Paired Tumor-Normal Sequencing Provides Insights into TP53-Related Cancer Spectrum in Li-Fraumeni Patients.
Li-Fraumeni syndrome (LFS) genetic testing is performed using blood specimens from patients selected based on phenotype-dependent guidelines. This approach is problematic for understanding LFS clinical spectrum, because patients with non-classical presentations are missed, clonal hematopoiesis (CH)-related somatic blood mutations cannot be distinguished from germline variants, and unrelated tumors cannot be differentiated from those driven by germline TP53 defects.
To provide insights into LFS-related cancer spectrum, we analyzed paired tumor-blood DNA sequencing results in 17,922 cancer patients, and distinguished CH-related, mosaic, and germline TP53 variants. Loss-of-heterozygosity (LOH) and TP53 mutational status were assessed in tumors, followed by immunohistochemistry for p53 expression on a subset to identify those lacking biallelic TP53 inactivation.
Pathogenic/likely pathogenic TP53 variants were identified in 50 patients, 12 (24.0%) of which were CH-related and four (8.0%) were mosaic. Twelve (35.3%) of 34 patients with germline TP53 variants did not meet LFS testing criteria. LOH of germline TP53 variant was observed in 96.0% (95% CI = 79.7-99.9%) of core LFS-spectrum type tumors versus 45.5% (95% CI = 16.8-76.6%) of other tumors, and 91.3% (95% CI = 72.0-98.9%) of tumors from patients who met LFS testing criteria versus 61.5% (95% CI = 31.6-86.1%) of tumors from patients who did not. Tumors retaining wild-type TP53 allele exhibited wild-type p53 expression.
Our results indicate that some TP53 variants identified in blood-only sequencing are not germline and a substantial proportion of LFS patients are missed by current testing guidelines. Additionally, a subset of tumors from LFS patients do not have biallelic TP53 inactivation and may represent cancers unrelated to their germline TP53 defect.
Publication Date: 2021-07-10
Journal: Journal of the National Cancer Institute
Prevalence of predictive biomarkers in a large cohort of molecularly defined adult-type ovarian granulosa cell tumors.
The objective of this study was to determine the prevalence of predictive biomarkers associated with FDA-approved therapies in molecularly defined adult-type ovarian granulosa cell tumors (aGCTs).
We performed a retrospective cross-sectional cohort study of tumor profiles using the inclusion criteria of molecularly defined (FOXL2 c.C402G positive) aGCTs previously sequenced at Foundation Medicine, Inc. The dataset included coding variants for up to 406 genes, microsatellite instability, tumor mutational burden, and genomic loss of heterozygosity (gLOH). PD-L1 expression was determined using the tumor proportion score, as measured using the DAKO 22C3 immunohistochemistry assay.
423 tumor profiles met inclusion criteria. The median age at the time of sample submission was 57 years (interquartile range 48-65). The mean tumor mutational burden was 1.8 mutations per megabase (range 0-8.8). No tumors exhibited microsatellite instability, and none were gLOH-High (≥16%). Sixty-seven tumors had PD-L1 expression measurement, and 94% were negative. Potentially actionable variants including MTAP deletion (12/173, 5.8%) and activating PIK3CA mutations (23/423, 5.4%) were identified. TP53-mutated aGCT had a higher tumor mutational burden (mean 2.4 mut/Mb, 95% CI 1.7-3.0 mut/Mb vs mean 1.7 mut/Mb, 95% CI 1.5-1.9 mut/Mb; P = .02) and higher gLOH score (mean 4.4%, 95% CI 2.7-6.1% vs mean 1.4%, 95% CI 1.2-1.6%; P = .002) than TP53 non-mutated tumors.
No women with molecularly defined aGCT in this large cohort would be eligible for FDA-approved pembrolizumab based on either microsatellite instability or high tumor mutational burden. TP53 mutation identified a subset of this tumor type with distinct molecular features. The development of precision treatment options remains a critical unmet need for this rare disease.
