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.
This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e19 (https://www. gastrojournal.org/cme/home). Learning Objective: Upon completion of this CME activity, successful leaners will be able to identify current clinically relevant genomic alterations in pancreatic ductal adenocarcinoma.
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 (GA) 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 GAs detected in ctDNA and assessed concordance with tissue-based CGP. Results: A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 837 patients had BRCA1/2 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 (e.g., in ATM and CHEK2). Potential androgen receptor resistance alterations were detected in 940 of 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 BRCA1/2 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. See related commentary by Hawkey and Armstrong, p. 2961
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.
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.
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 BRCA1/2 alterations ( BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non– BRCA1/2-associated) cancer types, the association between BRCA1/2 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. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non– BRCA1/2-associated cancers. The fraction of BRCA1/2-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2-associated (89.9%) versus non– BRCA1/2-associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency ( BRCA1/2-associated cancers, 8.9%; non– BRCA1/2-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.
BackgroundEstrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer.Patients and methodsTo identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287–395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots.ResultsWe identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3′ partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations.ConclusionsCollectively, these data indicate that N-terminal ESR1 fusions involving exons 6–7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.
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