Publications by authors named "Jon Chung"

45 Publications

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms.

Clin Cancer Res 2021 Feb 8. Epub 2021 Feb 8.

Clinical Development, Foundation Medicine

Purpose: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations that inform clinical care.

Experimental Design: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of genomic alterations detected in ctDNA and assessed concordance with tissue based CGP.

Results: 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; were mutated in 295 (8.8%). In concordance analysis, 72/837 patients had mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (for example in and ). Potential resistance alterations were detected in 940/2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.

Conclusions: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of mutations but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4805DOI Listing
February 2021

Targetable gene fusions and aberrations in genitourinary oncology.

Nat Rev Urol 2020 Nov 12;17(11):613-625. Epub 2020 Oct 12.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Gene fusions result from either structural chromosomal rearrangement or aberrations caused by splicing or transcriptional readthrough. The precise and distinctive presence of fusion genes in neoplastic tissues and their involvement in multiple pathways central to cancer development, growth and survival make them promising targets for personalized therapy. In genitourinary malignancies, rearrangements involving the E26 transformation-specific family of transcription factors have emerged as very frequent alterations in prostate cancer, especially the TMPRSS2-ERG fusion. In renal malignancies, Xp11 and t(6;11) translocations are hallmarks of a distinct pathological group of tumours described as microphthalmia-associated transcription factor family translocation-associated renal cell carcinomas. Novel druggable fusion events have been recognized in genitourinary malignancies, leading to the activation of several clinical trials. For instance, ALK-rearranged renal cell carcinomas have shown responses to alectinib and crizotinib. Erdafitinib has been tested for the treatment of FGFR-rearranged bladder cancer. Other anti-fibroblast growth factor receptor 3 (FGFR3) compounds are showing promising results in the treatment of bladder cancer, including infigratinib and pemigatinib, and all are currently in clinical trials.
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http://dx.doi.org/10.1038/s41585-020-00379-4DOI Listing
November 2020

Pan-Cancer Analysis of and Genomic Alterations and Their Association With Genomic Instability as Measured by Genome-Wide Loss of Heterozygosity.

JCO Precis Oncol 2020 30;4:442-465. Epub 2020 Apr 30.

Foundation Medicine, Cambridge, MA.

Purpose: BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline alterations (-associated cancers: breast, ovarian, pancreatic, prostate), alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non--associated) cancer types, the association between alteration and HRD is less clear.

Methods: A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD.

Results: alterations were observed at a 4.7% frequency. mutations were predicted germline in 57.4% of -associated and 37.2% of non--associated cancers. The fraction of -altered cases that were biallelic was 68.7%, with a higher biallelic fraction in -associated (89.9%) versus non--associated cancers (43.6%). Differences in tissue distribution of biallelic versus alterations were noted, including a higher rate of biallelic alteration in prostate cancer. Biallelic alteration was observed at a 3.2% frequency (-associated cancers, 8.9%; non--associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic alteration was associated with increased gLOH versus monoallelic or wild-type ; predicted germline or somatic mutations were both associated with elevated gLOH.

Conclusion: Biallelic alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic status, and biallelic alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.
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http://dx.doi.org/10.1200/po.19.00345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446440PMC
April 2020

Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma.

Eur Urol Focus 2020 Aug 26. Epub 2020 Aug 26.

Foundation Medicine, Inc., Cambridge, MA, USA.

Background: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms.

Objective: To describe the genomic landscape of UC based on the anatomic site of the primary tumor.

Design, Setting, And Participants: In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT).

Intervention: Hybrid-capture-based CGP.

Outcome Measurements And Statistical Analysis: Descriptive analyses and differences between anatomic subgroups were reported.

Results And Limitations: In total, 39% of patients with UC harbored one or more tier 1-2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p=0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p<0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p=0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p<0.001).

Conclusions: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.

Patient Summary: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.
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http://dx.doi.org/10.1016/j.euf.2020.08.001DOI Listing
August 2020

Retrospective analysis of real-world data to determine clinical outcomes of patients with advanced non-small cell lung cancer following cell-free circulating tumor DNA genomic profiling.

Lung Cancer 2020 10 6;148:69-78. Epub 2020 Aug 6.

Foundation Medicine, Cambridge, MA, USA.

Objectives: Liquid biopsy and comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) are increasingly used for detection of targetable genomic alterations (GA) in non-small cell lung cancer (NSCLC). To examine the clinical outcomes for patients following CGP using liquid biopsy versus tissue biopsy, receipt of matched targeted therapy post-CGP and associated outcomes were evaluated in the real-world setting.