Publication Date: 2021-07-10
Journal: Gynecologic oncology
Combined Histopathologic Risk Score using TP53 Protein Expression, CD8+ T-cell Density, and Intratumoural Budding is an Independent Predictor of Neoadjuvant Therapy Response in Rectal Adenocarcinoma.
Neoadjuvant therapy is the recommended treatment for locally advanced rectal adenocarcinoma; however, there remains significant variability in response to therapy. TP53 has been associated with therapy response and prognosis with conflicting data. Recently, we demonstrated that immune cell density and intratumoural budding (ITB) are predictive factors in rectal cancer. We investigated the predictive value of TP53 immunohistochemistry with CD8+ T-cell density and ITB on pre-treatment biopsies of rectal adenocarcinoma for response to neoadjuvant therapy.
Pre-treatment biopsies of rectal adenocarcinoma from 117 patients with neoadjuvant therapy were analyzed for TP53 expression by immunohistochemistry, ITB, CD8+ T-cell density, and mismatch repair protein (MMR) status. Most rectal adenocarcinomas displayed aberrant TP53 expression (86/117, 74%). Compared to TP53 wild-type, aberrant TP53 expression was associated with proficient MMR status (P=0.003) and low CD8+ T-cell density (P=0.001). Aberrant TP53 was significantly associated with a partial to poor response to neoadjuvant therapy (OR=2.42, 95% CI 1.04-5.62, P=0.04). A combined histopathologic risk score (HRS) was created using CD8+ T-cell density, ITB, and TP53 expression. Patients were separated into low (0-1 factors) and high (2-3 factors) HRS categories. In the multivariable model, patients with a high HRS were 3.25-fold more likely to have a partial or poor response to neoadjuvant therapy (95% CI 1.48-7.11, P=0.003).
Our study demonstrates that aberrant TP53 expression, high ITB, and low CD8+ T-cell density in pre-treatment biopsies can help predict response to neoadjuvant therapy. These biomarkers may be helpful in identifying patients at risk for therapy resistance.
Publication Date: 2021-06-15
Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification.
Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER-) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR-/ER + , PR-/ER-) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04-0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14-5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours-which are typically CTNNB1-mutant and TP53 wild-type-experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.
Publication Date: 2021-06-04
Journal: NPJ precision oncology
Overexpression of NOP58 as a Prognostic Marker in Hepatocellular Carcinoma: A TCGA Data-Based Analysis.
NOP58 ribonucleoprotein, a core component of box C/D small nucleolar ribonucleoproteins, is involved in various cell physiological processes. However, its role in hepatocellular carcinoma (HCC) remains very unclear. We aim to investigate NOP58 expression and its probable prognostic value in patients with HCC based on The Cancer Genome Atlas (TCGA) database.
RNA sequencing data and clinicopathological characteristics of patients with HCC were collected from TCGA database. Expression of NOP58 in HCC tissues and normal tissues was analyzed by Wilcoxon rank-sum test. Patients were divided into high and low subgroups according to median expression of NOP58. Logistic regression, gene set enrichment analysis (GSEA), and single-sample gene set enrichment analysis (ssGSEA) were conducted to annotate biological function and immune infiltration of NOP58.
NOP58 was significantly overexpressed in HCC tissues and correlated with significantly high tumor stage [odds ratio (OR) 10.01, 95% confidence interval (CI) 10.01-10.03; P = 0.003], advanced pathologic stage (OR 10.02, 95% CI 10.01-10.03; P < 0.001), advanced histologic stage (OR 10.03, 95% CI 10.02-10.04; P < 0.001), vascular invasion (OR 10.02, 95% CI 10.01-10.03; P = 0.003), poor performance status (OR 10.01, 95% CI 10.01-10.03; P = 0.003), and Mut-TP53 status (OR 10.02, 95% CI 10.01-10.03; P < 0.001). Elevated NOP58 expression had poor disease-specific survival (DSS; P < 0.001), progression-free interval (P = 0.006), and overall survival (OS; P < 0.001). NOP58 expression was independently correlated with OS (HR 1.731, 95% CI 10.037-2.890; P = 0.036). GSEA demonstrated that various cell cycle pathways along with RB-1 pathway, interleukin-10 signaling, regulation of TP53 activity, and P53 downstream pathway were differentially enriched in NOP58 high expression phenotype. NOP58 expression was positively correlated with infiltrating the levels of T helper type 2 (Th2) cells.
