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1.
Nat Metab ; 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833465

RESUMO

Mitochondrial DNA (mtDNA) encodes protein subunits and translational machinery required for oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, in the present study we demonstrate that pathogenic mtDNA mutations arise in tumours at a rate comparable to those in the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumour lineages. Loss-of-function mutations accumulate at an elevated rate specifically in complex I and often arise at specific homopolymeric hotspots. In contrast, complex V is depleted of all non-synonymous mutations, suggesting that impairment of ATP synthesis and mitochondrial membrane potential dissipation are under negative selection. Common truncating mutations and rarer missense alleles are both associated with a pan-lineage transcriptional programme, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal cancer patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with major implications for patient stratification, prognosis and therapeutic development.

2.
Clin Cancer Res ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795256

RESUMO

PURPOSE: To delineate recurrent oncogenic driver alterations and dysregulated pathways in esophageal adenocarcinoma and to assess their prognostic value. EXPERIMENTAL DESIGN: We analyzed a large cohort of patients with lower esophageal and junctional adenocarcinoma, prospectively sequenced by MSK-IMPACT with high-quality clinical annotation. Patients were subdivided according to treatment intent, curative vs. palliative, which closely mirrored clinical staging. Genomic features, alterations, and pathways were examined for association with overall survival using Cox proportional hazard models, adjusted for relevant clinicopathologic factors knowable at the time of diagnosis. RESULTS: Analysis of 487 patients revealed 16 oncogenic driver alterations, mostly amplifications, present in {greater than or equal to}5% of patients. Patients in the palliative-intent cohort, compared to those in the curative-intent cohort, were more likely to have metastatic disease, ERBB2 amplifications, Cell Cycle and RTK-RAS pathway alterations, as well as a higher fraction of genome altered and rate of whole-genome doubling. In multivariable analyses, CDKN2A alterations, SMAD4 alterations, KRAS amplifications, Cell Cycle and TGFb pathways, and overall number of oncogenic drivers were independently associated with worse overall survival. ERBB2 amplification was associated with improved survival, presumably due to trastuzumab therapy. CONCLUSIONS: Our study suggests that higher levels of genomic instability are associated with more advanced disease in esophageal adenocarcinoma. Furthermore, CDKN2A, KRAS, and SMAD4 represent prognostic biomarkers, given their strong association with poor survival.

3.
J Mol Diagn ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33781965

RESUMO

Cell free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system (CNS) but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using MSK IMPACTTM (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA vs gDNA (genomic DNA from cell pellets [CP]) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions), were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming CNS involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation (43.6% [55/126] vs 19.8% [25/126]) and harbored 1.6X more mutations (6.94 vs 4.65, p=0.005) with higher mean variant allele fractions (41.1% vs. 13.0%, p<0.0001). Among mutation positive cfDNAs, the corresponding gDNA was frequently negative (44.6%, 25/55) or failed sequencing (17.8%, 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high VAF even in the context of a negative cytology.