Methods: 6491 patients with NSCLC and liquid biopsy (N = 937 tests) and/or tissue (N = 5582 tests) CGP were included in a de-identified commercial clinico-genomic database. Targetable GAs included National Comprehensive Cancer Network NSCLC guideline biomarkers. Clinical characteristics, real-world progression, and real-world response (rwR) were obtained via technology-enabled abstraction of clinician notes and radiology/pathology reports.

Results: At the time of liquid biopsy CGP, 53% (496/937) of patients were documented to have received ≥1 line of prior therapy (tissue CGP: 13%, 735/5582). 90% (832/928) of liquid biopsy cases had evidence of ctDNA. A targetable GA was detected in 20% (188/937) of liquid biopsy and 22% (1215/5582) of tissue CGP cases. Use of matched targeted therapy overall was similar post-liquid biopsy or post-tissue CGP but varied considerably across emerging (25%, 79/317) versus standard of care (SOC) (74%, 475/640) GA. Real-world-progression free survival for patients receiving SOC first line matched targeted therapy administered following liquid biopsy (n = 33) and tissue (n = 229) CGP were similar (13.8 vs 10.6 months; aHR = 0.68 [0.36-1.26]). Among patients evaluated for rwR, overall response rate (partial/complete response) to matched targeted therapy post-liquid biopsy CGP was 75% (39/52) versus 66% post-tissue CGP (254/385, P = 0.51).

Conclusion: Retrospective analysis of real-world clinico-genomic data demonstrated that clinical outcomes on matched targeted therapy were similar following liquid biopsy and tissue CGP in NSCLC, which suggests routine clinical use of liquid biopsy CGP can reliably guide therapy selection.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.033DOI Listing
October 2020

Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER Metastatic Breast Cancer.

Clin Cancer Res 2020 Nov 28;26(22):5974-5989. Epub 2020 Jul 28.

Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER breast cancer.

Experimental Design: We conducted a genome-scale functional screen spanning 10,135 genes to investigate genes whose overexpression confer resistance to selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing in paired pretreatment and postresistance biopsies from 60 patients with ER metastatic breast cancer who had developed resistance to ER-targeted therapy. Furthermore, we performed experiments to validate resistance genes/pathways and to identify drug combinations to overcome resistance.

Results: Pathway analysis of candidate resistance genes demonstrated that the FGFR, ERBB, insulin receptor, and MAPK pathways represented key modalities of resistance. The FGFR pathway was altered via , or amplifications or mutations in 24 (40%) of the postresistance biopsies. In 12 of the 24 postresistance tumors exhibiting FGFR/FGF alterations, these alterations were acquired or enriched under the selective pressure of ER-directed therapy. experiments in ER breast cancer cells confirmed that FGFR/FGF alterations led to fulvestrant resistance as well as cross-resistance to the CDK4/6 inhibitor palbociclib. RNA sequencing of resistant cell lines demonstrated that FGFR/FGF induced resistance through ER reprogramming and activation of the MAPK pathway. The resistance phenotypes were reversed by FGFR inhibitors, a MEK inhibitor, and/or a SHP2 inhibitor.

Conclusions: Our results suggest that FGFR pathway is a distinct mechanism of acquired resistance to ER-directed therapy that can be overcome by FGFR and/or MAPK pathway inhibitors.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3958DOI Listing
November 2020

Predicting the Pathologic Complete Response After Neoadjuvant Pembrolizumab in Muscle-Invasive Bladder Cancer.

J Natl Cancer Inst 2021 Jan;113(1):48-53

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: In the PURE-01 study (NCT02736266), we aimed to evaluate the ability to predict the pathologic complete response (pT0N0) after pembrolizumab by using clinical and tumor biomarkers.

Methods: In an open-label, single-arm, phase 2 study, 3 courses of 200 mg pembrolizumab preceding radical cystectomy were administered in patients with T2-4aN0M0 muscle-invasive bladder cancer. The analyses included a comprehensive genomic profiling and programmed cell-death-ligand-1 (PD-L1)-combined positive score assessment (CPS; Dako 22C3 antibody) of pre- and posttherapy samples. Multivariable logistic regression analyses evaluated baseline clinical T stage and tumor biomarkers in association with pT0N0 response. Corresponding coefficients were used to develop a calculator of pT0N0 response based on the tumor mutational burden (TMB), CPS, and the clinical T stage. Decision-curve analysis was also performed. All statistical tests were 2-sided.

Results: From February 2017 to June 2019, 112 patients with biomarker data were enrolled (105 with complete TMB and CPS data). Increasing TMB and CPS values featured a linear association with logistic pT0N0 probabilities (P = .02 and P = .004, respectively). For low TMB values (≤11 mut/Mb, median value, n = 53), pT0N0 probability was not associated with increasing CPS. Conversely, for high TMB values (>11 mut/Mb, n = 52), pT0N0 was statistically significantly associated with higher CPS (P = .004). The C index of the pT0N0 probability calculator was 0.77. On decision-curve analysis, the net benefit of the model was higher than the "treat-all" option within the clinically meaningful threshold probabilities of 40%-50%.