Overexpression of NOP58 is negatively correlated with overall survival in patients with HCC and might be a potential biomarker for prognosis of HCC.
Publication Date: 2021-05-21
Journal: Advances in therapy
The Association of Aging-Related Polymorphisms with Susceptibility to Lung Cancer: A Case-Control Study in a Japanese Population.
Telomere length is associated with cancer as well as aging. Telomerase reverse transcriptase (TERT), telomere RNA component (TERC) and oligonucleotide/oligosaccharide-binding fold containing 1 (OBFC1) are known to be involved in telomere length regulation. The tumor suppressor p53 (TP53), which has been shown to interact with tumor protein p53-binding protein 1 (TP53BP1), is implicated in the response to telomere shortening and aging. Polymorphisms in the TP53 and TP53BP1 genes are associated with various types of cancer. The aim of this study is to evaluate the impact of aging-related polymorphisms on lung cancer risk.
This case-control study consists of 462 lung cancer cases and 379 controls from Japan. We examined the effect of TERT rs2736100, TERC rs1881984, OBFC1 rs11191865, TP53 rs1042522 and TP53BP1 rs560191 on the risk of lung cancer using a Taq-Man real-time PCR assay. Unconditional logistic regression was used to assess the adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
None of the main effects of any of the telomere-related polymorphisms were related to the risk of lung cancer. Similarly, none of the interactive effects of any of the telomere-related polymorphisms with smoking were associated with lung cancer risk. The significant multiplicative interaction between TERT rs2736100 and TP53BP1 rs560191 was statistically significant (OR for interaction = 0.34, 95% CI = 0.14-0.84). The multiplicative interaction between OBFC1 rs11191865 and TP53BP1 rs560191 was also statistically significant (OR for interaction = 2.44, 95% CI = 1.02-5.87) but the OR for interaction was in the opposite direction.
Our findings indicate that TP53BP1 rs560191 may predispose to lung cancer risk depending on the genotypes of telomere-related polymorphisms. Additional studies are warranted to confirm the findings suggested in the present study.
Publication Date: 2021-04-29
Journal: Asian Pacific journal of cancer prevention : APJCP
Germline mutations and age at onset of lung adenocarcinoma.
To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset.
The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model.
Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking.
Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.
Publication Date: 2021-04-16
Distinct genomic landscapes of gastroesophageal adenocarcinoma depending on PD-L1 expression identify mutations in RAS-MAPK pathway and TP53 as potential predictors of immunotherapy efficacy.
The impact of molecular alterations on programmed death-ligand 1 (PD-L1) combined positive score (CPS) is not well studied in gastroesophageal adenocarcinomas (GEAs). We aimed to characterize genomic features of tumors with different CPSs in GEAs.
Genomic alterations of 2518 GEAs were compared in three groups (PD-L1 CPS ≥ 10, high; CPS = 1-9, intermediate; CPS < 1, low) using next-generation sequencing. We assessed the impact of gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) and tumor immune environment based on the Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases.
