Durable Response to Crizotinib in a MET-Amplified, KRAS-Mutated Carcinoma of Unknown Primary

Abstract

Background: Carcinoma of unknown primary (CUP) accounts for 3-5% of all adult solid tumors. An extensive search for the anatomic site of origin is often undertaken in an attempt to tailor systemic treatment, but the latter often has limited efficacy - especially in the setting of an initial treatment failure. Molecularly targeted therapy is an emerging approach that may offer greater efficacy and less toxicity but is most likely to be effective when pairing a tumor harboring a sensitizing genomic alteration with an agent directed at the altered gene product. We report a patient with a CUP harboring a MET amplification with a complete metabolic response to crizotinib despite also harboring a KRAS mutation.

Methods: Ge-nomic profiling was performed using a clinical next-generation-sequencing-based assay, FoundationOne(®), in a CAP-accredited laboratory certified by Clinical Laboratory Improvement Amendments (Foundation Medicine, Cambridge, Mass., USA).

Results: The CUP harbored both MET amplification (16 copies) and a KRAS G12V mutation. The patient was treated with crizotinib, a MET inhibitor, and has experienced a complete normalization of tumor metabolic activity for more than 19 months.

Conclusions: Genomic profiling of CUP may reveal clinically meaningful genomic alterations that can guide targeted therapy decision-making. The use of this approach should be studied prospectively as a strategy for the effective treatment of CUP patients and for avoiding resource-intensive workups to identify the tumor site of origin.

Keywords: Carcinoma of unknown primary; Crizotinib; KRAS mutation; MET amplification; Next-generation sequencing.

Fig. 1

Adenocarcinoma metastatic to the brain. Resection of a cerebral metastasis sample revealed a high-grade adenocarcinoma lacking tubular lumens but containing mucin and signet ring cells (a; ×20). Immunohistochemical workup demonstrated weak inconclusive thyroid transcription factor-1 staining (b; ×40), positive staining for CK7 (c; ×20) and negative staining for S100, p63 and CK20 (data not shown).

Fig. 2

Metabolic imaging of tumor response. Low-dose CT (top) and ¹⁸F-FDG PET/CT (bottom) fusion of the transaxial left mid-abdominal mesenteric mass. a One month prior to starting treatment with crizotinib (max. SUV = 5.5; mass measures 3.6 cm by 2.8 cm AP). b Three months after starting treatment with crizotinib (max. SUV = 2.0; indicates that the minimal residual mass is metabolically inactive).

Fig. 3

Genomic profiling identified amplification of MET. Genomic profiling by a NGS-based assay was performed on the resected brain specimen (FFPE tissue) to a coverage depth of 1,392X, revealing 6 distinct genomic alterations including MET amplification. MET copy number (16 copies) was determined by modeling copy variation and aneuploidy across the genome and was compared to process-matched normal controls.