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Osteosarcoma with cell-cycle and fibroblast growth factor genomic alterations: case report of Molecular Tumor Board combination strategy resulting in long-term exceptional response

Abstract

There is a paucity of information about molecularly driven therapy in osteosarcomas. We report a 31-year-old woman with chemotherapy–refractory metastatic osteosarcoma who was successfully treated with the combination of palbociclib (CDK4/6 inhibitor) and lenvatinib (multikinase FGFR inhibitor), selected based on next generation sequencing that showed CDK4 and CCND2 amplifications (upregulates CDK4/6), and FGF6 (ligand for FGFR1,2 and 4), FGF23 (ligand for FGFR1,2,3, and 4) and FRS2 (adaptor protein for FGFR signaling) amplifications. The patient’s tumor showed 68% reduction in positron emission tomography (PET) avidity, lasting 31 months after therapy initiation, when a solitary recurrence occurred, was resected, and treatment continued. The patient remains on matched targeted therapy at 51 + months from the start of the combination. Treatment was given at reduced dosing (lenvatinib 10 mg oral daily (approved dose = 24 mg daily)) and palbociclib 75 mg oral daily, one week on and one week off (approved dose = 125 mg oral daily, three weeks on/one week off) and is tolerated well. Therefore, co-targeting the aberrant cyclin and FGFR pathways resulted in long-term exceptional response in a patient with refractory advanced osteosarcoma.

To the Editor,


Osteosarcoma is the most common primary bone tumor in children and young adults. Unfortunately, metastatic disease treated with front-line chemotherapy shows a three-year event-free survival of only 32% [1].

At the molecular level, osteosarcomas most commonly harbor alterations in TP53 (74%), RB1 (64%), and MYC (39%), which are challenging targets [2]. However, some osteosarcomas have potentially actionable targets, including CDK4 (11%) and PTEN (56%) alterations [2].

A limitation of targeted therapy in osteosarcoma and other malignancies could be due to multiple co-existing driver molecular alterations in metastatic disease [3,4,5]. For instance, amongst 31 osteosarcomas, there was a median of 21 single-nucleotide variants/cancer (whole exome sequencing) [6]. Similarly, in 112 osteosarcomas who underwent exome or whole genome sequencing, another report found a median of 38 mutations per tumor. Even so, clinical trials that utilize genomic biomarkers generally only target one gene at a time. However, recent data suggests that customized combinations of drugs matched to genomic alterations can be safe and effective across cancer types [4, 5, 7, 8].

Herein, we describe a patient with treatment-refractory metastatic osteosarcoma who was successfully managed long-term with a genomically matched (chemotherapy-free) combination strategy.

Case presentation

A 30-year-old woman with recurrent, refractory metastatic osteosarcoma was referred. At age 17, she underwent limb-sparing surgery for a left leg (femur) periosteal osteosarcoma. Eleven years later, computerized tomography (CT) detected a right hilar mass and multiple pulmonary nodules. Lung lesion resection confirmed osteosarcoma, and was followed by adriamycin and cisplatin and later adriamycin and ifosfamide administration (total = 6 cycles). Eight months later, CT scan revealed new pulmonary lesions. She received ifosfamide (progression-free survival [PFS] = 4 months) followed by stereotactic body radiation therapy and ipilimumab (clinical trial) (PFS = 21 months). Tissue was then analyzed by next-generation sequencing (Foundation Medicine (https://www.foundationmedicine.com/) (N = 405 genes)), which revealed CDK4, MDM2 and FRS2 amplification (≥ 8 copy number alterations) as well as 6–7 copy number amplifications in CCND2, FGF6 and FGF23. The patient was referred to the University of California San Diego (UCSD) Moores Cancer Center Molecular Tumor Board (MTB).

The UCSD MTB is a tumor-agnostic tumor board comprised of medical, surgical and radiation oncologists, radiologists and pathologists, bioinformatics specialists and basic scientists, clinical study coordinators and navigators, and medication acquisition specialists [4] that focuses on discussing therapies based on patients’ tumor multi-omic results. The MTB recommended combination therapy with palbociclib (CDK4/6 inhibitor for CDK4 and CCND2 amplifications) and lenvatinib (an FGFR inhibitor for FGF6 (ligand for FGFR1,2 and 4), FGF23 (ligand for FGFR1,2,3, and 4) and FRS2 (adaptor protein for FGFR signaling) amplifications) (Fig. 1) (50% inhibitory concentration (IC50) for CDK4 with palbociclib: 9 nM; IC50 for FGFR1-4 with lenvatinib: 27–61 nM (IC50 was determined from FDA pharmacological reviews (available online))). The patient signed consent for the PREDICT study (NCT02478931). She began palbociclib 75 mg orally/day (three weeks on/one week off) and lenvatinib 10 mg orally/day. Thrombocytopenia necessitated dose reduction of palbociclib to 75 mg/day, one week on/one week off (approved palbociclib dose = 125 mg orally/day, 3 weeks on/one week off). Lenvatinib was increased to 14 mg orally/day; however, due to mucositis, the dose was re-reduced to 10 mg orally/day (approved lenvatinib dose = 24 mg orally/day). Four months later, positron emission tomography (PET)/computed tomography (CT) scan demonstrated marked improvement in mid-right lung mass PET avidity (Fig. 2A) while a CT scan (Fig. 2B) showed overall stable disease (68% reduction in PET avidity: SUV = 4 [before therapy] down to SUV = 1.3 [nadir]). Subsequent images showed no evidence of progression until 31 months later, when a right hemi-diaphragm mass appeared. The mass was resected and confirmed to be osteosarcoma. Molecular profiling on the cartilaginous surgical sample failed. Post-surgery, the patient resumed palbociclib and lenvatinib. Therapy has been ongoing for 51 + months since its initiation, with excellent tolerance and continued response.