High, intermediate, and low CPSs were seen in 18%, 54% and 28% of GEAs, respectively. PD-L1 positivity was less prevalent in women and in tissues derived from metastatic sites. PD-L1 CPS was positively associated with mismatch repair deficiency/microsatellite instability-high, but independent of tumor mutation burden distribution. Tumors with mutations in KRAS, TP53, and RAS-mitogen-activated protein kinase (MAPK) pathway were associated with higher PD-L1 CPSs in the mismatch repair proficiency and microsatellite stability (pMMR&MSS) subgroup. Patients with RAS-MAPK pathway alterations had longer overall survival (OS) from ICIs compared to wildtype (WT) patients [27 versus 13 months, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.19-0.7, P = 0.016] and a similar trend was observed in the MSS subgroup (P = 0.11). In contrast, patients with TP53 mutations had worse OS from ICIs compared to TP53-WT patients in the MSS subgroup (5 versus 21 months, HR = 2.39, 95% CI: 1.24-4.61, P = 0.016).
This is the largest study to investigate the distinct genomic landscapes of GEAs with different PD-L1 CPSs. Our data may provide novel insights for patient selection using mutations in TP53 and RAS-MAPK pathway and for the development of rational combination immunotherapies in GEAs.
Publication Date: 2021-04-03
Journal: Annals of oncology : official journal of the European Society for Medical Oncology
Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: a biomarker analysis of a multicenter international trial.
Plasma tumor DNA fraction is prognostic in metastatic cancers. This could improve risk stratification before commencing a new treatment. We hypothesized that a second sample collected after one cycle of treatment could refine outcome prediction of patients identified as poor prognosis based on plasma DNA collected pre-treatment.
Plasma DNA [128 pre-treatment, 134 cycle 2 day 1 (C2D1), and 49 progression] from 151 chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) patients in a phase II study of abiraterone acetate (NCT01867710) were subjected to custom targeted next-generation sequencing covering exons of these genes: TP53, AR, RB1, PTEN, PIK3CA, BRCA1, BRCA2, ATM, CDK12, CHEK2, FANCA HDAC2 and PALB2. We also captured 1500 pan-genome regions enriched for single nucleotide polymorphisms to allow detection of tumor DNA using the rolling B-allele method. We tested associations with overall survival (OS) and progression-free survival (PFS).
Plasma tumor DNA detection was associated with shorter OS [hazard ratio (HR): 2.89, 95% confidence intervals (CI): 1.77-4.73, P ≤ 0.0001] and PFS (HR: 2.05; 95% CI: 1.36-3.11, P < 0.001). Using a multivariable model including plasma tumor DNA, patients who had a TP53, RB1 or PTEN gene alteration pre-treatment and at C2D1 had a significantly shorter OS than patients with no alteration at either time point (TP53: HR 7.13, 95% CI 2.37-21.47, P < 0.001; RB1: HR 6.24, 95% CI 1.97-19.73, P = 0.002; PTEN: HR 11.9, 95% CI 3.6-39.34, P < 0.001). Patients who were positive pre-treatment and converted to undetectable had no evidence of a difference in survival compared with those who were undetectable pre-treatment (P = 0.48, P = 0.43, P = 0.5, respectively). Progression samples harbored AR gain in all patients who had gain pre-treatment (9/49) and de novo AR somatic point mutations were detected in 8/49 patients.
Plasma gene testing after one cycle treatment refines prognostication and could provide an early indication of treatment benefit.
Publication Date: 2021-04-02
Journal: Annals of oncology : official journal of the European Society for Medical Oncology
High mutation burden in the checkpoint and micro-RNA processing genes in myelodysplastic syndrome.
A number of sequencing studies identified the prognostic impact of somatic mutations in myelodysplastic syndrome (MDS). However the majority of them focused on methylation regulation, apoptosis and proliferation genes. Despite the number of experimental studies published on the role of micro-RNA processing and checkpoint genes in the development of MDS, the clinical data about mutational landscape in these genes is limited. We performed a pilot study which evaluated mutational burden in these genes and their association with common MDS mutations. High prevalence of mutations was observed in the genes studied: 54% had mutations in DICER1, 46% had mutations in LAG3, 20% in CTLA4, 23% in B7-H3, 17% in DROSHA, 14% in PD-1 and 3% in PD-1L. Cluster analysis that included these mutations along with mutations in ASXL1, DNMT3A, EZH2, IDH1, RUNX1, SF3B1, SRSF2, TET2 and TP53 effectively predicted overall survival in the study group (HR 4.2, 95%CI 1.3-13.6, p = 0.016). The study results create the rational for incorporating micro-RNA processing and checkpoint genes in the sequencing panels for MDS and evaluate their role in the multicenter studies.
