Comprehensive Genomic Profiling of Aggressive Central Giant Cell Lesion Identifies Targeted Therapy Treatment Option With Subsequent Response

Purpose: Aggressive central giant cell lesions (CGCL) of the jaws are managed with surgical and/or medical therapy (corticosteroid injections or systemic calcitonin, denosumab, or interferon-α).  These therapies can cause significant morbidity and/or adverse effects, and a subset of aggressive CGCL are refractory to some or all of these measures.  In a patient with locally advanced, multiply recurrent, and refractory CGCL, can comprehensive genomic profiling (CGP) identify clinically relevant genomic alterations (CRGA) and possible targeted medical therapy, a novel treatment concept for CGCL?

Methods: CGP was performed on two CGCL samples from the same patient: an early curettage specimen and a subsequent recurrence 8 years later. Hybridization capture from 236 cancer-related genes and 19 genes commonly rearranged in cancer (FoundationOne^TM) was applied to ≥ 50ng of DNA extracted from formalin fixed paraffin embedded CGCL specimens and sequenced to high, uniform coverage.  All classes of genomic alterations were assessed including base substitutions, small insertions and deletions, rearrangements, and copy number alterations. CRGA, mutations for which cancer drugs on the market or in registered clinical trials could be identified, were reported.

Case description: A 16 year old non-syndromic female without hyperparathyroidism or cherubism originally presented to another institution with left maxillary and mandibular CGCL and underwent six enucleation/curettage procedures and multiple steroid injections over 10 years.  At age 27, she presented to Mayo Clinic with 9.5x5.5x3.5cm right mandibular CGCL with cortical perforation and inferior alveolar nerve paresthesia.  She underwent right hemi-mandibulectomy with immediate free fibula flap reconstruction.  She developed extra-osseous recurrence likely related to intra-operative seeding in the right pterygomandibular space (3.2x2.2x4.0cm), and intrabony recurrences in the left mandibular body (0.85x0.65x0.65cm) and the right pterygoid plate region (3.2 x2.2x4.0cm).  Surgical ablation would have included skull base surgery with significant associated operative morbidity.  Localized enucleation/curettage, steroid injections, and subcutaneous and intranasal calcitonin were utilized with no response.  Interferon-α dosed at 4.5 million units/day for five days/week only slowed the disease progression and was associated with adverse systemic effects.  CGP was then pursued to identify any CRGA and possible targeted drug therapies.

Results: CGP of the curettage specimen obtained 8 years earlier demonstrated alteration KRAS (L19F) gene.  CGP of the recent specimen revealed somatic mutations in KRAS (A146V) and HRAS(G13V) genes, which are predicted to constitutive activation of RAS/RAF/MEK/ERK pathways inducing cell transformation and conferring oncogenic properties.  With these CRGA, trametinib, a reversible MEK pathway inhibitor, was identified as a possible targeted drug to treat this patient’s CGCL.  A well-tolerated four week trial of trametinib resulted in CT radiographic signs of lesion stabilization and decreased lesion size, indicating initial clinical response with targeted therapy.  Continued clinical and radiographic follow up will occur.

Conclusions: Comprehensive genomic profiling of biopsy specimens did identify clinically relevant genomic alterations in the MEK pathway in this patient’s aggressive CGCL.  By identifying somatic mutations when present, targeted therapeutic approaches can also be identified: these are novel treatments for aggressive CGCL, typically better tolerated than systemic therapy, and may improve outcomes.  Continued follow-up in this case and further studies are needed.  Furthermore, MEK pathway mutations are known oncogenic drivers in melanoma, colon, and lung cancers, and results of CGP could yield new insights into the etiologic mechanisms underlying aggressive CGCL.  It is clear that the presence of somatic mutations in HRAS and KRAS genes and the clinical response to MEK pathway inhibition by trametinib in this case provide support for an underlying neoplastic rather than reactive process in at least some aggressive CGCL.  Further studies with CGP of other aggressive CGCL to characterize the prevalence and types of mutations, if present, are indicated.