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Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer - PubMed

Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer

Mariangela Russo et al. Cancer Discov. 2016 Feb.

Abstract

How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient.

Significance: Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance.

©2015 American Association for Cancer Research.

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Figures

Figure 1
Figure 1. Initial treatment course and analysis of serial tumor biopsies

The initial clinical course of the CRC patient is summarized, with serum carcinoembryonic antigen (CEA, normal defined as <3.5 ng/mL) tumor marker levels shown throughout treatment. Shaded areas indicate periods of administration of the indicated chemotherapeutic agents: 5-fluorouracil (5FU), oxaliplatin (OX), irinotecan (IRI), cetuximab (CET), radiation therapy (XRT), bevacizumab (BEV), regorafenib (REG). Arrows indicate timing of tumor specimen acquisition from surgical procedures or biopsy. At the bottom of panel A, sequencing data for each specimen are summarized. A p.K57T missense mutation in the MAP2K1 gene (which encodes for MEK1 protein) was detected in a progressing liver lesion following a prolonged response to cetuximab and irinotecan. The MAP2K1 p.K57T mutation was not detected in tumor specimens gathered prior to cetuximab and irinotecan therapy (specimens 1-3). Conversely, a nonsense mutation in TP53 at codon 171 (p.E171*) was detectable in all tumor specimens throughout the clinical course. Variant reads as a fraction of total sequencing reads are shown, with the variant allele percentage shown in parentheses.

Figure 2
Figure 2. MEK1 K57 mutations confer resistance to anti-EGFR therapies

(A-C) Cetuximab-resistant preclinical models were derived in vitro from HCA46, a RAS-wildtype CRC cell line. (A) The sensitivity of parental cells and resistant clones to cetuximab and panitumumab in an in vitro viability assay are shown. (B) Exogenous expression of MEK1 K57T or MEK1 K57N in an independent cetuximab-sensitive RAS-WT CRC cell line (LIM1215) confers resistance to cetuximab, relative to expression of WT MEK1. (C) The combination of 50μg/ml cetuximab (Cetux) and 2nM trametinib (Tramet) or 50μg/ml panitumumab (Panit) and 2nM trametinib can restore sensitivity to MEK1 mutated cetuximab-resistant clones.

Figure 3
Figure 3. Serial analysis of plasma circulating tumor DNA during subsequent therapy with panitumumab and trametinib

(A) Timing of panitumumab and trametinib administration is denoted by the grey bar. Timing of discontinuation of therapy is indicated by the dashed line. Serum CEA levels were monitored throughout treatment. Serial assessments of plasma circulating tumor DNA for the percent abundance of variant alleles for TP53 p.E171* (an early mutational event, present in all of the patient's tumor cells), MAP2K1 (MEK1) p.K57T, and KRAS p.Q61H are shown throughout treatment. While levels of the known MAP2K1 p.K57T mutation decreased during therapy with panitumumab and trametinib, a KRAS p.Q61H mutation was discovered in the plasma, which increased steadily throughout treatment. (B) Axial CT images of the abdomen taken at the start of panitumumab and trametinib therapy (July 2014) and after approximately three months of therapy (November 2014) show a decrease in the size of the segment 8 liver lesion, which harbored the MEK1 K57T mutation. Sequencing data from the biopsy of this lesion obtained after progression on cetuximab and irinotecan and prior to panitumumab and trametinib therapy is summarized on the right. Variant reads as a fraction of total reads are shown, with the variant allele percentage shown in parentheses. (C) Conversely, CT images show that a segment 5 liver lesion increased in size despite therapy with panitumumab and trametinib over the same time period. The segment 5 liver lesion was biopsied after progression on panitumumab and trametinib, and next-generation sequencing detected the same KRAS p.Q61H mutation that was identified in the plasma ctDNA, as well as the TP53 p.E171* mutation present in all tumor specimens from this patient, as summarized on the right. The MAP2K1 p.K57T mutation that was present in the segment 8 liver lesion was not detected in this biopsy of the segment 5 liver lesion, suggesting independent evolution of distinct resistance mechanisms in these two metastatic lesions.

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