Publication Date: 2021-03-18
Journal: PloS one
Endometrial Cancer Risk in Women with Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.
Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain, therefore we assessed this in a large Dutch nationwide cohort study.
5,980 BRCA1/2 (3,788 BRCA1, 2,151 gBRCA2, 41 both BRCA1/BRCA2) and 8,451 non-BRCA1/2 mutation carriers were selected from the HEBON-cohort. Follow-up started at date of nationwide PALGA coverage (January 1, 1989) or at the age of 25 years (whichever came last), and ended at date of EC diagnosis, last follow-up or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared to: 1) general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were two-sided.
Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119,296 and 160,841 person-years, respectively (SIR = 2.83, 95% confidence interval (CI) = 2.18-3.65; and HR = 2.37, 95% CI = 1.53-3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61-4.72; HR = 2.91, 95% CI = 1.83-4.66), serous-like EC (SIR: 12.64, 95% CI = 7.62-20.96; HR = 10.48, 95% CI = 2.95-37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80-3.83; HR = 2.01, 95% CI = 1.18-3.45) and TP53-mutated EC (HR = 15.71, 95% CI = 4.62-53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01-2.87), and serous-like EC risks (SIR = 5.11, 95% CI = 1.92-13.63) were increased when compared to the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%).
BRCA1/2 mutation carriers have a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.
Publication Date: 2021-03-13
Journal: Journal of the National Cancer Institute
Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.
This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1).
Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal.
EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007).
We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC.
Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.
Publication Date: 2021-03-04
Journal: Cancer medicine
Role of next generation sequencing-based liquid biopsy in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: impact of STK11, KRAS and TP53 mutations and co-mutations on outcome.
Characterization of tumor-related genetic alterations is promising for the screening of new predictive markers in non-small cell lung cancer (NSCLC). Aim of the study was to evaluate prognostic and predictive role of most frequent tumor-associated genetic alterations detected in plasma before starting immune checkpoint inhibitors (ICIs).
Between January 2017 and October 2019, advanced NSCLC patients were prospectively screened with plasma next-generation sequencing (NGS) while included in two trials: VISION (NCT02864992), using Guardant360
A total of 103 patients receiving ICIs were analyzed: median overall survival (OS) was 20.8 (95% CI: 16.7-24.9) months and median immune-related progression free disease (irPFS) 4.2 (95% CI: 2.3-6.1) months. TP53 mutations in plasma negatively affected OS both in patients treated with ICIs and in control group (P=0.001 and P=0.009), indicating a prognostic role. STK11 mutated patients (n=9) showed a trend for worse OS only if treated with ICIs. The presence of KRAS/STK11 co-mutation and KRAS/STK11/TP53 co-mutation affected OS only in patients treated with ICIs (HR =10.936, 95% CI: 2.337-51.164, P=0.002; HR =17.609, 95% CI: 3.777-82.089, P<0.001, respectively), indicating a predictive role.
Plasma genotyping demonstrated prognostic value of TP53 mutations and predictive value of KRAS/STK11 and KRAS/STK11/TP53 co-mutations.
Publication Date: 2021-02-12
Journal: Translational lung cancer research
Correlation of mutational landscape and survival outcome of peripheral T-cell lymphomas.
To explore the correlation of mutation landscape with clinical outcomes in patients with peripheral T-cell lymphoma (PTCL).
We retrospectively analyzed the clinicopathological and prognosis data of 53 patients with PTCL from November 2011 to December 2017. Targeted next-generation sequencing of a 659-gene panel was performed for tissues from 53 patients with PTCLs. The correlation of mutation landscape with clinical outcomes was analyzed.
