Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer

Abstract

Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed. Meta-analysis of DNA and RNA sequencing studies of ATC was performed.Results: Sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways, respectively. Meta-analysis demonstrated 10.3% cooccurrence of MAPK and PI3K pathway alterations in ATC. These tumors display a separate transcriptional profile from other ATCs, consistent with a novel subgroup of ATC.Conclusions: BRAF and PIK3CA mutations define a distinct subset of ATC. Blockade of the MAPK and PI3K pathways appears necessary for tumor response in this subset of ATC. This identification of synergistic activity between targeted agents may inform clinical trial design in ATC. Clin Cancer Res; 23(9); 2367-73. ©2016 AACR.

Figure 1

Clinical history of an exceptional responder to combined MAPK and PI3K inhibition. A, Graphical description of clinical events. B, Radiographic documentation of response. The patient’s tumor continued to grow through everolimus and dabrafenib monotherapies individually. When combined, the patient’s tumor showed a dramatic response.

Figure 2

Genomic features of an exceptional responder to combined MAPK and PI3K inhibition. A, Biopsy locations from the tumor following near-total thyroidectomy (left), at recurrence (middle) and at autopsy (right). B, Phylogenetic architecture of the tumor. Putative cancer driver mutations are annotated. Red font indicated copy number gain of the indicated chromosome, blue font indicates copy number loss. Branch lengths are not proportional to number of mutations. C, Mutations detected in each biopsy.

Figure 3

Prevalence of BRAF/PIK3CA co-mutation. A, (top) Co-mutation of BRAF and PIK3CA in sequencing studies of anaplastic thyroid cancers. Each column of blocks represents an individual patient’s tumor. The source of the sequencing data, the presence of BRAF and PIK3CA mutations are represented from top to bottom. (bottom) Unsupervised clustering of expression data from ATC samples in MSKCC cohort. BRAF/PIK3CA co-mutated samples are indicated in red and cluster together (p = 0.006). B, Prevalence of BRAF^V600E co-mutation with non-synonymous PIK3CA mutations across tumor types. Only tumor types with non-zero co-mutation rates are depicted (17 other tumor types had no cases of co-mutation). C, Overlap of BRAF^V600E and PIK3CA mutations in head and neck cancers for which sequencing data is available. Circle area is proportional to the fraction of patients harboring mutations in the indicated gene.