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. 2019:3:PO.18.00283.
doi: 10.1200/PO.18.00283. Epub 2019 May 10.

Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors

Jon H Chung #  1 , Ninad Dewal #  1 , Ethan Sokol  1 , Paul Mathew  2 , Robert Whitehead  3 , Sherri Z Millis  1 , Garrett M Frampton  1 , Gennady Bratslavsky  4 , Sumanta K Pal  5 , Richard J Lee  6 , Andrea Necchi  7 , Jeffrey P Gregg  8 , Primo Lara Jr  8 , Emmanuel S Antonarakis  9 , Vincent A Miller  1 , Jeffrey S Ross  1   4 , Siraj M Ali  1 , Neeraj Agarwal  10
Affiliations

Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors

Jon H Chung et al. JCO Precis Oncol. 2019.

Abstract

Purpose: Comprehensive genomic profiling (CGP) is increasingly used for routine clinical management of prostate cancer. To inform targeted treatment strategies, 3,476 clinically advanced prostate tumors were analyzed by CGP for genomic alterations (GAs) and signatures of genomic instability.

Methods: Prostate cancer samples (1,660 primary site and 1,816 metastatic site tumors from unmatched patients) were prospectively analyzed by CGP (FoundationOne Assay; Foundation Medicine, Cambridge, MA) for GAs and genomic signatures (genome-wide loss of heterozygosity [gLOH], microsatellite instability [MSI] status, tumor mutational burden [TMB]).

Results: Frequently altered genes were TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). Potentially targetable GAs were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%) GAs. BRCA1/2, ATR, and FANCA GAs were associated with high gLOH, whereas CDK12-altered tumors were infrequently gLOH high. Median TMB was low (2.6 mutations/Mb). A subset of cases (3%) had high TMB, of which 71% also had high MSI. Metastatic site tumors were enriched for the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1 compared with primary tumors.

Conclusion: Routine clinical CGP in the real-world setting identified GAs that are investigational biomarkers for targeted therapies in 57% of cases. gLOH and MSI/TMB signatures could further inform selection of poly (ADP-ribose) polymerase inhibitors and immunotherapies, respectively. Correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency. GAs enriched in metastatic site tumors suggest therapeutic strategies for metastatic prostate cancer. Lack of clinical outcome correlation was a limitation of this study.

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Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/authorcenter. Jon H. Chung Employment: Foundation Medicine Ninad Dewal Employment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Ethan Sokol Employment: Foundation Medicine Paul Mathew Honoraria: Exelixis Patents, Royalties, Other Intellectual Property: Patent pending on new therapeutic invention Travel, Accommodations, Expenses: Exelixis Robert Whitehead Employment: UnitedHealthcare, Cancer Treatment Centers of America Sherri Z. Millis Employment: Foundation Medicine Garrett M. Frampton Employment: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Sumanta K. Pal Honoraria: Novartis, Medivation, Astellas Pharma Consulting or Advisory Role: Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai Research Funding: Medivation Richard J. Lee Consulting or Advisory Role: Janssen Pharmaceuticals, Exelixis Research Funding: Janssen Pharmaceuticals Andrea Necchi Employment: Bayer AG (I) Stock and Other Ownership Interests: Bayer AG (I) Honoraria: Roche, Merck, AstraZeneca, Janssen Pharmaceuticals, Foundation Medicine Consulting or Advisory Role: Merck Sharp & Dohme, Roche, Bayer AG, AstraZeneca, Clovis Oncology, Janssen Pharmaceuticals, Incyte, Seattle Genetics, Astellas Pharma, Bristol-Myers Squibb, Rainier Therapeutics Research Funding: Merck Sharp & Dohme (Inst), AstraZeneca (Inst) Travel, Accommodations, Expenses: Roche, Merck Sharp & Dohme, AstraZeneca, Janssen Pharmaceuticals Other Relationship: Bayer AG (I) Jeffrey P. Gregg Consulting or Advisory Role: AstraZeneca, Bristol-Myers Squibb, Roche, Foundation Medicine Speakers’ Bureau: AstraZeneca, Foundation Medicine, Bristol-Myers Squibb Primo Lara Jr Honoraria: Pfizer Consulting or Advisory Role: Exelixis, Pfizer, AstraZeneca, Bayer AG, Genentech, Roche, Janssen Pharmaceuticals, Bristol-Myers Squibb, AbbVie, Turnstone Bio, Foundation Medicine, Merck, CellMax Life, Nektar Research Funding: Millennium Pharmaceuticals (Inst), Polaris (Inst), GlaxoSmithKline (Inst), Genentech (Inst), Aragon Pharmaceuticals (Inst), Janssen Pharmaceuticals (Inst), Heat Biologics (Inst), TRACON Pharma (Inst), Merck (Inst), Pharmacyclics (Inst), Incyte (Inst) Emmanuel S. Antonarakis Honoraria: Sanofi, Dendreon, Medivation, Janssen Pharmaceuticals, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Consulting or Advisory Role: Sanofi, Dendreon, Medivation, Janssen Pharmaceuticals, ESSA, Astellas Pharma, Merck, AstraZeneca, Clovis Oncology Research Funding: Janssen Pharmaceuticals (Inst), Johnson & Johnson (Inst), Sanofi (Inst), Dendreon (Inst), Aragon Pharmaceuticals (Inst), Exelixis (Inst), Millennium Pharmaceuticals (Inst), Genentech (Inst), Novartis (Inst), Astellas Pharma (Inst), Tokai Pharmaceuticals (Inst), Merck (Inst), AstraZeneca (Inst), Clovis Oncology (Inst), Constellation Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Co-inventor of a biomarker technology that has been licensed to QIAGEN Travel, Accommodations, Expenses: Sanofi, Dendreon, Medivation Vincent A. Miller Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Consulting or Advisory Role: Revolution Medicines Patents, Royalties, Other Intellectual Property: Receive periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center Jeffrey S. Ross Employment: Foundation Medicine Leadership: Foundation Medicine Stock and Other Ownership Interests: Foundation Medicine Research Funding: Foundation Medicine Siraj M. Ali Employment: Foundation Medicine Leadership: Incysus Stock and Other Ownership Interests: Exelixis, Blueprint Medicines, Agios, Genocea Biosciences Consulting or Advisory Role: Revolution Medicines, Azitra (I), Princepx Tx (I) Patents, Royalties, Other Intellectual Property: Patents through Foundation Medicine, patents through Seres Health on microbiome studies in nonneoplastic disease (I) Neeraj Agarwal Consulting or Advisory Role: Pfizer, Exelixis, Medivation, Astellas Pharma, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, Nektar, Eli Lilly, Bayer AG, Foundation Medicine, Argos Therapeutics