TET2 was the most frequently mutated gene (64%), followed by RHOA (43%), PCLO (23%), DNMT3A (19%), IDH2 (17%), PIEZO1 (17%) and TP53 (15%). When mutated genes were categorized into functional groups, the most common mutations were those involved in epigenetic/chromatin modification (75%), T-cell activation (74%), and the DNA repair/TP53 pathway (64%). TET2/TP53 mutations were significantly associated with positive B symptoms (P = 0.045), and elevated lactate dehydrogenase (LDH) level (P = 0.011). Moreover, TET2/TP53 mutation was a risk factor for PTCL patient survival (HR 3.574, 95% CI 1.069 - 11.941, P = 0.039). The occurrence of JAK/STAT pathway mutations in angioimmunoblastic T-cell lymphoma (AITL) patients conferred a worse progression-free survival (HR 2.366, 95% CI 0.9130-6.129, P = 0.0334).
Heterogeneous gene mutations occur in PTCL, some of which have a negative impact on the survival outcome.
Publication Date: 2021-02-07
Journal: Experimental hematology & oncology
Mutated p53 portends improvement in outcomes when bevacizumab is combined with chemotherapy in advanced/recurrent endometrial cancer: An NRG Oncology study.
Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.
TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.
Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.
This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.
Publication Date: 2021-02-06
Journal: Gynecologic oncology
Real-world outcomes following venetoclax therapy in patients with chronic lymphocytic leukemia or Richter syndrome: a FILO study of the French compassionate use cohort.
The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.
Publication Date: 2021-01-27
Journal: Annals of hematology
A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma.
Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence.
To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system.
This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018.
The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model.
Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation.
The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.
Publication Date: 2020-12-24
Journal: JAMA surgery
RAS/TP53 co-Mutation is Associated with Worse Survival after Concurrent Resection of Colorectal Liver Metastases and Extrahepatic Disease.
To determine if tumor genetics are associated with overall survival (OS) after concurrent resection of colorectal liver metastases (CLM) and extrahepatic disease (EHD).
The prognosis for patients who undergo concurrent resection of CLM/EHD is unclear and the impact of somatic mutations has not been reported.
Patients undergoing concurrent resection of CLM and EHD from 2007-2017 were identified from two academic centers. From 1 center, patients were selected from a pre-existing database of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). The Kaplan-Meier method was used to construct survival curves, compared using the log-rank test. Multivariable Cox analysis for OS was performed.
One hundred nine patients were included. Most common EHD sites included lung (33 patients), peritoneum (32), and portal lymph nodes (14). TP53 mutation was the most common mutation, identified in 75 patients (69%), and RAS/TP53 co-mutation was identified in 31 patients (28%). The median OS was 49 months (IQR, 24-125), and 3- and 5-year OS rates were 66% and 44%, respectively. Compared to patients without RAS/TP53 co-mutation, patients with RAS/TP53 co-mutation had lower median OS: 39 vs. 51 months (P = .02). On multivariable analysis, lung EHD (hazard ratio [HR], 0.7; 95% CI, 0.3-1.4), peritoneal EHD (HR, 2.2; 95% CI, 1.1-4.2) and RAS/TP53 co-mutation (HR, 2.8; 95% CI, 1.1-7.2) were independently associated with OS.
RAS/TP53 co-mutation is associated with worse OS after concurrent CLM/EHD resection. Mutational status and site of EHD should be included in the evaluation of patients considered for concurrent resection.
Publication Date: 2020-12-23
Journal: Annals of surgery
Discovery and Validation of Serum Autoantibodies Against Tumor-Associated Antigens as Biomarkers in Gastric Adenocarcinoma Based on the Focused Protein Arrays.
