non-Hereditary Retinoblastoma
95% CI = (2.4% – 11.1%)
0
0
10
20
30
40
50
Time After Retinoblastoma Diagnosis, yrs
Hereditary
963
30
760
615
401
147
570
500
317
134
Non-Hereditary
638
46
Number of Patients at Risk
Kleinerman et al. J Clin Oncol 2005
0.4
0.6
0.8
hereditary
hereditary
nonhereditary
nonhereditary
0.2
25.5% (21%-30%)
1.0% (0.2%-1.8%)
0.0
1.0
0.2
cumulative mortality
Cumulative
cumulativemortality
mortality
0.4
0.6
0.8
1.0
Cumulative mortality from second cancers
0
10
20
30
40
50
Time
since Rb
Rb diagnosis
(years)
Time
since
diagnosis,
yrs
.0
Yu et al, JNCI, 2009
Cumulative incidence of second cancers
by family history and laterality
Kleinerman et al., JCO, 2012
Causes of second cancers
Genetic
susceptibility
Cancer
treatments
Medical,
lifestyle,
environment
Second
cancer
External beam
radiotherapy for
retinoblastoma;
48 Gy (15-115 Gy) to
affected eye
GH Fletcher, Textbook of
Radiotherapy, 2nd ed. 1973
Risk for soft
tissue sarcoma
andtissue
bone
Radiation
dose-response
for soft
cancer after
retinoblastoma
sarcoma
14
12
Odds Ratio
10
8
6
4
2
0
0-4.9 Gy
5.0-9.9 Gy
10-29.9 Gy
30-59.9 Gy
≥60 Gy
Wong et al, JAMA, 1997
Risk for soft tissue sarcoma by histology
Histology
Leiomyosarcoma
Fibrosarcoma
Observed
23
13
SIR (95%CI)
390 (247-585)
398 (211-681)
Malignant fibrous
histiocytoma
STS and sarcomas
NOS
Rhabdomyosarcoma
Liposarcoma
12
100 (52-175)
10
96 (46-177)
8
3
279 (120-551)
99 (20-286)
TOTAL
69
184 (143-233)
Kleinerman et al. JNCI 2007
Risks
Tissue sarcomas
Sarcomasby
bytime
Years
Risks of
of Soft
soft tissue
Since
Diagnosis
since of
RbRB
diagnosis
Standardized incidence ratio
450
400
350
300
250
All soft tissue
sarcomas
Leiomyosarcoma
200
150
100
50
0
1-9 Yr
10-19 Yr 20-29 Yr
30+ Yr
Kleinerman et al. JNCI, 2007
Cumulative incidence %
Cumulative incidence of soft tissue
sarcoma after radiotherapy
7.9% (5.5%-10.2%)
In-field
5.1% (2.8%-7.3%)
Out of field
Time since Rb diagnosis, yrs
Risk of leiomyosarcoma by treatment for
hereditary retinoblastoma
Cumulative incidence (%)
16
14
12
10
8
Radiotherapy + Chemotherapy
6
4
Radiotherapy
2
0
0
10
20
30
40
Attained age (years)
Wong et al, JCO, in press
Risk
for softdose-response
tissue sarcomafor
and
bone
Radiation
soft
cancer
afterbone
retinoblastoma
tissue and
sarcoma
12
Odds Ratio
10
8
6
4
2
0
0-4.9 Gy
5.0-9.9 Gy
10-29.9 Gy
30-59.9 Gy
≥60 Gy
Wong et al, JAMA, 1997
Age at bone sarcoma by proximity to
radiation field
18
16
Number of sarcomas
14
12
10
BONE_IN
8
BONE_OUT
6
4
2
0
0
5
10
15
20
25
30
Age at bone sarcoma
35
40
45
50
Cumulative incidence %
Cumulative incidence of bone sarcoma
after radiotherapy
7.9% (5.8%-10.0%)
In-field
Out of
field
Time since Rb diagnosis, yrs
3.8% (2.4%-5.2%)
Risk of bone sarcoma by treatment for
hereditary retinoblastoma
16
Radiotherapy + Chemotherapy
Cumulative incidence (%)
14
12
10
Radiotherapy
8
6
4
2
0
0
10
20
30
40
Attained age (years)
Wong et al, JCO, in press
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 early and persists for decades
•
Second cancers higher in bilateral patients + family history of
Rb
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
Future
• Continue to follow survivors
• Inform re: risk of second cancers
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
Acknowledgements
•
National Cancer Institute
•
•
Memorial Sloan Kettering Cancer Center
•
•
David Abramson, Jasmine Francis
Tufts New England Medical Center
•
•
Lindsay Morton, Margaret Tucker, Jeannette Wong, Mark Little,
Chu-ling Yu, Sara Schonfeld, Josh Sampson
Johanna Seddon
M.D. Anderson Cancer Center
•
Marilyn Stovall, Susan Smith, Rita Weathers
Original Cohort Study: John D Boice, Jr, NCRP; Charis Eng
(Cleveland Clinic); Fred Li, Dana Farber Cancer Institute
(retired); Robert Tarone (IEI): Lennie Wong (City of Hope)