Conclusions: The study presents a composite biomarker-based pT0N0 probability calculator that reveals the complex interplay between TMB and CPS, added to the clinical T stage.
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http://dx.doi.org/10.1093/jnci/djaa076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781448PMC
January 2021

Unfavorable Cancer-specific Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients With Bladder Cancer and Squamous Cell Variant: A Multi-institutional Study.

Clin Genitourin Cancer 2020 10 8;18(5):e543-e556. Epub 2020 Feb 8.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs).

Patients And Methods: We relied on a retrospective, multicenter database of 2858 patients with BCa who had undergone radical cystectomy with or without NAC from 1990 to 2017. Pure and mixed HVs were grouped into 6 categories: squamous cell carcinoma (SCC; n = 283; 45%), other subtypes (n = 95; 15%), micropapillary (n = 85; 14%), adenocarcinoma (n = 65; 10%), small cell (n = 54; 8.6%), and sarcomatous (n = 47; 7.6%). Kaplan-Meier and Cox regression analyses were used to examine cancer-specific survival (CSS) according to the HV, using pure UC as the reference. Logistic regression models were used to examine the odds of clinical-to-pathologic downstaging after NAC according to the HV.

Results: Overall, we identified 2229 cases of pure UC and 629 cases of BCa with HVs at radical cystectomy. Of the 450 NAC-treated patients, only those patients with SCC (n = 44; 9.8%) had had worse CSS (median CSS, 33 vs. 116 months; P < .001) and higher mortality rates (hazard ratio, 2.1; P = .03) compared with those with pure UC (n = 328; 72.9%). The results of the analyses were also confirmed when the pure and mixed cases were considered separately. After adjusting for NAC, only SCC showed a lower rate of clinical-to-pathologic downstaging (odds ratio, 0.4; P = .03) compared with UC.

Conclusions: SCC was the HV exhibiting the lowest effect of NAC in terms of activity and CSS. Compared with pure UC, SCC seemed to be insensitive to traditional NAC regimens.
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http://dx.doi.org/10.1016/j.clgc.2020.01.007DOI Listing
October 2020

Urothelial cancer harbours EGFR and HER2 amplifications and exon 20 insertions.

BJU Int 2020 05 23;125(5):739-746. Epub 2020 Feb 23.

Foundation Medicine, Cambridge, MA, USA.

Objective: To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations.

Materials And Methods: Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase.

Results: In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFR ) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2 occurred in 3.6% (20/552) of cases. EGFR and ERBB2 occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E-14 and 20% vs 68%, P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations.

Conclusion: EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFR and ERBB2 were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.
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http://dx.doi.org/10.1111/bju.15006DOI Listing
May 2020

Comprehensive Assessment of Immuno-oncology Biomarkers in Adenocarcinoma, Urothelial Carcinoma, and Squamous-cell Carcinoma of the Bladder.

Eur Urol 2020 04 17;77(4):548-556. Epub 2020 Jan 17.

Foundation Medicine, Cambridge, MA, USA; Upstate Medical University, Syracuse, NY, USA.

Background: In patients with rare histologies of bladder cancer, including adenocarcinoma of the bladder (ACB) and squamous-cell carcinoma (SCC), there are limited standard therapy options, defining an unmet medical need.

Objective: In this comparative comprehensive genomic profiling (CGP) study, genomic alterations (GAs), and immuno-oncology (IO) biomarkers have been analyzed.

Design, Setting, And Participants: Within the Foundation Medicine database, 143 cases with centrally reviewed pure ACB, 2142 with pure urothelial carcinoma (UC), and 83 with pure SCC were subjected to CGP. All patients developed advanced disease following a primary diagnosis of bladder cancer.

Intervention: CGP using a hybrid capture-based assay and immunohistochemistry (IHC).

Outcome Measurements And Statistical Analysis: Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci. Programmed cell-death ligand-1 (PD-L1) expression was determined by IHC (Ventana SP-142 assay), with >1% tumor cells (TCs) or tumor-infiltrating lymphocytes (TILs) scoring positive.

Results And Limitations: Pure ACB patients were younger and more often female than pure UC and pure SCC patients. UC and SCC had a significantly higher median TMB than ACB (p < 0.001). Rare CD274 (PD-L1) amplification cases were more frequently seen in SCC than in UC (5% vs 1%), and were not seen in ACB. MSI high status was very uncommon in all tumor types (0-1%). The frequencies of PD-L1 expression in both TCs and TILs was higher in UC and SCC (both 30%) than in ACB (18%). The results are limited by their retrospective nature and lack of clinical data annotation.