4.
JAMA Oncol ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33599686

RESUMO

Importance: In June 2020, the US Food and Drug Administration approved the anti-programmed cell death 1 drug pembrolizumab for patients with malignant solid tumors of any histologic type with high tumor mutational burden (TMB; ≥10 mutations per megabase). The predictive value of this universal cutoff for high TMB is not well understood. Objective: To examine the performance of a universal definition of high TMB in an independent cohort of patients with solid tumors treated with immune checkpoint inhibitors. Design, Setting, and Participants: This retrospective cohort study included 1678 patients at a single cancer referral center treated with immune checkpoint inhibitors from January 1, 2015, to December 31, 2018. Patients had 16 different cancer types and were treated with anti-programmed cell death 1 or programmed cell death ligand-1 immunotherapy. Tumors underwent next-generation sequencing. Exposures: At least 1 dose of immune checkpoint inhibitors. Main Outcomes and Measures: Best overall response to immune checkpoint inhibitor therapy. The hypothesis tested was formulated after data collection and prior to analysis. Results: Of 1678 patients, 924 (55%) were male, and the median age was 64 years (interquartile range, 55-71 years). Using the universal cutoff of 10 mutations per megabase, 416 tumors (25%) were categorized as having high TMB. Across cancer types, the proportion of TMB-high tumors ranged from 0% of kidney cancers to 53% of melanomas (113 of 214). Tumors categorized as TMB-high had higher response rates compared with TMB-low tumors in only 11 of 16 cancer types. In the entire cohort, response rates increased with higher cutoffs for TMB-high categorization, reaching 41% (169 of 416) for TMB more than 10 and 56% (90 of 161) for TMB more than 18, the highest TMB decile. Response rates also increased with TMB percentile within cancer type. Using cancer-specific cutoffs, 457 tumors (27%) were categorized as TMB-high. Response rates within cancer type ranged from 4% for pancreatic cancer (1 of 26) to 70% for melanoma (46 of 66). Cancer-specific cutoffs were associated with numerically higher response rates for TMB-high compared with TMB-low tumors in 14 of 16 cancer types. Conclusions and Relevance: The data from this cohort study validate the finding of generally higher response rates following immune checkpoint inhibitor therapy for tumors with TMB of 10 or more mutations per megabase, across multiple cancer types. However, the predictive value of a universal numerical threshold for TMB-high was limited, owing to variability across cancer types and unclear associations with survival outcomes. Further investigation will help define cancer type-specific TMB cutoffs to guide decision-making.

5.
Nat Commun ; 12(1): 729, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526794

RESUMO

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.


Assuntos
/uso terapêutico , Linfócitos/imunologia , Neoplasias/tratamento farmacológico , Neutrófilos/imunologia , Idoso , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Seguimentos , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/mortalidade , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Retrospectivos
6.
JCO Clin Cancer Inform ; 5: 221-230, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33625877

RESUMO

PURPOSE: Cancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT), and National Cancer Institute Thesaurus (NCIt) provide large sets of cancer classification terminologies but they lack a dynamic modernized cancer classification platform that addresses the fast-evolving needs in clinical reporting of genomic sequencing results and associated oncology research. METHODS: To meet these needs, we have developed OncoTree, an open-source cancer classification system. It is maintained by a cross-institutional committee of oncologists, pathologists, scientists, and engineers, accessible via an open-source Web user interface and an application programming interface. RESULTS: OncoTree currently includes 868 tumor types across 32 organ sites. OncoTree has been adopted as the tumor classification system for American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), a large genomic and clinical data-sharing consortium, and for clinical molecular testing efforts at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. It is also used by precision oncology tools such as OncoKB and cBioPortal for Cancer Genomics. CONCLUSION: OncoTree is a dynamic and flexible community-driven cancer classification platform encompassing rare and common cancers that provides clinically relevant and appropriately granular cancer classification for clinical decision support systems and oncology research.

7.
Nat Commun ; 12(1): 338, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436578

RESUMO

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.


Assuntos
Aberrações Cromossômicas , Evolução Clonal/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Hematológicas/genética , Humanos , Pessoa de Meia-Idade , Mosaicismo , Neoplasias/genética , Medição de Risco , Seleção Genética , Adulto Jovem
8.
Nat Genet ; 53(1): 11-15, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398197

RESUMO

In multiple cancer types, high tumor mutational burden (TMB) is associated with longer survival after treatment with immune checkpoint inhibitors (ICIs). The association of TMB with survival outside of the immunotherapy context is poorly understood. We analyzed 10,233 patients (80% non-ICI-treated, 20% ICI-treated) with 17 cancer types before/without ICI treatment or after ICI treatment. In non-ICI-treated patients, higher TMB (higher percentile within cancer type) was not associated with better prognosis; in fact, in many cancer types, higher TMB was associated with poorer survival, in contrast to ICI-treated patients in whom higher TMB was associated with longer survival.


