Impact Of Somatic Mutations Research Articles

P199. Impact of somatic mutations on survival and neurological outcomes in spinal metastases from breast cancer

P199. Impact of somatic mutations on survival and neurological outcomes in spinal metastases from breast cancer

P200. Impact of somatic mutations on survival and neurological outcomes in spinal metastases from lung cancer

P200. Impact of somatic mutations on survival and neurological outcomes in spinal metastases from lung cancer

ADAMTS13, von Willebrand Factor, Platelet Microparticles, Factor VIII, and Impact of Somatic Mutations in the Pathogenesis of Splanchnic Vein Thrombosis Associated with BCR-ABL-Negative Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) are often associated with splanchnic vein thrombosis (SVT). Not all the factors involved in the thrombotic tendency are currently known. This study aims to evaluate a possible association between ADAMTS13, von Willebrand factor (VWF), platelet microvesicles (MV), and factor VIII activity (FVIII:C) with thrombotic events in MPN patients. In total, 36 consecutive MPN patients with SVT were enrolled. The MPNs were diagnosed based on clinical characteristics and one or more gene mutations among JAK-2, CALR, and MPL. As controls, 50 randomly selected patients with MPN without thrombosis, 50 patients with deep vein thrombosis without MPNs, and 50 healthy blood donors were evaluated. Complete blood count, ADAMTS13, VWF, MV, and FVIII:C in plasma were measured in all the subjects. The JAK-2 mutation was found in 94% of the patients with SVT, but none were triple-negative for genetic mutations (JAK2 V617F, CALR, MPL, and exon 12). Compared to the normal subjects, in all the MPN patients (with or without SVT), the levels of ADAMTS13 were found to be significantly lower (p < 0.001) and the MV concentrations were significantly higher (p < 0.001). Among the MPN patients, the VWF and FVIII:C levels were significantly higher in the patients with SVT than those without thrombosis (p = 0.007 and p = 0.04, respectively). Splenomegaly was present in 78% of MPN patients with SVT and in 30% of those without SVT (p < 0.001). The ADAMTS13/VWF ratio was reduced in all the patients, but not in the healthy blood donors (p < 0.001). The significant increase in circulating MV, VWF, and FVIII:C in the MPN patients and in the patients with thrombosis supports the role of endothelium damage in promoting thrombotic events. In particular, a significant increase in VWF and FVIII:C levels was found in the MPN patients with SVT.

Mutations in myeloid transcription factors and activated signaling genes predict chronic myeloid leukemia outcomes

AbstractAdvancements in genomics are transforming the clinical management of chronic myeloid leukemia (CML) toward precision medicine. The impact of somatic mutations on treatment outcomes is still under debate. We studied the association of somatic mutations in epigenetic modifier genes and activated signaling/myeloid transcription factors (AS/MTFs) with disease progression and treatment failure in patients with CML after tyrosine kinase inhibitor (TKI) therapy. A total of 394 CML samples were sequenced, including 254 samples collected at initial diagnosis and 140 samples taken during follow-up. Single-molecule molecular inversion probe (smMIP)–based next-generation sequencing (NGS) was conducted targeting recurrently mutated loci in 40 genes, with a limit of detection of 0.2%. Seventy mutations were detected in 57 diagnostic samples (22.4%), whereas 64 mutations were detected in 39 of the follow-up samples (27.9%). Carrying any mutation at initial diagnosis was associated with worse outcomes after TKI therapy, particularly in AS/MTF genes. Patients having these mutations at initial diagnosis and treated with imatinib showed higher risks of treatment failure (hazard ratio, 2.53; 95% confidence interval, 1.13-5.66; P = .0239). The adverse prognostic impact of the mutations was not clear for patients treated with second-generation TKIs. The multivariate analysis affirmed that mutations in AS/MTF genes independently serve as adverse prognostic factors for molecular response, failure-free survival, and progression risk. Additionally, there was an observable nonsignificant trend indicating a heightened risk of progression to advanced disease and worse overall survival. In conclusion, mutations in the AS/MTF genes using smMIP-based NGS can help identify patients with a potential risk of both treatment failure and progression and may help upfront TKI selection.