Conclusions: Deep sequencing revealed significant differences in IO biomarkers among the three major subtypes of bladder carcinomas. UC and SCC revealed higher frequencies of PD-L1 expression and higher TMB than ACB, and SCC has the highest frequency of CD274 amplification. The presence of pure SCC features should not disqualify patients for inclusion in IO trials.

Patient Summary: Tumor samples from patients diagnosed with advanced pure adenocarcinoma of the bladder (ACB) or pure squamous-cell carcinoma (SCC) have been analyzed in terms of frequency of putative immunotherapy biomarkers. The results indicated that pure SCC of the bladder was characterized by genomic features that portend similar response possibilities to immunotherapy compared with the classical pure urothelial carcinoma. Conversely, for pure ACB there might be different therapeutic opportunities, such as targeted therapies against peculiar genomic alterations in selected patients.
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http://dx.doi.org/10.1016/j.eururo.2020.01.003DOI Listing
April 2020

Squamous Transformation of Prostate Adenocarcinoma: A Report of Two Cases With Genomic Profiling.

Clin Genitourin Cancer 2020 06 4;18(3):e289-e292. Epub 2019 Dec 4.

Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA. Electronic address:

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http://dx.doi.org/10.1016/j.clgc.2019.11.020DOI Listing
June 2020

Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study.

Eur Urol 2020 05 25;77(5):636-643. Epub 2019 Dec 25.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Background: In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients.

Objective: To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0).

Design, Setting, And Participants: Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist.

Intervention: To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used.

Outcome Measurements And Statistical Analysis: The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen's kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps.

Results And Limitations: From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%).

Conclusions: In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies.

Patient Summary: Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies.
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http://dx.doi.org/10.1016/j.eururo.2019.12.016DOI Listing
May 2020

Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies.

Eur Urol 2020 04 8;77(4):439-446. Epub 2019 Nov 8.

San Raffaele Hospital and Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Background: Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited.

Objective: To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266).

Design, Setting, And Participants: In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH.

Intervention: Neoadjuvant pembrolizumab and RC.

Outcome Measurements And Statistical Analysis: Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response.

Results And Limitations: From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28-46) and the pT ≤ 1 rate was 55% (95% CI: 46-65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology.

Conclusions: The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes.

Patient Summary: In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.
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http://dx.doi.org/10.1016/j.eururo.2019.10.026DOI Listing
April 2020

The Pan-Cancer Landscape of Coamplification of the Tyrosine Kinases KIT, KDR, and PDGFRA.

Oncologist 2020 01 11;25(1):e39-e47. Epub 2019 Oct 11.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Purpose: Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large-scale analysis is lacking. We assess the pan-cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon.

Experimental Design: Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186-315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases.

Results: Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6-344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months.

Conclusion: We define 4q12amp as a significant event across the pan-cancer landscape, comparable to known pan-cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy.

Implications For Practice: Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan-cancer drug development strategy.
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http://dx.doi.org/10.1634/theoncologist.2018-0528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964135PMC
January 2020

Genomic profiling of cell-free circulating tumor DNA in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy.

J Gastrointest Oncol 2019 Oct;10(5):831-840

Foundation Medicine, Cambridge, MA, USA.

Background: Liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor DNA (ctDNA) to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of a sequenced tissue sample obtained from the same tumor. The clinical utility study (CUS) for the FoundationACT™ ctDNA assay (Foundation Medicine, Cambridge, MA, USA; NCT02620527) is a multi-center prospective clinical study for multiple solid tumor types to compare genomic profiling of paired tissue and blood samples from the same patient. In this subset of the study, paired specimens from 96 patients with colorectal cancer (CRC) were analyzed with comprehensive genomic profiling (CGP) of the tumor tissue sample (FoundationOne) and blood sample (FoundationACT™).

Methods: Both samples underwent CGP using the hybrid capture-based Illumina Hi-Seq technology. Maximum somatic allele frequency (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both tumor and liquid were compared for each subject.

Results: Among these patients, 61% were male; 74% had clinical stage IV disease, 19% had clinical stage III disease, and 7% had clinical stage II disease. Time between the tissue biopsy and liquid biopsy (range, 0709 days) had a significant impact on the positive percent agreement (PPA) between the two assays. Eighty percent of cases had evidence of ctDNA in the blood (MSAF >0). For all cases with MSAF >0, 171 base substitutions and insertions/deletions (indels) were identified in the tumor, and 79% (PPA) of these identical alterations were also identified in matched ctDNA samples; PPA increased to 87% for cases <270 days between the tissue and liquid biopsy, 95% for <90 days, and 100% PPA for <30 days. All known and likely short variants in , and were analyzed independently as testing of these genes is recommended by the National Comprehensive Cancer Network (NCCN) for patients with CRC and have therapeutic implications. For NCCN genes, PPA was 80% for all time points for short variants; PPA increased to 90% for cases <270 days between the tissue and liquid biopsy. There was high concordance for G12X between tissue and liquid: overall percent agreement (97%), PPA (93%), negative percent agreement (NPA) (100%), positive predictive value (PPV) (100%), and negative predictive value (NPV) (96%) for the <270 day cohort.