Assuntos
Mutação/genética , Neoplasias/diagnóstico , Neoplasias/genética , Idoso , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida
9.
J Mol Diagn ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285287

RESUMO

Promoter mutations involving the TERT gene have been identified in multiple cancer types. Other TERT alterations remain poorly characterized. Sequencing data from 30,773 tumors analyzed by a hybridization capture next-generation sequencing assay (MSK- IMPACT) was analyzed for the presence of TERT alterations. Promoter rearrangements (500 bases upstream of the transcriptional start site), hypermethylation (n=57) and gene expression (n=155) was evaluated for a subset of cases. We identified mutually exclusive and recurrent promoter mutations at 3 hotspots upstream of the transcriptional start site in 11.3% of cases (-124: 74%; -146: 24%; -136: <2%). Mutually exclusive amplification events were identified in another 2.3% of cases, while mutually exclusive rearrangements proximal to the TERT gene were seen in 24 cases. The highest incidence of TERT promoter mutations was seen in cutaneous melanoma (82%), while amplification events significantly outnumbered promoter mutations in well differentiated/ dedifferentiated liposarcoma (14.1% vs 2.4%) and adrenocortical carcinoma (13.6% vs 4.5%). Gene expression analysis suggests that the highest levels of gene expression are seen in cases with amplifications and rearrangements. Hypermethylation events upstream of the TERT coding sequence were not found to be mutually exclusive with known pathogenic alterations. Future studies aimed at defining the prevalence and prognostic impact of TERT alterations should attempt to incorporate other pathogenic TERT alterations as these might significantly impact telomerase function.

10.
medRxiv ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33269365

RESUMO

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. 1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. 2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. 7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10 -3 ) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

11.
Clin Cancer Res ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199489

RESUMO

BACKGROUND: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBAs) in the setting of LS have not been well-studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. METHODS: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via immunohistochemical (IHC) staining. Germline DNA was analyzed for mutations in known cancer-predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, EPCAM). Clinical variables were correlated with MMR/MSI status. RESULTS: 26% (26/100; 95% CI: 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). LS prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-LS MMR-D vs MMR-proficient (MMR-P) SBAs (65 vs 61, p= 0.75), but significantly younger in LS (47.5 vs 61; p=0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P vs 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in LS (p=0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared to 23.1% (6/26) in the MMR-D group (p=0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared to 18.2% (2/11) in the MMR-D group (p=0.0002). CONCLUSIONS: When compared to MMR-P SBA, MMR-D SBA is associated with earlier-stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline LS testing in MMR-D SBA is warranted.

12.
Clin Cancer Res ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199492

RESUMO

PURPOSE: Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explore the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities. EXPERIMENTAL DESIGN: We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wildtype and mutant ERCC2 or ERCC3 cell lines were created and used to assess response to several candidate drugs. RESULTS: We found that putative damaging germline and somatic alterations in NER genes are present with frequencies up to 10% across multiple cancer types. Both in vitro and in vivo studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to a current standard of care agent, cisplatin. Hypomorphic ERCC2/3 mutant cells have impaired ability to repair irofulven induced DNA damage. Transcriptomic profiling of tumor tissues suggested co-dependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by in vitro studies. CONCLUSIONS: These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33163850

RESUMO

PURPOSE: Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease. PATIENTS AND METHODS: Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients. RESULTS: The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype. CONCLUSION: Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs.

14.
Cancer Discov ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004339

RESUMO

On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKA G667 and TRKC G696 xDFG substitutions reduce drug binding by generating steric hindrance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leveraging inhibitor class affinity switching to address recalcitrant resistant alterations.

15.
Nat Cancer ; 1(4): 382-393, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32864625

RESUMO

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

16.
Cancer ; 126(20): 4532-4544, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32767682

RESUMO

BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. LAY SUMMARY: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.