Genomic determinants of progression-free survival after second line of therapy (PFS-2) for patients on immunotherapy-based combination therapies for advanced clear cell renal cell carcinoma.

4545 Background: The role of somatic genomic mutations in predicting outcomes in clear cell renal cell carcinoma (ccRCC) is poorly defined. Both ipilimumab/nivolumab (IO/IO) and several combinations of VEGFR-targeted tyrosine kinase inhibitor (TKI/IO) are preferred first-line treatment options for metastatic ccRCC. The impact of somatic mutations on PFS-2 for IO combination therapies was evaluated in this retrospective analysis. Methods: One-hundred forty-one patients with ccRCC had sequencing with MSK-IMPACT and initiated 1st line combination IO at Memorial Sloan Kettering (MSK) Cancer Center between 1/1/2014 and 12/30/2020. Treatment groups are defined as IO/IO (n=76) and TKI/IO (n=65). PFS-2 is defined as time from start of 1st line to progression on next therapy, or death, and is estimated using Kaplan-Meier method. PFS-2 association with each mutation was assessed via log-rank test and a model-based approach. Restricted mean survival time (RMST) up to 48 months was calculated for PFS-2 and modeled using a generalized linear model adjusted for IMDC risk. To test for heterogeneity of effect among treatment groups, an interaction test between somatic mutation and treatment group is performed in the model. Results: VHL, PBRM1, SETD2, mTOR pathway, BAP1, and TP53 were the most common somatic mutations. Only BAP1 was significantly associated with PFS-2: median PFS-2 was 44 months for patients without BAP1 mutation and 17 months for patients with BAP1 mutation (log-rank p=0.006). After adjusting for IMDC risk group, 48 month RMST for PFS-2 was 13 months lower in patients with BAP1 mutation. An interaction test performed in the RMST model showed no significant variation in the treatment effect of IO/IO or TKI/IO based on the presence or absence of BAP1 mutation (p=0.97), although sample size limits power to detect differences. Results for other somatic mutations are shown. Conclusions: PFS-2 was significantly inferior for ccRCC patients with somatic BAP1 mutation treated with IO-based therapy. Interaction test did not suggest a significant advantage for IO/IO or TKI/IO for mutation-present or -absent groups. Clinical stratification remains key for selecting TKI/IO or IO/IO for patients. [Table: see text]

Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) uniformly present with aggressive disease, but the mutational landscape of tumors varies. We aimed to determine whether tumor mutations affect survival outcomes in ATC. Patients who underwent mutation sequencing using targeted gene panels between 2005 and 2019 at a tertiary referral center were included. Associations between mutation status and survival outcomes were assessed using Cox proportional hazards models. A total of 202 patients were included, where 122 died of ATC (60%). The median follow-up was 31 months (interquartile range, 18-45 months). The most common mutations were in TP53 (59%), BRAF (41%), TERT promoter (37%), and the RAS gene family (22%). Clinicopathologic characteristics and overall survival (OS) significantly correlated with mutations in BRAFV600E and RAS, which were mutually exclusive. The BRAFV600E mutation was associated with the presence of a papillary thyroid carcinoma precursor and significantly better OS (median OS: 24 months). RAS-mutated patients more commonly presented without cervical lymph node involvement but had the worst OS (median OS: 6 months). Tumors that were wild-type for both BRAF and RAS were enriched for NF1 mutations and harbored intermediate prognosis (median OS: 15 months). In multivariate analyses, RAS mutations were associated with a more than 2.5-fold higher risk of death (adjusted hazard ratio, 2.64; 95% CI, 1.66 to 4.20) compared with BRAFV600E. In patients treated with BRAF-directed therapy (n = 60), disease progression occurred in 48% of patients (n = 29). The median progression-free survival was 14 months. The presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy (adjusted hazard ratio, 2.89; 95% CI, 1.35 to 6.21). Mutation analysis provides prognostic information in ATC and should be incorporated into routine clinical care.

Functional impact of somatic mutations in early-onset (EO) versus average onset (AO) microsatellite stable (MSS) stage III colorectal cancer (CRC).