Previous studies have demonstrated that autoantibodies against tumor-associated antigens (TAAs) in patients with cancer can be used as sensitive immunodiagnostic biomarkers for the detection of cancer. Most of these TAAs are involved in the tumorigenesis pathway. Cancer driver genes with intragenic mutations can promote tumorigenesis. This study aims to identify autoantibodies against TAAs encoded by cancer driver genes in sera as potential immunodiagnostic biomarkers for gastric adenocarcinoma (GAC).
Protein arrays based on cancer driver genes were customized for screening candidate TAAs in 100 GAC sera and 50 normal control (NC) sera. Autoantibodies against candidate TAAs were assessed by enzyme-linked immunosorbent assay in both training group (205 GAC sera and 205 NC sera) and independent validation group (126 GAC sera and 126 NC sera). Moreover, the immunodiagnostic models were respectively established and validated in the training group and validation group.
A panel with 5 autoantibodies including anti-TP53, anti-COPB1, anti-GNAS, anti-serine/arginine-rich splicing factor 2, and anti-SMARCB1 was selected by the Fisher linear discriminant analysis model with an areas under receiver operating characteristic curve (AUC) of 0.928 (95% confidence interval [CI]: 0.888-0.967) in the training cohort and an AUC of 0.885 (95% CI: 0.852-0.918) in the validation cohort. Besides, the panel with 5 autoantibodies including anti-TP53, anti-COPB1, anti-GNAS, anti-PBRM1, and anti-ACVR1B which were selected by the binary logistic regression model showed an AUC of 0.885 (95% CI: 0.852-0.919) in the training cohort and 0.884 (95% CI: 0.842-0.925) in the validation cohort.
Two panels which were selected in this study could boost the detection of anti-TAA autoantibodies in sera as biomarkers for the detection of GAC.
Publication Date: 2020-12-22
Journal: Clinical and translational gastroenterology
Distinct Genomic Profiles are Associated With Conversion to Resection and Survival in Patients With Initially Unresectable Colorectal Liver Metastases Treated With Systemic and Hepatic Artery Chemotherapy.
To examine genomic correlates of CTR and overall survival (OS) in patients with IU-CRLM treated with combination systemic and hepatic artery infusion (HAI) chemotherapy.
In patients presenting with IU-CRLM, combination systemic and HAI chemotherapy enables CTR with associated long-term OS in a subset of patients. Genomic correlates of CTR and OS in IU-CRLM have not been previously explored.
Specimens from IU-CRLM patients receiving systemic/HAI chemotherapy (2003-2017) were submitted for next-generation sequencing. Fisher Exact test assessed associations with CTR, and Kaplan-Meier/Cox methods assessed associations with OS from HAI initiation.
Of 128 IU-CRLM patients, 51 (40%) underwent CTR at median 6 months (range: 3-35) from HAI initiation. CTR and persistently unresectable cohorts differed significantly in preoperative systemic chemotherapy exposure, node-positive primary status, and size of largest liver metastasis. Median and 5-year OS was 66 months and 51%. CTR was associated with prolonged survival (time-dependent HR 0.23, 95% CI: 0.12-0.46, P < 0.001). The most frequently altered genes were APC (81%), TP53 (77%), and KRAS (37%). Oncogenic mutations in SOX9 and BRAF were associated with CTR. BRAF mutations, any RAS pathway alterations, and co-altered RAS/RAF-TP53 mutations were associated with worse survival. Classification and regression tree analysis defined prognostically relevant clusters of genomic risk to reveal co-altered RAS/RAF-TP53 as the highest risk subgroup. Co-altered RAS/RAF-TP53 remained independently associated with worse survival (HR 2.52, 95% CI: 1.37-4.64, P = 0.003) after controlling for CTR, number of liver metastases, and preoperative extrahepatic disease.
Distinct genomic profiles are associated with CTR and survival in patients with IU-CRLM treated with HAI/systemic chemotherapy. Presence of SOX9, BRAF, and co-altered RAS/RAF-TP53 mutations are promising biomarkers that, when validated in larger datasets, may impact treatment of IU-CRLM patients.
Publication Date: 2020-11-21
Journal: Annals of surgery