TKCC/Garvan Cancer Biology Seminars Principles of multidisciplinary - PowerPoint PPT Presentation

TKCC/Garvan Cancer Biology Seminars Principles of multidisciplinary musculoskeletal tumour management Prof David Thomas 4 th March 2016

Aims of presentation An state-of-the-art overview of: • Australian epidemiology • Etiology • Risk factors • Pathology • Staging • Treatment

Embryonic derivation of tumours

Unique features of sarcomas 1. Rare and diverse 2. Younger patients 3. Patterns of spread typically non-lymphatic, frequently metastasise to lungs (>80%) 4. Two genetic patterns Chromosomal instability/aneuploidy • Signature lesions with relative diploidy • 5. Two (at least) pathologic groups Neuroectodermal origin (SRBCT) • Mesodermal origins (spindle cell tumours) • 6. Chemo- and radio-resistance (allegedly) 7. Scarcity of clinical trials

Sarcomas: malignant tumours of soft tissues and bone Uncommon: 15% of childhood cancers 1% of adult cancers 853 sarcomas in Australia in 1988 Benign STS 100 times more common than malignant tumours Benign: 99% superficial to deep fascia, 95%< 5cm diamter 30% lipomas 30% fibrohistiocytic and fibrous tumours 10% vascular tumours 5% PNST

Clinical presentation Often painless Sometimes long-standing Deep to deep fascia >5cm Courtesy of Peter Choong

Soft-tissue sarcomas in Australia 1983-2000 700 600 500 C47 Peripheral nerves and ANS Numbers 400 C48 Retroperitoneum and peritoneum C49 Other connective and soft tissue 300 All STS 200 100 0 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 0 8 8 8 8 8 8 8 9 9 9 9 9 9 9 9 9 9 0 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 Bone and cartilage tumours in Australia 1983-2000 200 150 Numbers All Bone and cartilage sarcomas 100 C40 Bone and articular cartilage C41 Other bone and articular cartilage 50 0 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Overview Diagnosis and staging Imaging key biopsy critical Multidisciplinary management Surgery is critical Adequate margins Limb-preservation Reconstruction Adjuvant treatment Radiotherapy for STS Chemotherapy PNET/Ewings sarcoma/SRBCT Osteosarcoma Relatively controversial: high-risk STS where RT impractical evidence of chemosensitivity (eg Synovial cell sarcoma) Supportive care AYA Rehabilitation and survivorship

Histopathology and sarcomas Difficult and uncertain Pathologic review ECOG sarcoma trials (424 patients): 10% not sarcoma 14% disagreement regarding subtype SWCG trials (216 patients): 6% not sarcoma 27% subtype incorrect Scandinavian Sarcoma Group 20% of diagnoses disputed Sarcoma NOS or Malignant fibrous histiocytoma Disputed entity MFH represents de-differentiated forms of other defined entities ( Fletcher, 2001 ) OR MFH is a discrete category in its own right

(Fletcher et al., 2001, JCO)

Genetics of sarcomas

Importance of molecular subtype The advent of targeted therapies makes accurate classification essential (Baselga and Arteaga, 2004) GIST KIT Imatinib Dermatofibroma protruberans PDGFR Imatinib NSCLC EGFR Gefitinib PEComa mTOR Everolimus ASPS angiogenesis Cediranib Giant cell tumor of bone RANKL Denosumab PLX3397/RG7155 PVNS/dTGCT CSF1 Clear impact on efficacy and tolerability Implications for rational clinical trial design?

Genetics of sarcomas

Congenital syndromes in sarcomas Disorder Inheritance Locus Gene Tumours Albright osteodystrophy AD 20q13 GNAS1 Ectopic calcification and osteomas Carney complex AD 17q23-24, 2p16 PRKAR1AK Myxomas, schwannomas Mazabrayd syndrome Sporadic 20q13 GNAS1 Polyostotic fibrous dysplasia, osteosarcoma, myxomas McCune Albright syndrome Sporadic 20q13 GNAS1 Polyostotic fibrous dysplasia, osteosarcoma, myxomas Ollier's disease Sporadic 3p21-22 PTHR1 Enchondromas, chondrosarcomas Rubinstein-Taybi syndrome AD 16p13 CREBBP Myogenic sarcomas Bannayan-Riley-Ruvucalba syndrome AD 10q23 PTEN Lipomas, haemangiomas Cowden disease AD 10q23 PTEN Lipomas, haemangiomas Rothmund-Thomson syndrome AR 8q24 RECQL4 Osteosarcomas Bloom syndrome AR 15q26 BLM Osteosarcomas Werner syndrome AR 8p11-12 WRN Various bone and STS Beckwith-Wiedemann syndrome sporadic/AD 11p15 Complex (IGF2, Emb. Rhabdomyosarcomas, myxomas, fibromas p57KIP2) Familial Paget's disease of bone AD 18q21, 5q31, 5q35 TNFRSF11A Osteosarcomas Familial expansile osteolysis AD 18q21 TNFRSF11A Osteosarcomas Li-Fraumeni syndrome AD 17p13, 22q11 TP53, CHEK2 Osteosarcomas, rhabdomyosarcomas, other STS Langer-Giedion syndrome Sporadic 8q24 EXT1 Osteochondromas, chondrosarcomas Multiple osteochondromas AD 8q24, 11p11-12 EXT1, EXT2 Osteochondromas, chondrosarcomas Neurofibromatosis I AD 17q11 NF1 Neurofibromas, MPNST Neurofibromatosis II AD 22q12 NF2 Schwannomas Familial adenomatous polyposis AD 5q21 APC Craniofacial osteomas, desmoid tumour Familial infiltrative fibromatosis AD 5q21 APC Desmoid tumours Retinoblastoma AD 13q14 RB1 Osteosarcomas, STS Rhabdoid predisposition syndrome AD 22q11 SMARCB1 Malignant rhabdoid tumours Familial chordoma AD 7q33 Chordomas Costello syndrome sporadic Rhabdomyosarcomas Diaphyseal meduallry stenosis with MFH AD 9p21-22 MFH of bone Familial multiple lipomas AD Lipomas Symmetrical lipomatosis Sporadic Lipomas Maffucci syndrome Sporadic Enchondromas, chondrosarcomas, haemangiomas, angiosarcomas Myofibromatosis AR Myofibromas Proteus syndrome Sporadic Lipomas Venous malformations with glomus cells AD 1p21-22 Glomus tumours