17.
Cancer ; 126(18): 4126-4135, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663328

RESUMO

BACKGROUND: Fibrolamellar carcinoma (FLC) is a rare primary liver cancer of young adults. A functional chimeric transcript resulting from the in-frame fusion of the DNAJ homolog, subfamily B, member 1 (DNAJB1), and the catalytic subunit of protein kinase A (PRKACA) genes on chromosome 19 is believed to be unique in FLC, with a possible role in pathogenesis, yet with no established therapeutic value. The objective of the current study was to understand the molecular landscape of FLC and to identify potential novel therapeutic targets. METHODS: Archival fresh, formalin-fixed, paraffin-embedded samples from patients with FLC who prospectively consented to an institutional review board-approved protocol were analyzed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a next-generation sequencing assay encompassing up to 468 key cancer genes. Custom targeted RNA-Seq was performed in selected patients. Demographics, treatment, and outcome data were collected prospectively. Survival outcomes were estimated and correlated with mutation and/or copy number alterations. RESULTS: A total of 33 tumor samples from 31 patients with FLC were analyzed. The median age of the patients at the time of diagnosis was 18 years and approximately 53% were women. The DNAJB1-PRKACA fusion transcript was detected in 100% of patients. In 10 of 31 patients in which MSK-IMPACT did not detect the fusion, its presence was confirmed by targeted RNA-Seq. TERT promoter mutation was the second most common, and was detected in 7 patients. The median follow up was 30 months (range, 6-153 months). The 3-year overall survival rate was 84% (95% CI, 61%-93%). CONCLUSIONS: The DNAJB1-PRKACA fusion transcript is nonspecific and nonsensitive to FLC. Its potential therapeutic value currently is under evaluation. Opportunities currently are under development for therapy that may be driven or related to the DNAJB1-PRKACA fusion transcript or any therapeutic target identified from next-generation sequencing in patients with FLC.

18.
Cancer Med ; 9(17): 6093-6101, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32633890

RESUMO

PURPOSE: The enucleation rate for retinoblastoma has dropped from over 95% to under 10% in the past 10 years as a result of improvements in therapy. This reduces access to tumor tissue for molecular profiling, especially in unilateral retinoblastoma, and hinders the confirmation of somatic RB1 mutations necessary for genetic counseling. Plasma cell-free DNA (cfDNA) has provided a platform for noninvasive molecular profiling in cancer, but its applicability in low tumor burden retinoblastoma has not been shown. We analyzed cfDNA collected from 10 patients with available tumor tissue to determine whether sufficient tumorderived cfDNA is shed in plasma from retinoblastoma tumors to enable noninvasive RB1 mutation detection. METHODS: Tumor tissue was collected from eye enucleations in 10 patients diagnosed with advanced intra-ocular unilateral retinoblastoma, three of which went on to develop metastatic disease. Tumor RB1 mutation status was determined using an FDA-cleared tumor sequencing assay, MSK-IMPACT. Plasma samples were collected before eye enucleation and analyzed with a customized panel targeting all exons of RB1. RESULTS: Tumor-guided genotyping detected 10 of the 13 expected somatic RB1 mutations in plasma cfDNA in 8 of 10 patients (average variant allele frequency 3.78%). Without referring to RB1 status in the tumor, de novo mutation calling identified 7 of the 13 expected RB1 mutations (in 6 of 10 patients) with high confidence. CONCLUSION: Plasma cfDNA can detect somatic RB1 mutations in patients with unilateral retinoblastoma. Since intraocular biopsies are avoided in these patients because of concern about spreading tumor, cfDNA can potentially offer a noninvasive platform to guide clinical decisions about treatment, follow-up schemes, and risk of metastasis.

19.
Cancer Res ; 80(19): 4233-4243, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32641410

RESUMO

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation.See related commentary by Whitehead and Sebolt-Leopold, p. 4042.

20.
Cancer ; 126(17): 3939-3949, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32573775

RESUMO

BACKGROUND: KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection. METHODS: Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genomic alterations were determined on the basis of MSK-IMPACT results from formalin-fixed, paraffin-embedded samples. Associations between genomic alterations and clinical outcomes were assessed. RESULTS: Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow-up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months [95% CI, 33.0-45.5 months] vs 91.0 months [95% CI, 34.8 months to not available (NA)]; P = .043; median for TP53, 37.4 months [95% CI, 32.1-42.8 months] vs 65.0 months [95% CI, 33.0 months to NA]; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months [95% CI, 25.3-45.5 months] vs 39.2 months [95% CI, 37.4-75.2 months]; P = .012). TP53 truncating mutations (median, 39.6 months [95% CI, 32.4-75.2 months] vs 33.9 months [95% CI, 24.0-39.0 months]; P = .020) and those associated with loss of heterozygosity (median, 26.6 months [95% CI, 21.6-44.2 months] vs 39.2 months [95% CI, 34.5-49.1 months]; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01-2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0-49.8 months; P = .035). CONCLUSIONS: In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.

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