Conclusions: In cases where tumor tissue profiling is not possible, these results provide compelling evidence that genomic profiling of ctDNA in late stage CRC shows a high concordance with tumor tissue sequencing results and can be used to identify most clinically relevant alterations capable of guiding therapy for these patients.
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http://dx.doi.org/10.21037/jgo.2019.05.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776816PMC
October 2019

Pan-Cancer Analysis of Loss-of-Function Alterations and Their Association with the Focal Tandem-Duplicator Phenotype.

Oncologist 2019 12 10;24(12):1526-1533. Epub 2019 Jul 10.

Johns Hopkins University School of Medicine and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Baltimore, Maryland, USA

Background: loss-of-function (LOF) genomic alterations are associated with focal tandem duplications (FTDs) in ovarian and prostate cancers. Because these FTDs may produce fusion-induced neoantigens (FINAs), alteration is a candidate biomarker for immune checkpoint inhibitor sensitivity. Here we determine the prevalence of LOF alterations and their association with FTDs across diverse tumor types.

Materials And Methods: A total of 142,133 tumor samples comprising 379 cancer types were sequenced (August 2014 to April 2018) by hybrid capture-based comprehensive genomic profiling (Foundation Medicine, Cambridge, MA) as part of routine clinical care. Results were analyzed for base substitutions, short insertions/deletions, rearrangements, and copy number alterations. LOF genomic alterations were assessed for zygosity status and association with FTDs/focal copy number gain.

Results: genomic alterations were detected in 1.1% of all cases, most frequently in prostate cancer (5.6%), but were also observed at >1% frequency in 11 cancer types. Across multiple cancer types, including prostate, gastric/esophageal, ovarian, breast, and endometrial cancer, the number of FTDs was significantly increased in LOF versus wild-type cases. Notably, -LOF was not consistently associated with a homologous recombination deficiency genomic signature. Quantitative assessment of associated FTDs by measurement of single copy number gains identified novel likely deleterious kinase-domain mutations in prostate and ovarian cancers.

Conclusion: Detection of LOF genomic alterations and their association with FTDs in a diverse spectrum of malignancies suggests that immunotherapy approaches targeting FINAs derived from associated FTDs may be a broadly applicable strategy that could be explored across cancer types in a tumor-agnostic manner.

Implications For Practice: inactivation in ovarian and prostate cancer results in the generation of focal tandem duplications, which can cause fusion-induced neoantigens. In prostate cancer, alterations have demonstrated promise as a potential predictive biomarker for response to immune checkpoint blockade. This study evaluated genomic profiling data from >142,000 tumors to determine the prevalence of loss-of-function genomic alterations across tumor types and demonstrated that alterations are associated with the tandem-duplicator phenotype in cancer types other than ovarian and prostate cancer. The association of alterations with focal tandem duplications across broad cancer types suggests that inactivation warrants further investigation as a pan-cancer biomarker for immunotherapy benefit.
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http://dx.doi.org/10.1634/theoncologist.2019-0214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975947PMC
December 2019

Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors.

JCO Precis Oncol 2019 10;3. Epub 2019 May 10.

University of Utah, Salt Lake City, UT.

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 (44%), (32%), (31%), and (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%), (6%), and mismatch repair (4%) GAs. and GAs were associated with high gLOH, whereas 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 ( and GAs in and 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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http://dx.doi.org/10.1200/PO.18.00283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583915PMC
May 2019

Genomic Features of Metastatic Testicular Sex Cord Stromal Tumors.

Eur Urol Focus 2019 09 27;5(5):748-755. Epub 2019 May 27.

Upstate Medical University, Syracuse, NY, USA.

Background: Metastatic testicular sex cord stromal tumors of the testis (MSCSTs) comprise an extremely uncommon form of genitourinary malignancy.

Objective: To perform comprehensive genomic profiling (CGP) to enable the search for potential therapy targets.

Design, Setting, And Participants: Ten patients with testicular Leydig cell tumors (LCTs), six with Sertoli cell tumors (SCTs), and three with undifferentiated sex cord stromal tumors (USCSTs) and a comparison group of 366 patients with ovarian sex cord stromal tumors (SCSTs) underwent hybrid-capture-based CGP to evaluate all classes of genomic alterations (GAs). The tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA, and microsatellite instability (MSI) was determined on 114 loci.

Intervention: CGP on tumor samples.

Outcome Measurements And Statistical Analysis: Descriptive analyses and differences between histological subgroups were reported.