One in 30 TP53 muta,on carriers amongst adult-onset sarcomas Gene(c Reported Reported Inheritance Clinical Case variant TP53 Amino acid change Muta(on type Condel Sex Proband primary cancers, age at diagnosis (yrs) soma(c cases germline cases pa;ern classifica(on 1 c.72del p.Lys24AsnfsX20 FS NA 0 0 unconfirmed # M rhabdomyosarcoma 33 LFS 2 c.586C>T p.Arg196X nonsense NA 241 13 paternal M osteosarcoma 20 LFS 3 c.559+1G>T exon skipping splice site NA 10 0 unconfirmed # M chondrosarcoma 24; liposarcoma 39 LFS 4 c.329G>C p.Arg110Pro missense del 15 0 de novo M sarcoma NOS 37; liposarcoma 44 LFS 5 c.916C>T p.Arg306* nonsense NA 164 17 unknown M sarcoma NOS 50; lymphoma 51; melanoma 53 LFS 6 c.659A>G p.Tyr220Cys missense del 396 37 unconfirmed# M sarcoma NOS 28 LFS 7 c.328_329ins p.Phe109ArginsHis indel NA 0 0 unconfirmed# M sarcoma NOS 23 LFS 8 c.503A>T p.His168Leu missense neutral? 9 0 maternal M leiomyosarcoma 39 LFS 9 c.783-1G>A exon skipping splice site NA 7 0 unconfirmed # F angiosarcoma 25 Chomp LFL 10 c.700T>C p.Tyr234His missense del 33 0 unknown F breast 33; leiomyosarcoma 48 Chomp LFL 11 c.853G>A p.Glu285Lys missense del 186 5 unknown F breast 38; leiomyosarcoma 45 ; thyroid 46 Chomp LFL 12 c.997C>T p.Arg333Cys missense del 0 0 maternal F ALL 10; Ewing sarcoma 16 Chomp LFL 13 c.473G>A p.Arg158His missense del 113 9 unknown F breast 26; sarcoma NOS 36 ; pheochromocytoma 37 Chomp LFL 14 c.877G>T p.Gly293Trp missense del 6 2 unknown M Hodgkin's lymphoma 34; melanoma 47; sarcoma NOS 60 Chomp LFL 15 c.467G>A p.Arg156His missense del 19 11 unknown F chondrosarcoma 45; breast 49; breast 57; CRC 61 Chomp LFL 16 c.647T>G p.Val216Gly missense del 5 0 maternal F bilateral breast; chondrosarcoma ; lung; gastric; thyroid Chomp LFL 17 c.847C>T p.Arg283Cys missense del 29 10 unknown M DSRCT 21 Nega,ve 18 c.586C>T p.Arg196X FS NA 241 13 unknown M tes,s 36; rectum 69; leiomyosarcoma 69 Nega,ve 19 c.826_840del p.Ala276_Arg280del indel NA 1 0 unknown F chondrosarcoma 57 Nega,ve 20 c.843C>A p.Asp281Glu missense del 28 0 mosaic M osteosarcoma 19 Nega,ve 21 c.841G>A p.Asp281Asn missense del 37 4 unknown M osteosarcoma 31 Nega,ve 22 c.469G>A p.Val157Ile missense del/neut 19 0 paternal F leiomyosarcoma 58 Nega,ve 23 c.835G>A p.Gly279Arg missense del 8 0 unknown F liposarcoma 62 Nega,ve 24 c.587G>A p.R196Q missense del 10 0 unknown M chondrosarcoma 36 Nega,ve 25 c.1073A>T p.Glu358Val missense del 1 0 unknown F spindel cell sarcoma 60 Nega,ve 26 c.586C>T p.Arg196X FS del 237 17 unknown M osteosarcoma 20 Nega,ve 27 c.1073A>T p.Glu358Val missense del 1 0 unknown F sarcoma NOS 43 Nega,ve # parent deceased at young age from cancer- related cause

Anatomic imaging CT scan MRI scan Plain Xray Functional imaging Thallium scan Bone scan FDG PET Biopsy Critical Open vs core vs needle

Key surgical principles Adequate resection margins are critical Reconstruction essential, and often astonishingly successful Neo-adjuvant treatment can Limit size of resection Be more effective than post-operative treatment, where tissue oxygenation is key Have prognostic value But also complicate wound healing

Radiotherapy principles For curable STS, standard of care is pre-operative RT Usually 50-60Gy (radioresistant) Note that PNET radiosensitive (usually 30-40Gy) Decreases local relapse rates to ~10% (cf 50%) Wound complications Short-term Long-term For palliation, shorter course RT