Dynamic molecular analysis and clinical correlates of tumor evolution within a phase II trial of panitumumab-based therapy in metastatic colorectal cancer

S Siena, A Sartore-Bianchi, R Garcia-Carbonero, M Karthaus, D Smith, J Tabernero, E Van Cutsem, X Guan, M Boedigheimer, A Ang, B Twomey, B A Bach, A S Jung, A Bardelli, S Siena, A Sartore-Bianchi, R Garcia-Carbonero, M Karthaus, D Smith, J Tabernero, E Van Cutsem, X Guan, M Boedigheimer, A Ang, B Twomey, B A Bach, A S Jung, A Bardelli

Abstract

Background: Mutations in rat sarcoma (RAS) genes may be a mechanism of secondary resistance in epidermal growth factor receptor inhibitor-treated patients. Tumor-tissue biopsy testing has been the standard for evaluating mutational status; however, plasma testing of cell-free DNA has been shown to be a more sensitive method for detecting clonal evolution.

Materials and methods: Archival pre- and post-treatment tumor biopsy samples from a phase II study of panitumumab in combination with irinotecan in patients with metastatic colorectal cancer (mCRC) that also collected plasma samples before, during, and after treatment were analyzed for emergence of mutations during/post-treatment by next-generation sequencing and BEAMing.

Results: The rate of emergence of tumor tissue RAS mutations was 9.5% by next-generation sequencing (n = 21) and 6.3% by BEAMing (n = 16). Plasma testing of cell-free DNA by BEAMing revealed a mutant RAS emergence rate of 36.7% (n = 39). Exploratory outcomes analysis of plasma samples indicated that patients who had emergent RAS mutations at progression had similar median progression-free survival to those patients who remained wild-type at progression. Serial analysis of plasma samples showed that the first detected emergence of RAS mutations preceded progression by a median of 3.6 months (range, -0.3 to 7.5 months) and that there did not appear to be a mutant RAS allele frequency threshold that could predict near-term outcomes.

Conclusions: This first prospective analysis in mCRC showed that serial plasma biopsies are more inclusive than tissue biopsies for evaluating global tumor heterogeneity; however, the clinical utility of plasma testing in mCRC remains to be further explored.

Clinicaltrials.gov identifier: NCT00891930.

Keywords: biomarkers and intervention studies; colorectal; gastrointestinal cancers; panitumumab; phase I–III trials.

© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
(A) Study schema and (B) patient tumor RAS status results determined by tissue and plasma testing biomarker analyses. The RAS status of pre-and post-treatment patient tumor samples were analyzed by each testing method. Total patient samples and the number of patients whose RAS status did (e.g. WT→MT, MT→WT) or did not (WT→WT, MT→MT) change pre- to post-treatment are indicated. The numbers in the central intersection of the Venn diagram represent those cases for whom comparisons of analyses by the three indicated methods and source of samples were available. Samples were categorized as discordant if the results varied between testing methods. BEAM, beads, emulsion, amplification, magnetics; CT, computed tomography; IGF-1 R, insulin-like growth factor receptor 1; MRI, magnetic resonance imaging; MT, mutant; ND, no data; NGS, next-generation sequencing; Q2W, every 2 weeks; Q4W, every 4 weeks; WT, wild-type. aBlood collection for plasma analysis at week 37 and every 4 weeks thereafter until disease progression intolerability. bBased on first restaging CT or MRI. cNine patients were either not doing or unevaluable for tumor response assessment. dOnly patients who had an objective response or stable disease after part 1 underwent a second biopsy. eA monoclonal antibody that inhibits the insulin-like growth factor 1 (IGF-1 R) pathway. fPatients without both before-treatment and after-treatment samples for both tests were not characterized as discordant. gPatient was characterized as RAS wild-type at baseline by NGS.
Figure 2.
Figure 2.
Plasma testing schema and results. PD, progressive disease; RAS, rat sarcoma; t, time. aAll patents included were supposed to have a best response of at least stable disease; however, two patients who were mutant to mutant (progressive disease, n = 1; unevaluable, n = 1) and one patient who was wild-type to wild-type (progressive disease) were analyzed.
Figure 3.
Figure 3.
(A) Maximum percentage reduction of the SLD of target lesions in the 30 patients with plasma wild-type RAS mCRC at baseline and evaluable RAS status post-baseline. (B) Time to progression in the 30 patients with wild-type RAS mCRC at baseline and evaluable RAS status post-baseline. (C) Select patient temporal analyses of reductions in SLD during the emergence of RAS mutations as evaluated by plasma BEAMing during treatment with panitumumab + irinotecan. Data from all patients with RAS mutations are shown in supplementary Figure S1, available at Annals of Oncology online. mCRC, metastatic colorectal cancer; PD, progressive disease; RAS, rat sarcoma; SLD, sum of longest diameters.
Figure 3.
Figure 3.
(A) Maximum percentage reduction of the SLD of target lesions in the 30 patients with plasma wild-type RAS mCRC at baseline and evaluable RAS status post-baseline. (B) Time to progression in the 30 patients with wild-type RAS mCRC at baseline and evaluable RAS status post-baseline. (C) Select patient temporal analyses of reductions in SLD during the emergence of RAS mutations as evaluated by plasma BEAMing during treatment with panitumumab + irinotecan. Data from all patients with RAS mutations are shown in supplementary Figure S1, available at Annals of Oncology online. mCRC, metastatic colorectal cancer; PD, progressive disease; RAS, rat sarcoma; SLD, sum of longest diameters.

