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Osteosarcoma

Osteosarcoma (OS) is the most common primary bone tumor in both dogs and people. While the disease incidence is relatively low in people (800-1000 cases/year), over 25,000 new cases are diagnosed in dogs every year. Most dogs develop OS at approximately 7 years of age, with a smaller early peak in younger dogs.

Description

Osteosarcoma (OS) is the most common primary bone tumor in both dogs and people. While the disease incidence is relatively low in people (800-1000 cases/year), over 25,000 new cases are diagnosed in dogs every year. Most dogs develop OS at approximately 7 years of age, with a smaller early peak in younger dogs. In large breed dogs (Great Pyrenees, Irish Wolfhounds, Greyhounds, etc), OS typically occurs in the appendicular skeleton, representing 75% of all OS cases. Outside of the appendicular skeleton, OS is also found in the axial skeleton (<30% each mandible, maxilla, spine, cranium, ribs, nasal/paranasal cavity, pelvis) in small breed dogs, and in extra-skeletal locations.

Similarities in humans

Canine OS recapitulates many key features of the disease in people, including a similar clinical disease presentation, response to treatment and progression of drug-resistant metastatic disease. Additionally, many genetic aberrations in signaling pathways (p53, PI3K, MAPK, etc) are conserved between species, including a relatively low mutation burden and predominance of large structural changes.

Differences in humans

In contrast to the biomodal age distribution found in dogs, OS in people most commonly occurs in adolescence (at approximately 10-14 years of age). Additionally, in the setting of nonmetastatic disease, the overall 5-year survival rate is approximately 67%. This represents a significant improvement over the expected survival time in dogs with OS, and supports the notion that canine OS is a model of aggressive human OS.

Disease etiology

Breed-specific predispositions for OS suggest a strong heritable genetic component; for example, Scottish deerhounds have a 15% incidence of OS. Several tumor suppressor gene aberrations have been associated with both human and canine OS, including somatic mutations and loss of heterozygosity (LOH) in p53, Rb and PTEN. In addition, mitogenic signals in the metaphysis of weight-bearing bones secondary to microtrauma has been suggested as a contributing factor. Finally, implant- and ionizing radiation-associated OS have been described, although the incidence is likely lower than previously reported.

Clinical presentation

Weight-bearing lameness and pain is the predominant clinical sign noted in dogs with appendicular OS. Dogs may also present with a pathologic fracture of the a ected bone, without a history of trauma. OS occurs most commonly in the forelimbs (distal radius, proximal humerus) in comparison to the hindlimbs (distal femur, proximal tibia). Most dogs (90%) will present with microscopic metastatic disease, which become evident within 3 months in the absence of therapeutic intervention. When gross metastatic disease commonly develops in the lungs, however skeletal and extraskeletal/visceral metastasis are reported as well.

Treatment

Treatment of OS requires addressing both the primary tumor site and metastatic disease. Amputation or limb-sparing surgery are the most common methods to remove the primary tumor; however, radiation therapy is also used to alleviate pain associated with the primary tumor in dogs that may not be good surgical candidates. The addition of chemotherapy (e.g. carboplatin or doxorubicin) to the treatment regimen improves outcome, with a median survival time of approximately 10 months.

Recent Publications

1. Ren L, Khanna C. Role of ezrin in osteosarcoma metastasis. Adv Exp Med Biol. 2014;804:181-201. Epub 2014/06/14. doi: 10.1007/978-3-319-04843-7_10. PubMed PMID: 24924175.

2. Karlsson EK, Sigurdsson S, Ivansson E, Thomas R, Elvers I, Wright J, et al. Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome Biol. 2013;14(12):R132. doi: 10.1186/gb-2013-14-12-r132. PubMed PMID: 24330828; PubMed Central PMCID: PMCPMC4053774.

3. Angstadt AY, Motsinger-Reif A, Thomas R, Kisseberth WC, Guillermo Couto C, Duval DL, et al. Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosomes Cancer. 2011;50(11):859-74. doi: 10.1002/gcc.20908. PubMed PMID: 21837709.

4. Laver T, London CA, Vail DM, Biller BJ, Coy J, Thamm DH. Prospective evaluation of toceranib phosphate in metastatic canine osteosarcoma. Vet Comp Oncol. 2017. doi: 10.1111/vco.12328. PubMed PMID: 28621057.

5. Selmic LE, Burton JH, Thamm DH, Withrow SJ, Lana SE. Comparison of carboplatin and doxorubicin-based chemotherapy protocols in 470 dogs a er amputation for treatment of appendicular osteosarcoma. J Vet Intern Med. 2014;28(2):554-63. Epub 2014/02/12. doi: 10.1111/jvim.12313. PubMed PMID: 24512451; PubMed Central PMCID: PMCPMC4857984.

6. Paoloni M, Davis S, Lana S, Withrow S, Sangiorgi L, Picci P, et al. Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression. BMC Genomics. 2009;10:625. doi: 10.1186/1471-2164-10-625. PubMed PMID: 20028558; PubMed Central PMCID: PMCPMC2803201.

7. Sakthikumar S, Elvers I, Kim J, Arendt ML, Thomas R, Turner-Maier J, et al. SETD2 is recurrently mutated in whole-exome sequenced canine osteosarcoma. Cancer Res. 2018. Epub 2018/05/05. doi: 10.1158/0008-5472.CAN-17-3558. PubMed PMID: 29724721.

8. Scott MC, Temiz NA, Sarver AE, LaRue RS, Rathe SK, Varshney J, et al. Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma. Cancer Res. 2018;78(2):326-37. Epub 2017/10/27. doi: 10.1158/0008-5472.CAN-17-0576. PubMed PMID: 29066513; PubMed Central PMCID: PMCPMC5935134.

9. Scott MC, Sarver AL, Gavin KJ, Thayanithy V, Getzy DM, Newman RA, et al. Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach. Bone. 2011;49(3):356-67. Epub 2011/05/31. doi: 10.1016/ j.bone.2011.05.008. PubMed PMID: 21621658; PubMed Central PMCID: PMCPMC3143255.

10. Fenger JM, London CA, Kisseberth WC. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR J. 2014;55(1):69-85. doi: 10.1093/ilar/ilu009. PubMed PMID: 24936031.