Results And Limitations: In these patients, all of whom had metastatic disease at the time of sequencing, the primary testis tumor was sequenced in six (32%) patients and a metastatic site in 13 (68%) patients. The overall frequencies of GAs were similar in LCTs, SCTs, and USCSTs, ranging from 3.0 to 3.5 GAs/tumor. The most frequent untargetable GAs included CTNNB1 and CDKN2A/B, both ranging from 20% to 33% of cases. Targetable GAs were uncommon in all MSCST subgroups, but several tumors showed potential for cell-cycle inhibitors (CDK4 in LCTs), mTOR inhibitors (RICTOR, NF2, and PTEN in all three tumor types), hedgehog inhibitors (PTCH1 in LCTs), and poly(ADP-ribose) polymerase inhibitors (BAP1 in SCTs). No MSI-high status was identified. The TMB was also low in all MSCST groups, and tumors featuring a TMB of ≥10 mutations/Mb were not identified. GA findings from ovarian SCSTs largely recapitulated those from MSCSTs. A lack of clinical outcome correlation is a limitation of the present analyses.

Conclusions: Rare cases of testicular MSCSTs have GAs linked to potential targeted therapy benefits on CGP. In contrast, the lack of MSI-high status and an overall low TMB indicate a likely lack of benefit for immunotherapies.

Patient Summary: Genomic profiling can guide clinical research and disclose therapeutic opportunities for patients with rare testicular cancers for which standard therapies are lacking.
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http://dx.doi.org/10.1016/j.euf.2019.05.012DOI Listing
September 2019

Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With Existing Drugs or Used as Biomarkers.

Gastroenterology 2019 06 2;156(8):2242-2253.e4. Epub 2019 Mar 2.

Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background & Aims: It has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations.

Methods: We performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci.

Results: KRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.

Conclusions: In targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.
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http://dx.doi.org/10.1053/j.gastro.2019.02.037DOI Listing
June 2019

Genomic Features for Therapeutic Insights of Chemotherapy-Resistant, Primary Mediastinal Nonseminomatous Germ Cell Tumors and Comparison with Gonadal Counterpart.

Oncologist 2019 04 18;24(4):e142-e145. Epub 2019 Jan 18.

Upstate Medical University, Syracuse, New York, USA.

Primary mediastinal nonseminomatous germ cell tumors (PMNSGCT) frequently become refractory to chemotherapy, and no effective salvage therapy exists. We performed genomic profiling on a series of 44 PMNSGCT and compared the results with those from chemorefractory, metastatic pure seminomatous (Sem, = 22) and nonseminomatous (NS, = 86) testicular germ cell tumors. Archival tissues were sequenced by a hybrid capture-based technology (FoundationONE; Foundation Medicine, Inc., Cambridge, MA). Microsatellite instability (MSI) and tumor mutational burden (TMB, mutations [mut]/Mb) were determined.Statistically significant differences in genomic alterations (GA) of PMNSGCT versus NS included higher TP53 pathway GA ( < .0001), PIK3CA pathway GA ( < .0001), and lower cell-cycle pathway GA ( = .0004). There were no MSI-high PMNSGCT cases. Mean TMB was similar between the groups, but there were more ≥10 mut/Mb in the PMNSGCT group versus NS (11.4% vs. 4.6%).The GA identified in PMNSGCT were similar to the findings from NS, with differential opportunities for targeted therapies and immunotherapies. Further study of precision treatments appears warranted.
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http://dx.doi.org/10.1634/theoncologist.2018-0430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459248PMC
April 2019

RET rearrangements are actionable alterations in breast cancer.

Nat Commun 2018 11 16;9(1):4821. Epub 2018 Nov 16.

Department of Medicine, Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA.

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.
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http://dx.doi.org/10.1038/s41467-018-07341-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240119PMC
November 2018

Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy.

Oncologist 2019 06 29;24(6):791-797. Epub 2018 Oct 29.

Foundation Medicine Inc., Cambridge, Massachusetts, USA.

Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics.

Methods: We performed hybrid-capture-based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy.

Results: There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were (38%), (38%), and (31%). All -mutated cases also had loss of heterozygosity at that locus, but in contrast all -mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in (25%), (12.5%), (12.5%), (12.5%), and (12.5%). A patient whose tumor harbored T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity.

Conclusion: CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors.

Implications For Practice: Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life-threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid-capture-based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including , , , , and and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating mutation is also presented. These findings should be further investigated for their therapeutic potential.
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http://dx.doi.org/10.1634/theoncologist.2018-0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656481PMC
June 2019

Hybrid Capture-Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Non-Small Cell Lung Cancer.

J Thorac Oncol 2019 02 24;14(2):255-264. Epub 2018 Oct 24.

Foundation Medicine, Inc., Cambridge, Massachusetts.

