Recent studies suggest that circulating tumor cells and cell-free DNA may represent powerful non-invasive tools for monitoring disease in patients with solid and hematologic malignancies. Here, we conducted a pilot study in 27 myeloma patients to explore the clonotypic V(D)J rearrangement for monitoring circulating myeloma cells and cell-free myeloma DNA. Next-generation sequencing was used to define the myeloma V(D)J rearrangement and for subsequent peripheral blood tracking after treatment initiation. Positivity for circulating myeloma cells/cell-free myeloma was associated with conventional remission status (P<0.001) and 91% of non-responders/progressors versus 41% of responders had evidence of persistent circulating myeloma cells/cell-free myeloma DNA (P<0.001). About half of the partial responders showed complete clearance of circulating myeloma cells/cell-free myeloma DNA despite persistent M-protein, suggesting that these markers are less inert than the M-protein, rely more on cell turnover and, therefore, decline more rapidly after initiation of effective treatment. Positivity for circulating myeloma cells and for cell-free myeloma DNA were associated with each other (P=0.042), but discordant in 30% of cases. This indicates that cell-free myeloma DNA may not be generated entirely by circulating myeloma cells and may reflect overall tumor burden. Prospective studies need to define the predictive potential of high-sensitivity determination of circulating myeloma cells and DNA in the monitoring of multiple myeloma.
Head and neck squamous cell carcinomas (HNSCC) exhibiting resistance to the EGFR-targeting drug cetuximab poses a challenge to their effective clinical management. Here, we report a specific mechanism of resistance in this setting based upon the presence of a single nucleotide polymorphism encoding EGFR-K (K-allele), which is expressed in >40% of HNSCC cases. Patients expressing the K-allele showed significantly shorter progression-free survival upon palliative treatment with cetuximab plus chemotherapy or radiation. In several EGFR-mediated cancer models, cetuximab failed to inhibit downstream signaling or to kill cells harboring a high K-allele frequency. Cetuximab affinity for EGFR-K was reduced slightly, but ligand-mediated EGFR activation was intact. We found a lack of glycan sialyation on EGFR-K that associated with reduced protein stability, suggesting a structural basis for reduced cetuximab efficacy. CetuGEX, an antibody with optimized Fc glycosylation targeting the same epitope as cetuximab, restored HNSCC sensitivity in a manner associated with antibody-dependent cellular cytotoxicity rather than EGFR pathway inhibition. Overall, our results highlight EGFR-K expression as a key mechanism of cetuximab resistance to evaluate prospectively as a predictive biomarker in HNSCC patients. Further, they offer a preclinical rationale for the use of ADCC-optimized antibodies to treat tumors harboring this EGFR isoform. .
Resistance to epidermal growth factor receptor (EGFR)-targeted therapy is insufficiently understood in head and neck squamous cell carcinoma (HNSCC), entailing the lack of predictive biomarkers.Here, we studied resistance-mediating EGFR ectodomain and activating RAS mutations by next-generation sequencing (NGS) of cell lines and tumor tissue of cetuximab-naïve patients (46 cases, 12 cell lines), as well as liquid biopsies taken during and after cetuximab/platinum/5-fluorouracil treatment (20 cases). Tumors of cetuximab-naïve patients were unmutated, except for HRAS mutations in 4.3% of patients. Liquid biopsies revealed acquired KRAS, NRAS or HRAS mutations in more than one third of patients after cetuximab exposure. 46% of patients with on-treatment disease progression showed acquired RAS mutations, while no RAS mutations were found in the non-progressive subset of patients, indicating that acquisition of RAS mutant clones correlated significantly with clinical resistance (Chi square p=0.032). The emergence of mutations preceded clinical progression in half of the patients, with a maximum time from mutation detection to clinical progression of 16 weeks.RAS mutations account for acquired resistance to EGFR-targeting in a substantial proportion of HNSCC patients, even though these tumors are rarely mutated at baseline. Liquid biopsies may be used for mutational monitoring to guide treatment decisions.
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