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

Russo, Mariangela; Siravegna, Giulia; Blaszkowsky, Lawrence S.; Corti, Giorgio; Crisafulli, Giovanni; Ahronian, Leanne G.; Mussolin, Benedetta; Kwak, Eunice L.; Buscarino, Michela; Lazzari, Luca; Valtorta, Emanuele; Truini, Mauro; Jessop, Nicholas A.; Robinson, Hayley; Hong, Theodore S.; Mino‐Kenudson, Mari; Nicolantonio, Federica Di; Thabet, Ashraf; Sartore-Bianchi, Andrea; Siena, Salvatore; Iafrate, A. John; Bardelli, Alberto; Corcoran, Ryan B.

doi:10.1158/2159-8290.cd-15-1283

Cited by 352 publications

(326 citation statements)

References 23 publications

Supporting

Mentioning

314

Contrasting

Unclassified

Order By: Relevance

“…Response to the multikinase inhibitor sorafenib was also observed in a CRC patient with FLT3 amplification [42]. Furthermore, a recent study reported a response to panitumumab in combination with trametinib in a patient with a MEK1 K57Tmutation [43]. A subset of colorectal tumors with neuroendocrine features and BRAF V600E mutations is also predicted to respond to combined inhibition with BRAF and MEK inhibitors [44].…”

Section: Discussionmentioning

confidence: 99%

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Rankin¹,

Klempner

Erlich³

et al. 2016

The Oncologist

View full text Add to dashboard Cite

Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti‐epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid‐capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non‐codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild‐type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti‐EGFR therapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti‐EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. Implications for Practice: Comprehensive genomic profiling (CGP) detects diverse genomic alterations associated with lack of benefit to anti‐epidermal growth factor receptor therapy in advanced colorectal cancer (CRC), as well as targetable alterations in many other genes. This includes detection of a broad spectrum of activating KRAS alterations frequently missed by focused molecular hotspot testing, as well as other RAS/RAF pathway alterations, mutations shown to disrupt antibody binding, RTK activating point mutations, amplifications, and rearrangements, and activating alterations in downstream effectors including PI3K and MEK1. The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC.

show abstract

Section: Discussionmentioning

confidence: 99%

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Rankin¹,

Klempner

Erlich³

et al. 2016

The Oncologist

View full text Add to dashboard Cite

show abstract

“…Problems inherent to tumor sampling bias due to ITH may be mitigated with ctDNA sampling (Jamal-Hanjani et al, 2016;Russo et al, 2016;Siravegna et al, 2015). Moreover, such methods can track mechanisms of resistance to targeted agents, which may emerge during the course of therapy.…”

Section: Longitudinal Sampling Strategiesmentioning

confidence: 99%

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

McGranahan

Swanton

2017

Cell

2,030

1,694

View full text Add to dashboard Cite

Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

show abstract

“…Further, 24% of those resistance-harboring samples (91/381) had >1 alteration associated with resistance to the same therapy, suggesting independent evolution in distinct tumor lesions (20) or sequential treatment with distinct therapies targeted to the same gene. For example, one NSCLC patient had an EML4-ALK fusion (VAF of 7.1%) and ALK SNVs reported to confer resistance to crizotinib (L1196M, 2.5%), crizotinib/alectinib (I1171T, 0.1%), and crizotinib/ceritinib/alectinib (G1202R, 5% relative to the original driver alteration and many were missed by single-metastatic-site tissue biopsy but confirmed by repeat biopsy or biopsy of multiple metastases at autopsy (21,22,25).…”

Section: The Landscape Of Actionable Resistance Alterations In Cfdnamentioning

confidence: 99%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

290

249

View full text Add to dashboard Cite

Running title: Somatic genomic landscape of circulating tumor DNA Keywords: circulating tumor DNA, tumor heterogeneity, resistance, genomic landscape, cfDNA clonality Financial support: The study was funded by and conducted at Guardant Health, Inc. No additional grant support or administrative support was provided for the study. *Corresponding author:Stephen R. Fairclough Translational relevanceThis study describes genomic alterations from the largest cell-free circulating tumor DNA cohort to date, as derived from regular clinical practice. The high prevalence of resistance alterations found in advanced, treated cancer patients necessitated accurate methods for determining mutation clonality and driver/resistance status from plasma. We provide such methods, thereby extending the utility of cell-free DNA sequencing analysis. Our finding of an association between estimated circulating tumor DNA (ctDNA) levels and tumor mutational burden ascertained from plasma suggests that ctDNA level is likely an important variable to consider for immunotherapy applications of ctDNA analysis. Although cell-free DNA can provide a summary of tumor heterogeneity across multiple metastatic sites in a patient, our findings of high variability in ctDNA levels across patients, and its impact on variant detection, highlight the need for an improved understanding of factors influencing ctDNA levels and safe methods for maximizing them at the time of ctDNA testing. AbstractPurpose: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC;, with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR=5x10 -7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel ...

show abstract

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

Cited by 352 publications

References 23 publications

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Contact Info

Product

Resources

About