Introduction: Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in NSCLC. Tissue biopsy is the criterion standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative.

Methods: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 1552 patients with NSCLC.

Results: Evidence of ctDNA was detected in 80% of samples, and in 86% of these cases, at least one reportable genomic alteration (GA) was detected. Frequently altered genes were tumor protein p53 gene (TP53) (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (N = 21,500) showed similar frequencies of GAs per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both p < 0.0001), likely reflecting the use of liquid versus tissue biopsy after relapse during targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in their blood, 64% of GAs detected in tissue were also detected in ctDNA, including 78% of short variants (58 of 74) and 100% of rearrangements (four of four), but only 16% of amplifications (four of 25).

Conclusions: Genomic profiling of ctDNA detected clinically relevant GAs in a significant subset of NSCLC cases. Most alterations detected in matched tissue were also detected in ctDNA. These results suggest the utility of ctDNA testing in advanced NSCLC as a complementary approach to tissue testing. Blood-based ctDNA testing may be particularly useful at the time of progression during targeted therapy.
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http://dx.doi.org/10.1016/j.jtho.2018.10.008DOI Listing
February 2019

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study.

J Clin Oncol 2018 12 20;36(34):3353-3360. Epub 2018 Oct 20.

Andrea Necchi, Andrea Anichini, Daniele Raggi, Simona Massa, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Elena Farè, Francesco Monopoli, Antonella Messina, Roberto Salvioni, and Luigi Mariani, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori; Alberto Briganti, Roberta Lucianò, Marco Bianchi, Renzo Colombo, Andrea Gallina, Andrea Salonia, and Francesco Montorsi, Vita Salute San Raffaele University and Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy; Siraj M. Ali, Russell Madison, Jeffrey S. Ross, and Jon H. Chung, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Upstate Medical University, Syracuse, NY.

Purpose: To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used.

Patients And Methods: In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay.

Results: Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors.

Conclusion: Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1-positive or high-TMB tumors.
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http://dx.doi.org/10.1200/JCO.18.01148DOI Listing
December 2018

Genomic Characterization of Testicular Germ Cell Tumors Relapsing After Chemotherapy.

Eur Urol Focus 2020 01 17;6(1):122-130. Epub 2018 Jul 17.

Upstate Medical University, Syracuse, NY, USA; Foundation Medicine Inc., Cambridge, MA, USA.

Background: Although both seminomatous and nonseminomatous testicular germ cell tumors (TGCTs) have favorable outcomes with chemotherapy, a subset is chemorefractory, and novel therapeutic options are needed.

Objective: To molecularly characterize chemotherapy-refractory TGCTs.

Design, Setting, And Participants: Archival tissues from 107 chemotherapy-treated and relapsed TGCT patients (23 seminomas; 84 nonseminomas) underwent hybrid-capture-based genomic profiling to evaluate four classes of genomic alterations (GAs). Tumor mutational burden (TMB) and microsatellite instability (MSI) were also measured.

Intervention: Genomic profiling on tumor samples from chemotherapy-refractory TGCTs.

Outcome Measurements And Statistical Analysis: Descriptive analyses and differences between seminoma and nonseminoma subgroups were reported.

Results And Limitations: The mean GA/tumor was 2.9 for seminomas and 4.0 for nonseminomas (p=0.04). KRAS alterations (mainly amplifications) were the most common GAs at the single-gene level (47.8% of seminomas and 51.2% of nonseminomas). RAS-RAF pathway (56.5% vs 52.3%) and cell-cycle pathway (52.2% vs 56.0%) were the most common GA classes in seminomas and nonseminomas, respectively. Receptor tyrosine kinase pathway and PI3K pathway GAs were more frequent in seminomas (p=0.02). Median TMB was 1.8 mutations/Mb for seminomas and 2.7 mutations/Mb for nonseminomas (p=0.098), and MSI-high status was found in one nonseminoma only (1.2%). A lack of clinical outcome correlation is a limitation of the present analyses.

Conclusions: In chemotherapy-refractory TGCTs, trials with agents targeting the KRAS pathway may be pursued due to the high frequency of KRAS GAs. Overall, the GAs found in refractory seminomas and nonseminomas differ significantly. Considering the frequency of high TMB or MSI-high status, immunotherapy may benefit a small subset of nonseminomas.

Patient Summary: Testicular cancers that are resistant to or relapse after standard chemotherapy may harbor genomic alterations that are potentially druggable, particularly in the clinical trial setting, and genomic profiling can guide clinical research and disclose therapeutic opportunities for these patients.
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http://dx.doi.org/10.1016/j.euf.2018.07.013DOI Listing
January 2020

Analytical Validation of a Hybrid Capture-Based Next-Generation Sequencing Clinical Assay for Genomic Profiling of Cell-Free Circulating Tumor DNA.

