Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets.

UNLABELLED Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors, and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. SIGNIFICANCE Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.

[1]  V. Seshan,et al.  Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases. , 2015, Cancer discovery.

[2]  Obi L. Griffith,et al.  Convergent loss of PTEN leads to clinical resistance to a PI3Kα inhibitor , 2014, Nature.

[3]  M. Horinaka,et al.  The Dual RAF/MEK Inhibitor CH5126766/RO5126766 May Be a Potential Therapy for RAS-Mutated Tumor Cells , 2014, PloS one.

[4]  A. Bass,et al.  Src Mutation Induces Acquired Lapatinib Resistance in ERBB2-Amplified Human Gastroesophageal Adenocarcinoma Models , 2014, PloS one.

[5]  H. Hirsch,et al.  MCL1 and BCL-xL Levels in Solid Tumors Are Predictive of Dinaciclib-Induced Apoptosis , 2014, PloS one.

[6]  Shibing Deng,et al.  Patterns of somatic alterations between matched primary and metastatic colorectal tumors characterized by whole-genome sequencing. , 2014, Genomics.

[7]  K. Aldape,et al.  Molecular Profiling of Patient-Matched Brain and Extracranial Melanoma Metastases Implicates the PI3K Pathway as a Therapeutic Target , 2014, Clinical Cancer Research.

[8]  A. McKenna,et al.  Genetic and Clonal Dissection of Murine Small Cell Lung Carcinoma Progression by Genome Sequencing , 2014, Cell.

[9]  A. McKenna,et al.  Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. , 2014, Cancer cell.

[10]  Dennis C. Friedrich,et al.  Whole-exome sequencing and clinical interpretation of formalin-fixed , paraffin-embedded tumor samples to guide precision cancer medicine , 2014 .

[11]  S. Carter,et al.  Clonal evolution in hematological malignancies and therapeutic implications , 2014, Leukemia.

[12]  Ben S. Wittner,et al.  A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity , 2014, Breast Cancer Research.

[13]  W. Isaacs,et al.  Tracking the clonal origin of lethal prostate cancer. , 2013, The Journal of clinical investigation.

[14]  W. Curry,et al.  Clinical discussion and review of the management of brain metastases. , 2013, Journal of the National Comprehensive Cancer Network : JNCCN.

[15]  A. Belldegrun,et al.  PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. , 2013, Anticancer research.

[16]  Denis Maillet,et al.  Ineffectiveness of crizotinib on brain metastases in two cases of lung adenocarcinoma with EML4-ALK rearrangement. , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[17]  Li Ding,et al.  Activating HER2 mutations in HER2 gene amplification negative breast cancer. , 2013, Cancer discovery.

[18]  Robert T. Jones,et al.  Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations , 2013, Nature Genetics.

[19]  A. McKenna,et al.  Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia , 2012, Cell.

[20]  M. Nishimura,et al.  Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells. , 2012, Lung cancer.

[21]  S. Markovic,et al.  Melanoma brain metastases and vemurafenib: need for further investigation. , 2012, Mayo Clinic proceedings.

[22]  A. Børresen-Dale,et al.  Mutational Processes Molding the Genomes of 21 Breast Cancers , 2012, Cell.

[23]  A. McKenna,et al.  Absolute quantification of somatic DNA alterations in human cancer , 2012, Nature Biotechnology.

[24]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[25]  G. Sauter,et al.  Relevance of PTEN loss in brain metastasis formation in breast cancer patients , 2012, Breast Cancer Research.

[26]  R. Jain,et al.  The biology of brain metastases—translation to new therapies , 2011, Nature Reviews Clinical Oncology.

[27]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[28]  Mingming Jia,et al.  Data mining using the Catalogue of Somatic Mutations in Cancer BioMart , 2011, Database J. Biol. Databases Curation.

[29]  E. Winer,et al.  The role of EGFR amplification in trastuzumab resistance: A correlative analysis of TBCRC003. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  A. Musolino,et al.  Multifactorial central nervous system recurrence susceptibility in patients with HER2‐positive breast cancer , 2011, Cancer.

[31]  J. Troge,et al.  Tumour evolution inferred by single-cell sequencing , 2011, Nature.

[32]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[33]  Andrew Menzies,et al.  The patterns and dynamics of genomic instability in metastatic pancreatic cancer , 2010, Nature.

[34]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[35]  Yoon-Koo Kang,et al.  Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial , 2010, The Lancet.

[36]  Joshua F. McMichael,et al.  Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft , 2010, Nature.

[37]  B. Peters,et al.  Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. , 2009, Cancer cell.

[38]  J. Dering,et al.  PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro , 2009, Breast Cancer Research.

[39]  Ryan D. Morin,et al.  Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution , 2009, Nature.

[40]  W. Gerald,et al.  Genes that mediate breast cancer metastasis to the brain , 2009, Nature.

[41]  M. Meyerson,et al.  PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. , 2009, Cancer research.

[42]  Jun Luo,et al.  Copy Number Analysis Indicates Monoclonal Origin of Lethal Metastatic Prostate Cancer , 2009, Nature Medicine.

[43]  G. Mills,et al.  Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. , 2009, Cancer research.

[44]  Ralph Weissleder,et al.  Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers , 2008, Nature Medicine.

[45]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[46]  Carlos L Arteaga,et al.  Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network , 2007, Clinical Cancer Research.

[47]  N. Pryer,et al.  Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. , 2004, Molecular cancer therapeutics.

[48]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[49]  K. Nixon,et al.  The Parsimony Ratchet, a New Method for Rapid Parsimony Analysis , 1999, Cladistics : the international journal of the Willi Hennig Society.

[50]  Kevin C. Nixon.  Regular ArticleThe Parsimony Ratchet, a New Method for Rapid Parsimony Analysis☆ , 1999 .

[51]  W R Markesbery,et al.  Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. , 1998, JAMA.

[52]  Y Maruyama,et al.  A randomized trial of surgery in the treatment of single metastases to the brain. , 1990, The New England journal of medicine.

[53]  T. P. Stortebecker.  Metastatic tumors of the brain from a neurosurgical point of view; a follow-up study of 158 cases. , 1954, Journal of neurosurgery.