Figures

FIG 1.
FIG 1.
Genomic characterization of primary and metastatic site prostate tumors. (A) The frequency of genomic alterations (GAs) identified in tumors from 3,476 patients with prostate cancer. Genes altered in 2% or more of cases are shown. (B) Frequency of major pathway alterations, including ETS fusions, BRAF rearrangements/mutations, SPOP/CUL3 mutations, CDK12 GAs, IDH1/2 mutations, AR GAs, phosphatidylinositol 3-kinase (PI3K) pathway GAs, homologous recombination GAs, G1/S-cell cycle GAs, WNT pathway GAs, Fanconi anemia/interstrand crosslink repair (FA/ICL) repair pathway GAs, RAS/RAF/MEK pathway GAs (other than BRAF), mismatch repair GAs, and POLE mutations (see Figs 1C to 1F for details). Each column represents a single patient sample, and samples that harbored an alteration in each pathway are indicated in black. (C to F) GAs identified in each pathway, including the (C) PI3K/AKT/mammalian target of rapamycin (mTOR) pathway, (D) G1/S-cell cycle pathway, (E) WNT pathway, and (F) RAS/RAF/MEK pathway (NF1 mutation, rearrangement, or copy number loss; BRAF or RAF1 mutations or rearrangements; ARAF, K/N/H-RAS, or MAP2K1/2 mutations were included); percent of altered cases is indicated. (G) Comparison of alteration frequencies for each gene in primary site samples versus metastatic site samples. The dotted line represents a 1:1 relationship. Genes that were enriched (difference between primary site v metastatic site frequency) by at least 2% are indicated (all P < .05 by Fisher’s exact test [two-tailed]), with genes enriched at least twofold indicated in red (all P < .001 by Fisher’s exact test [two-tailed]). Details are listed in Appendix Table A3. indel, insertion/deletion.
FIG 2.
FIG 2.
DNA repair genomic alterations (GAs) and association with genomic signatures. GAs identified in the (A) homologous recombination repair (HRR) pathway, Fanconi anemia/interstrand crosslink repair (FA/ICL) repair pathway, and CDK12 or (B) mismatch repair (MMR; MSH2, MSH6, MLH1, PMS2) or polymerase (POLE) V411L genes. (C) Mutations in DNA repair genes were assessed for germline or somatic status. For each gene, the number of cases with a germline mutation or somatic-only mutation is shown. (D) Genome-wide loss of heterozygosity (gLOH) score was evaluated for the overall data set (blue) and for association with each DNA repair gene altered at 0.5% or greater frequency. The frequency of cases with a gLOH-high score for each subset is shown. The term “all GAs” represents the association with any reportable GA (short variant mutation, homozygous deletion or rearrangement) in the specified gene. Homozygous deletions (homdel) were individually assessed for BRCA1/2, ATM, and FANCA. Germline (g) and somatic (s) mutations were individually assessed for BRCA1/2 and ATM. Each subset was individually compared with the overall data set, and unadjusted P values are shown (Fisher’s exact test [two-tailed]). (E) Tumor mutational burden (TMB) was evaluated for the overall data set and compared with various genomic subsets, including those harboring an HRR pathway GA, an FA/ICL pathway GA, a CDK12 GA, an MMR GA, a microsatellite instability-high (MSI-H) genomic signature, or a POLE V411L mutation. Box and whisker plots: Boxes span first and third quartiles, the median is denoted by the horizontal line in the box, and whiskers indicate maximum and minimum values within 1.5× the interquartile range.
FIG 3.
FIG 3.
TMPRSS2-ERG and other ETS fusions. (A) Distribution of 1,236 ETS fusions in this study. (B) The 5′ partner genes are identified. (C) Distribution of breakpoints identified in the ERG gene. Numbered boxes represent exons. Triangles represent observed breakpoints. (*) Fusion partners that have been previously described. bp, base pair; kbp, kilobase pair.
FIG 4.
FIG 4.
