Cancer Risk andManagement in RTS
Webinar Series, #5
Lisa L. Wang, MD
Associate Professor
Texas Children’s Cancer Center
Texas Children’s Hospital
Baylor College of Medicine
Houston, TX

Summary of Clinical Findings in 41 RTS Subjects
Baylor College of Medicine Study
Rash

41/41

100%

Small stature

25/38

66%

Skeletal dysplasia

15/20

75%

Radial ray defect

8/40

20%

Sparse scalp hair

15/30

50%

Sparse brows/lashes

19/26

73%

GI disturbance

7/41

17%

Cataracts

2/32

6%

Skin cancer

1/41

2%

Osteosarcoma

13/41

32%

Wang et al (2001) Am J Med Genet; 102:11-17Presence of RECQL4 mutations increases
risk of osteosarcoma (OS) in RTS
Type 2 RTS:
RECQL4 mutations
Increased risk of OS
compared to Type 1

Type 1 RTS:
No RECQL4 mutations

Lu et al, Adv Exp Med Biol. 2014;804:129-45

Osteosarcoma• Known associations–Prior irradiation–Li-Fraumeni syndrome (p53)–Bilateral retinoblastoma (RB)
–Adults with Paget’s disease–Werner syndrome (WRN)–Rothmund-Thomson syndrome (RECQL4)

Sporadic Osteosarcoma• Most common malignant bonetumor in children and adolescents• Patients usually present with painin the affected bone with nosystemic symptoms• Peak age during teenage years

Distribution of pediatric tumors under the age of 20 years
SEER 1986-1995

Osteosarcoma: Epidemiology
75% 15-25 yr• Bimodal age
distribution

25% elderly

Distribution ofOsteosarcoma in children• 2/3rds occur around knee
• Distal femur > proximal
tibia > proximal femur >proximal humerus• Axial lesions less common• Metastases to lungs andother bones: 25% atdiagnosis

Osteosarcoma: Radiology• Mixed lytic/blastic• Cortical breakthrough“Codman’s triangle”• Radial ossification“sunburst”Osteosarcoma: Management Schema
Histologic
Response

BiopsyPre-operative
chemotherapy

Definitive
surgery

Post-operative
chemotherapy• Diagnosis must be made by biopsy• Staging to determine metastases• Treatment consists of surgery and chemotherapy

OS: Management Schema
Histologic
Response~18 weeks~10 weeks

BiopsyPre-operative
chemotherapy

Definitive
surgery

Post-operative
chemotherapy• OS is relatively radio-resistant• Active agents: doxorubicin, cisplatin,
methotrexate, ifosfamideOsteosarcoma: Management Schema
Histologic
Response

BiopsyPre-operative
chemotherapy

DefinitivesurgeryPost-operative
chemotherapy• Determine histologic response at time ofdefinitive surgery• Amputation vs. limb salvage

Osteosarcoma: Outcomes• Non-metastatic
Overall ~65% cure rate
• Metastatic< 20 % cure rate
• No significant improvements in cure rates
for either group in the past 30 years

Treatment of OS in RTS
Questions:• Can RTS patients who develop OS be treatedthe same as OS patients without RTS?
• Will RTS patients have more toxicities fromchemotherapy?
• Are their clinical outcomes the same?

OS in RTS:
Clinicopathologic Features• Age at diagnosis of OS• Location of OS• Histologic subtype• Tumor response tochemotherapy• Toxicities to chemotherapy• Overall patient outcomesOS in RTS:
Clinicopathologic Features• 12 subjects with RTS; age range 4–20 years; 7males, 5 females• 7 subjects diagnosed with RTS prior to OS; 5subjects diagnosed with RTS after OS• Median age at diagnosis of OS: 10 years• All subjects received chemotherapy and surgery

Hicks et al. J Clin Oncol 2007; 25:370-375

OS in RTS: Results• Location of OS: similar to general
population, distal long bones, aroundthe knee (~75%)• Histologic subtype: similar to general
population; “conventional” OS mostcommon (~75%, osteoblastic,chondroblastic, fibroblastic)
Hicks et al. J Clin Oncol 2007; 25:370-375

OS in RTS: Results• Histologic (Tumor) Response toChemotherapy: similar to general
population: about 45% have good response• Overall patient outcomes: 9 patients aliveand disease-free--similar to general
population: ~65% survival
Hicks et al. J Clin Oncol 2007; 25:370-375

OS in RTS: Results• Toxicities to chemotherapy:– 5 subjects had toxicities without modifications– 4 had toxicities to doxorubicin requiring
modifications (maximum 25% dose reduction)– 2 subjects were started at lower doses ofchemotherapy up front– 2 subjects no treatment data was available
Hicks et al. J Clin Oncol 2007; 25:370-375

Cellular Sensitivity
Doxorubicin

Cisplatin

1000

100

10WTRTSAT

10.1

Survival (as % of untreated control)

Survival (as % of untreated control)

1000

100

10WTRTS

10.1

0.01
0.01

000.5

1

1.50.5

11.5

22.5

3CDDP uMDoxorubicin uM

Jin et al. Hum Genet 2008; 123(6):643-653

Cellular Sensitivity
UVIR
1000

100
WTRTS10AT

10.1

Survival (as % of untreated control)

Survival (as % of untreated control)

1000

100
WTRTS

10XP-D

10.1

01234IR Gy024

6810

UV J/M2

Jin et al. Hum Genet 2008; 123(6):643-653

Osteosarcoma in RTS Patients• Conclusions– OS in RTS patients occurs at a younger median age(10 years) compared to the general population.
– The locations and histologic subtypes of OS in RTSpatients do not differ greatly from that in the general
population.

Osteosarcoma in RTS Patients• Conclusions– Some RTS patients (33%) had enhanced
sensitivity to doxorubicin in the form of severe
mucositis, while others tolerated it well.
– No way to predict a priori who will have moresensitivity

Osteosarcoma in RTS Patients
Recommendations:• Counsel RTS patients with RECQL4 mutations
for awareness of OS risk
• Obtain baseline skeletal survey to define
underlying bone abnormalities• Treat OS with standard chemotherapy with noup-front reductions• Modify chemotherapy only as dictated by clinicalcourse of the individual patientScreening for Osteosarcoma in Type 2 RTS

Walsh et al., Clinical Cancer Research 2017

Surveillance in Type 2 RTS• Annual skin checks for skin cancer; sunscreen• No formal screening recommended for osteosarcoma• Increased awareness and understanding of the disease• Prompt attention to symptoms and signs• Baseline skeletal survey for comparison