3613 Background: Analysis of the IDEA database demonstrates significantly worse disease-free survival in high-risk stage III EO CRC vs AO CRC, regardless of adjuvant therapy intensity or duration. Critically this analysis omits somatic mutational data and germline status. Enrichment of TP53 in EO metastatic CRC (mCRC) is well described and functionality of individual TP53 mutations has been proposed as a potential mechanism of chemotherapy resistance. The prognostic and functional impact of somatic mutations merits analysis in the EO high-risk Stage III cohort. Methods: The Memorial Sloan Kettering MSKCC IMPACT database was queried for MSS Stage III AO CRC (≥50 yrs) and EO CRC ( &lt; 50 yrs) patients(pts); clinico-pathological characteristics, systemic therapies received, and survival outcomes were reviewed. MSI, POLE mutated or hereditary syndrome associated tumors were excluded. We further classified TP53 mutations as GOF (gain of function) versus non GOF/ LOF (loss of function) (Pan M, JCO. 2022, Muller PA, Cancer cell. 2014). Results: 272 pts were included in the analysis (EO = 184, AO = 88). 50% of the EO and 62.5 % of the AO cohorts were male. Tumors were predominantly adenocarcinoma (EO 89% vs AO 91%), moderately differentiated (EO 78% vs AO 74%) and left sided (EO 77% vs AO 48.8%). 87% of the EO and 63.6 % of the AO cohort were TP53mut (p value 0.0003); TP53mut was enriched in the EO cohort regardless of sidedness but there was no significant difference in TP53 mutations between EO high vs low risk. Classifying by 7 putative GOF mutations (R175H, R248Q/W, R249S, R273H/L and R282W) 28.7% of the EO cohort harbored a GOF mutation vs 19.6% of the AO cohort. There was no statistically significant survival difference between pts with TP53mut tumors vs TP53 wild type (TP53wt) in the entire cohort (AO+EO) (p 0.041) or EO or AO cohorts (p 0.049). There was no significant difference in survival outcomes across all cohorts of TP53mut groups, both high and low risk, both GOF and non GOF, treated with 3 vs 6 months of chemotherapy (p 0.67). The EO TP53wt group was enriched relative to the EO TP53mut group for KRAS (60% vs 32%), BRAF (11% vs 4%), and PI3K driver alterations (PIK3CA, 20% vs 13%) and PTEN: (8% vs 3%) In the multivariate survival analysis of EO Stage III CRC BRAFmut status is highly statistically significant (p &lt; 0.001). Conclusions: EO Stage III CRC is enriched for TP53 mutations regardless of sidedness and GOF mutations are identified in a higher proportion of EO CRC than AO CRC. We found no statistically significant difference in survival by TP53mut status across the entire MSS Stage III CRC cohort. There was no interaction between TP53mut status, duration of chemotherapy and overall survival. The functional impact of additional molecular features is being explored and the novel prognostic significance of BRAF demonstrated in this EO Stage III cohort requires further validation.

Enhancing our chances of picking a winner in higher-risk myelodysplastic syndromes.

Hypomethylating agents remain the current standard of care for patients with higher-risk myelodysplastic syndromes. Adès et al. report outcomes from a randomised 'pick-a-winner' study design that examined the addition of either lenalidomide, valproic acid or idarubicin in combination with azacitidine, compared to azacitidine alone. Commentary on: Adès et al. A randomised phase II study of azacitidine (AZA) alone or with lenalidomide (LEN), valproic acid (VPA) or idarubicin (IDA) in higher-risk MDS: GFM's 'pick a winner' trial, with the impact of somatic mutations. Br J Haematol 2022;198:535-544.

Impact of somatic mutations on clinical and pathologic outcomes in borderline resectable and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and stereotactic body radiotherapy followed by surgical resection.