Landscape of AR alterations. (A) AR genomic alterations (GAs) were identified in 721 cases, including amplification (red), mutation (green), and rearrangements (purple). (B) Graph that represents the number of cases with each AR GA. The percentages indicate the frequency of AR mutations at each codon as a fraction of all AR mutations. Letters denote amino acid abbreviations as recommended by the International Union of Pure and Applied Chemistry. (C) Map of AR rearrangements that describe breakpoints for translocations and deleted, duplicated, or inverted regions.
FIG A1.
FIG A1.
(A) Distribution of sites of sample collection (prostate, 47.8%; distant lymph node [LN (D)], 12.4%; regional LN [LN (R)], 3.7%; unspecified LN [LN (unk)], 0.3%; liver, 13.2%; bone, 10.0%; lung, 2.7%; other metastatic, 9.9%). (B) Distribution of prostate histologic types.
FIG A2.
FIG A2.
Details of the BRAF rearrangements, RAF1 rearrangements, and BRAF short variant mutations. The diagram illustrates BRAF (top) and RAF1 (bottom) rearrangements, including fusions, N-terminal deletions, and kinase domain duplications. Exons are numbered. For fusion, exons (e) are annotated with the last exon included in the 5′ partner and the first exon included in the 3′ partner. In addition, BRAF rearrangements at intron 9 (n = 6) and intron 7 (n = 1) and RAF1 rearrangement at intron 7 with no clear fusion partner were identified (data not shown). The table lists the 43 BRAF mutations identified.
FIG A3.
FIG A3.
(A) For metastasis-enriched tumor suppressor genes (see Fig 1G), short variant mutations were assessed for loss of heterozygosity. Frequency of short variant mutations under loss of heterozygosity (biallelic) is shown. (B) Frequency of genomic alterations for individual genes in G1/S-cell cycle pathway in primary versus metastatic site samples. Fold change is indicated.
FIG A4.
FIG A4.
(A) Genome-wide loss of heterozygosity (gLOH) score was assessable for 2,624 cases, and cases with 14% or more gLOH were designated LOH-high (LOH-H). All other cases were LOH-low (LOH-L). LOH-H cases were assessed for the presence (green) or absence (yellow) of a genomic alteration (GA) in the homologous recombination repair (HRR) or Fanconi anemia/interstrand crosslink repair (FA/ICL) pathway. (B) Genes were grouped together into HRR pathway (excluding non-BRCA1/2) or FA/ICL pathway (FANC); genes were categorized as in Figure 2A. All GAs or only homozygous deletions (homdel) were assessed for LOH-H and compared with the overall data set (green). Each subset was individually compared with the overall data set, and unadjusted P values are shown (Fisher’s exact test [two-tailed]).
FIG A5.
FIG A5.
(A) Microsatellite instability (MSI) status was assessable for 3,326 cases, and each case was designated as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS). MSI-H cases were assessed for the presence or absence of mismatch repair (MMR) genomic alterations (GAs). MSI-H or MMR GA–positive samples are indicated with a plus sign, and negative samples are indicated with a minus sign. Of the cases where both MSI status and MMR GA zygosity status could be determined, 82 cases had MMR GA that resulted in loss of function of both alleles (microsatellite status in this subset listed in table). (B) Tumor mutational burden (TMB) was evaluated for primary site and metastatic site cases. Box and whisker plots: Boxes span first and third quartiles, the median is denoted by the horizontal line in the box, and whiskers indicate maximum and minimum values with 1.5× the interquartile range. The percent TMB-high (TMB-H) or TMB of 10 or more mutations (mut)/Mb cases in primary site and metastatic site tumors is indicated. (C) TMB-H samples were assessed for whether they were MSI-H or MSS/MSI-L. TMB-H cases that were not MSI-H also were assessed for POLE V411L pathogenic mutations.
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