Fig. 1
figure 1

Chromosomal localization of the patient’s amplified genes CDK4, MDM2, FRS2, CCND2, FGF6 and FGF23 and FGF-FGFR signaling pathways cross talk with cell-cycle pathway. A Relevant (targeted) amplified genes are detected in chromosome 12, and their specific localization are demonstrated in the figure. MDM2 was also amplified and localizes to chromosome 12, but it was not considered druggable. B The binding of ligands to receptors triggers the conformational changes of FGFRs, leading to dimerization and activation of FGFRs. Activated FGFRs phosphorylate FRS2, and FRS2 binds to the SH2 domain-containing adaptor protein GRB2. GRB2 will subsequently bind to SHC, SOS and activates downstream the RAS-RAF-MEK-ERK pathway responsible for proliferation and survival. GRB2 also binds with another adaptor protein, GAB1, which has a YXXM motif responsible for the recruitment of p85, leading to activate the PI3K-AKT-mTOR pathway. The PI3K-AKT-mTOR pathway is responsible for proliferation, migration, angiogenesis, cap-dependent mRNA translation and inhibits apoptosis. Cyclin D1/D2/D3 is also activated by upstream RAS-MAPK and AKT-mTOR pathways. Cyclin D binds with CDK4/6 to promote RB phosphorylation, which depresses the E2F transcription factor to drive the expression of genes that promote cell cycle progression. The FGF-FGFR signaling pathway also activates downstream JAK-STAT and PLCγ-PKC pathways, both are responsible for various oncogenic phenotypes. Amplified genes from current case (FGF6, 23, FRS2, Cyclin D2, and CDK4) are showing in italic, and therapies (palbociclib and lenvatinib) are showing in the red boxes. FGF fibroblast growth factor, FGFR fibroblast growth factor receptor, FRS2 FGFR substrate 2, GAB1 GRB2 associated binding protein 1, GRB2 growth factor receptor-bound 2, SOS son of sevenless; PKC protein kinase C, PLCγ phospholipase C gamma, HSPG heparan sulfate proteoglycan

Fig. 2
figure 2

Osteosarcoma patient with multiple recurrences whose tumor progressed on several lines of therapy, now treated successfully with matched targeted combination treatment approach. Therapy ongoing at 51 + months. A (PET scan) and B (CT scan). Osteosarcoma patient with multiple recurrences whose tumor progressed on several lines of therapy, now treated successfully with matched targeted combination treatment approach. Therapy ongoing at 51 + months

Discussion

Relapsed/refractory osteosarcoma is a challenging disease. Periosteal osteosarcoma is very rare and has a better prognosis than conventional osteosarcoma. However, this patient had metastatic disease that had progressed after several chemotherapies. There is high molecular diversity in advanced osteosarcoma with several undruggable (to date) targets (such as TP53 and Rb). To date, precision therapies and direct bone targeting therapies such as alpha particle radium 223 have demonstrated limited activity [9]. Moreover, genomically matched CDK4/6 inhibitors (e.g., palbociclib, ribociclib and abemaciclib) as well as matched FGFR inhibitors as monotherapy have shown limited responses across malignancies [10,11,12]. CDK4/6 inhibitors have been used in liposarcoma, with activity. However, there are no trials published of CDK4/6 inhibitors in osteosarcoma; a single case report showed stable disease for about 10 months in a patient give the CDK4/6 inhibitor, ribociclib, together with gemcitabine.

In this context, the importance of the current case lies in showcasing the activity of molecularly matched combination therapy, specifically with a CDK4/6 inhibitor given together with a multi-kinase FGFR inhibitor for a relapsed osteosarcoma. Of note, not only were the drugs matched to the patient’s genomic alterations, but the dose of each drug was reduced from the approved dose and hence tailored to the patient’s tolerance. Most remarkably, the patient is doing well on the palbociclib with lenvatinib combination at over four years—51 + months. Further studies co-targeting FGFR and CDK4/6 signals in patients whose tumors harbor cognate alterations are warranted.

Availability of data and materials

N/A.

References

  1. Smeland S, Bielack SS, Whelan J, Bernstein M, Hogendoorn P, Krailo MD, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer. 2019;109:36–50.

    Article  Google Scholar 

  2. Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY, et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 2019;9(1):46–63.