References

    1. Douillard JY, Oliner KS, Siena S. et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369: 1023–1034.
    1. Misale S, Di Nicolantonio F, Sartore-Bianchi A. et al. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov 2014; 4: 1269–1280.
    1. Diaz LA Jr, Williams RT, Wu J. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012; 486: 537–540.
    1. Misale S, Yaeger R, Hobor S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 2012; 486: 532–536.
    1. Siravegna G, Mussolin B, Buscarino M. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat Med 2015; 21: 795–801.
    1. Sartore-Bianchi A, Di Nicolantonio F, Nichelatti M. et al. Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer. PLoS One 2009; 4: e7287..
    1. Bai H, Wang Z, Chen K. et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012; 30: 3077–3083.
    1. Murtaza M, Dawson SJ, Tsui DW. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013; 497: 108–112.
    1. Diaz LA Jr, Bardelli A.. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 2014; 32: 579–586.
    1. Siena S, Sartore-Bianchi A, Karthaus M. et al. A phase 2 study of mechanisms of acquired resistance to panitumumab (pmab) plus irinotecan (iri) for metastatic colorectal cancer (mCRC). Eur J Cancer 2015; 51: S394–S395.
    1. Peeters M, Kafatos G, Taylor A. et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: a pooled analysis of randomised controlled trials. Eur J Cancer 2015; 51: 1704–1713.
    1. Li M, Chen WD, Papadopoulos N. et al. Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol 2009; 27: 858–863.
    1. Kim TW, Price T, Peeters M. et al. Evaluation of emergent circulating tumor (ct) DNA RAS mutations in patients with metastatic colorectal cancer (mCRC) treated with panitumumab (pmab) monotherapy from the ASPECCT study [abstract]. Eur J Cancer 2016; 59: 21.
    1. Arena S, Bellosillo B, Siravegna G. et al. Emergence of multiple EGFR extracellular mutations during cetuximab treatment in colorectal cancer. Clin Cancer Res 2015; 21: 2157–2166.
    1. Misale S, Arena S, Lamba S. et al. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci Transl Med 2014; 6: 224ra226.
    1. Stachler MD, Rinehart E, Lindeman N. et al. Novel molecular insights from routine genotyping of colorectal carcinomas. Hum Pathol 2015; 46: 507–513.
    1. Zhang BM, Aleshin A, Lin CY. et al. IDH2 Mutation in a Patient with Metastatic Colon Cancer. N Engl J Med 2017; 376: 1991–1992.
    1. Morelli MP, Overman MJ, Dasari A. et al. Characterizing the patterns of clonal selection in circulating tumor DNA from patients with colorectal cancer refractory to anti-EGFR treatment. Ann Oncol 2015; 26: 731–736.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