J Mol Diagn 2018 09 22;20(5):686-702. Epub 2018 Jun 22.

Foundation Medicine, Inc., Cambridge, Massachusetts. Electronic address:

Genomic profiling of circulating tumor DNA derived from cell-free DNA (cfDNA) in blood can provide a noninvasive method for detecting genomic biomarkers to guide clinical decision making for cancer patients. We developed a hybrid capture-based next-generation sequencing assay for genomic profiling of circulating tumor DNA from blood (FoundationACT). High-sequencing coverage and molecular barcode-based error detection enabled accurate detection of genomic alterations, including short variants (base substitutions, short insertions/deletions) and genomic re-arrangements at low allele frequencies (AFs), and copy number amplifications. Analytical validation was performed on 2666 reference alterations. The assay achieved >99% overall sensitivity (95% CI, 99.1%-99.4%) for short variants at AF >0.5%, >95% sensitivity (95% CI, 94.2%-95.7%) for AF 0.25% to 0.5%, and 70% sensitivity (95% CI, 68.2%-71.5%) for AF 0.125% to 0.25%. No false positives were detected in 62 samples from healthy volunteers. Genomic alterations detected by FoundationACT demonstrated high concordance with orthogonal assays run on the same clinical cfDNA samples. In 860 routine clinical FoundationACT cases, genomic alterations were detected in cfDNA at comparable frequencies to tissue; for the subset of cases with temporally matched tissue and blood samples, 75% of genomic alterations and 83% of short variant mutations detected in tissue were also detected in cfDNA. On the basis of analytical validation results, FoundationACT has been approved for use in our Clinical Laboratory Improvement Amendments-certified/College of American Pathologists-accredited/New York State-approved laboratory.
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http://dx.doi.org/10.1016/j.jmoldx.2018.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593250PMC
September 2018

Responses to Alectinib in ALK-rearranged Papillary Renal Cell Carcinoma.

Eur Urol 2018 07;74(1):124-128

Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

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http://dx.doi.org/10.1016/j.eururo.2018.03.032DOI Listing
July 2018

in Lung Cancers: Analysis of Patient Cases Reveals Recurrent Mutations, Fusions, Kinase Duplications, and Concurrent Alterations.

JCO Precis Oncol 2018 19;2. Epub 2018 Apr 19.

, Vancouver General Hospital, Vancouver, British Columbia, Canada; , , , , , , , , , , , , , , , , , , and , Foundation Medicine, Cambridge, MA; , The Angeles Clinic and Research Institute and Cedars-Sinai Medical Center, Los Angeles; , University of California San Diego, San Diego; , University of California, San Francisco, San Francisco; and , University of California, Irvine, Medical Center, Irvine, CA; , Cleveland Clinic; and , University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH; , Soroka Medical Center and Ben-Gurion University, Beer-Sheve, Israel; , Northwestern University Feinberg School of Medicine Northwestern Medical Center, Chicago, IL; and , Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose: Dabrafenib and trametinib are approved for the management of advanced non-small-cell lung cancers (NSCLCs) that harbor V600E mutations. Small series and pan-cancer analyses have identified non-V600 alterations as therapeutic targets. We sought to examine a large genomic data set to comprehensively characterize non-V600 B alterations in lung cancer.

Patients And Methods: A total of 23,396 patients with lung cancer provided data to assay with comprehensive genomic profiling. Data were reviewed for predicted pathogenic base substitutions, short insertions and deletions, copy number changes, and rearrangements.

Results: Adenocarcinomas represented 65% of the occurrences; NSCLC not otherwise specified (NOS), 15%; squamous cell carcinoma, 12%; and small-cell lung carcinoma, 5%. was altered in 4.5% (1,048 of 23,396) of all tumors; 37.4% (n = 397) were V600E, 38% were non-V600E activating mutations, and 18% were inactivating. Rearrangements were observed at a frequency of 4.3% and consisted of N-terminal deletions (NTDs; 0.75%), kinase domain duplications (KDDs; 0.75%), and fusions (2.8%). The fusions involved three recurrent fusion partners: , and . V600E was associated with co-occurrence of alterations, but other alterations were not and were instead associated with , , and alterations ( < .05). Potential mechanisms of acquired resistance to V600E inhibition are demonstrated.

Conclusion: This series characterized the frequent occurrence (4.4%) of alterations in lung cancers. Recurrent alterations in NSCLC adenocarcinoma are comparable to the frequency of other NSCLC oncogenic drivers, such as , and exceed that of or . This work supports a broad profiling approach in lung cancers and suggests that non-V600E BR alterations represent a subgroup of lung cancers in which targeted therapy should be considered.
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http://dx.doi.org/10.1200/PO.17.00172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446447PMC
April 2018