    CAS  Article  Google Scholar 

  3. Carmagnani Pestana R, Groisberg R, Roszik J, Subbiah V. Precision oncology in sarcomas: divide and conquer. JCO Precis Oncol. 2019;3:66.

    Google Scholar 

  4. Kato S, Kim KH, Lim HJ, Boichard A, Nikanjam M, Weihe E, et al. Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy. Nat Commun. 2020;11(1):4965.

    CAS  Article  Google Scholar 

  5. Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019;25(5):744–50.

    CAS  Article  Google Scholar 

  6. Kovac M, Blattmann C, Ribi S, Smida J, Mueller NS, Engert F, et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015;6:8940.

    CAS  Article  Google Scholar 

  7. Kato S, Okamura R, Adashek JJ, Khalid N, Lee S, Nguyen V, et al. Targeting G1/S phase cell-cycle genomic alterations and accompanying co-alterations with individualized CDK4/6 inhibitor-based regimens. JCI Insight. 2021;6(1):66.

    Article  Google Scholar 

  8. Rodon J, Soria JC, Berger R, Miller WH, Rubin E, Kugel A, et al. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med. 2019;25(5):751–8.

    CAS  Article  Google Scholar 

  9. Subbiah V, Anderson PM, Kairemo K, Hess K, Huh WW, Ravi V, et al. Alpha particle radium 223 dichloride in high-risk osteosarcoma: a phase i dose escalation trial. Clin Cancer Res. 2019;25(13):3802–10.

    CAS  Article  Google Scholar 

  10. Ahn ER, Mangat PK, Garrett-Mayer E, Halabi S, Dib EG, Haggstrom DE, et al. Palbociclib in patients with non-small-cell lung cancer with CDKN2A alterations: results from the targeted agent and profiling utilization registry study. JCO Precis Oncol. 2020;4:757–66.

    Article  Google Scholar 

  11. Chae YK, Hong F, Vaklavas C, Cheng HH, Hammerman P, Mitchell EP, et al. Phase II study of AZD4547 in patients with tumors harboring aberrations in the FGFR pathway: results from the NCI-MATCH trial (EAY131) subprotocol W. J Clin Oncol. 2020;38(21):2407–17.

    CAS  Article  Google Scholar 

  12. Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Rev. 2015;34(3):479–96.

    CAS  Article  Google Scholar 

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Acknowledgements

Funded in part by the Joan and Irwin Jacobs Fund, and by National Cancer Institute Grants P30 CA023100 (SK).

Funding

Funded in part by the Joan and Irwin Jacobs Fund, and by National Cancer Institute grants P30 CA023100 (SK).

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Authors and Affiliations

Authors

Contributions

HEP, SK, and RK drafted the initial draft of manuscript. SK treated the patient. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Shumei Kato.

Ethics declarations

Ethics approval and consent to participate

This study was performed in accordance with the guidelines of the UCSD Internal Review Board (PREDICT [Profile Related Evidence Determining Individualized Cancer Therapy] protocol; NCT02478931, and/or I-PREDICT [Investigation of Profile Related Evidence Determining Individualized Cancer Therapy] protocol; NCT02534675). Both of these protocols are investigational studies for which the patients gave consent.

Consent for publication

Consent for publication was obtained from the patient.

Competing interests

HEP, JJA have no conflicts of interest. PD is a fulltime employee at Aver Cancer Institute and a paid consultant at Viecure. SK serves as a consultant for Foundation Medicine, NeoGenomics and CureMatch. He receives speaker’s fee from Roche and advisory board for Pfizer. He has research funding from ACT Genomics, Sysmex, Konica Minolta and OmniSeq. JKS receives research funding from Amgen Pharmaceuticals and Foundation Medicine, consultant fees from Deciphera, speaker’s fees from Deciphera, Foundation Medicine, La-Hoffman Roche, Merck, MJH Life Sciences, QED Therapeutics, and has stock in Personalis. VS reports a grant and advisory board/consultant position with Eli Lilly/Loxo Oncology during the conduct of the study. Vivek Subbiah also reports research grants from Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, and Medimmune; an advisory board/consultant position with Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, and Medimmune; travel funds from Pharmamar, Incyte, ASCO, and ESMO; other support from Medscape; all outside the submitted work. RK has receivedresearch funding from Genentech, Incyte, Merck, Serono, Pfizer, Sequenom, Foundation Medicine, Grifols, and Guardant, as well as consultant fees from Loxo, X Biotech, NeoMed, Biologic Dynamics, Roche, Iylon, Daiichi, and Actuate Therapeutics, speaker fees from Roche, and has an ownership interest in IDbyDNA and Curematch Inc and CureMetrix and is a Board member of CureMatch and CureMetrix Inc.

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Persha, H.E., Kato, S., De, P. et al. Osteosarcoma with cell-cycle and fibroblast growth factor genomic alterations: case report of Molecular Tumor Board combination strategy resulting in long-term exceptional response. J Hematol Oncol 15, 119 (2022). https://doi.org/10.1186/s13045-022-01344-x

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Keywords

  • Osteosarcoma
  • Targeted therapy
  • Precision
  • Genomic