PurposeThe purpose of this study was to determine if somatic mutations are associated with clinical and pathologic outcomes in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT). Materials and MethodsPatients treated with neoadjuvant chemotherapy and SBRT followed by surgical resection from August 2016 to January 2019 and who underwent next generation sequencing of their primary tumor were included in the study. Next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and pathologic and clinical outcomes. ResultsThirty-five patients were included in the study. Chemotherapy consisted of modified FOLFIRINOX, gemcitabine and nab-paclitaxel, or gemcitabine and capecitabine. Patients were treated with SBRT in 33 Gy in 5 fractions. On UVA and MVA, tumors with KRAS G12V mutation demonstrated better pathologic tumor regression grade (TRG) to neoadjuvant therapy when compared to tumors with other KRAS mutations (odds ratio = 0.087; 95% confidence interval [CI], 0.009–0.860; p = 0.036). On UVA and MVA, mutations in NOTCH1/2 were associated with worse overall survival (hazard ratio [HR] = 4.15; 95% CI, 1.57–10.95; p = 0.004) and progression-free survival (HR = 3.61; 95% CI, 1.41–9.28; p = 0.008). On UVA, only mutations in NOTCH1/2 were associated with inferior distant metastasis-free survival (HR = 3.38; 95% CI, 1.25–9.16; p = 0.017). Conclusion In BRPC and LAPC, the KRAS G12V mutation was associated with better TRG following chemotherapy and SBRT. Additionally, NOTCH1/2 mutations were associated with worse overall survival, distant metastasis-free survival, and progression-free survival.

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 to 2017 were identified from 2 academic centers. From 1 center, patients were selected from a pre-existing database of patients undergoing cytore-ductive surgery with hyperthermic intraperitoneal chemotherapy. 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 (interquartile range, 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 = 0.02). On multivariable analysis, lung EHD [hazard ratio (HR), 0.7; 95% confidence intervals (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.

Prevalence and prognostic impact of somatic mutations in patients with heart failure and reduced ejection fraction

Abstract Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF&amp;lt;45%). The presence of somatic mutations was assessed using next generation sequencing (Illumina HiSeq 2500), with a mutated allelic fraction of at least 2% and a panel of 55 genes related with clonal hematopoiesis. Patients were followed-up for a median of three years. The study endpoint was a composite of death or readmission for worsening HF. Kaplan-Meier analysis (log-rank test) and Cox proportional hazards regression models were performed adjusting for age, sex and LVEF. Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

Impact of Somatic Mutations in Non-Small-Cell Lung Cancer: A Retrospective Study of a Chinese Cohort.

BackgroundSomatic mutations are important biomarkers for selecting an optimal targeted therapy and predicting outcomes for non-small-cell lung cancer (NSCLC) patients that are often detected from tissue samples. However, tissue samples are not always readily available from these patients. The exploration of using circulating tumor DNA (ctDNA) to identify somatic mutations offers an alternative source that should be explored.MethodsIn this retrospective study, we included 280 patients diagnosed with adenocarcinoma between 2017 and 2018 in a hospital in eastern China. Tissue or ctDNA was collected, and a wide spectrum of somatic mutations was analyzed by targeted next-generation sequencing platforms. Associations among the mutation status, biomarkers, screening methods, disease stages, and interaction with treatment with overall survival (OS) were investigated.ResultsWe found that the EGFR L858R mutation was the most frequently identified mutation in adenocarcinoma in this population by both methods, followed by KRAS (p=3.7e-09), PIK3CA (p=5e-04), and HER2 mutations (p=6.3e-03). We observed that EGFR mutations were significantly mutually exclusive with KRAS, HER2, and MET. FGFR1 mutations were significantly more abundantly detected in the ctDNA group. We found an interaction effect between EGFR mutation and target therapies. The ability of the targeted therapy to improve OS in patients with a single EGFR mutation (HR=0.069, p=0.07) approached significance, but this was not the case for the patients with more than one EGFR mutation or without an EGFR mutation (HR=0.813, p=0.725). Furthermore, the effect of chemotherapy was more predominant in the EGFR group in comparison to the control group.ConclusionThese findings provide useful information on the distribution of somatic mutations via different screening methods and how this related to the optimal treatment selection in Chinese patients with NSCLC.

Impact of somatic mutations on response to lenalidomide in lower-risk non-del(5q) myelodysplastic syndromes patients

Impact of somatic mutations on response to lenalidomide in lower-risk non-del(5q) myelodysplastic syndromes patients

Identification of genomic aberrations associated with overall survival in metastatic clear cell renal cell carcinoma (mccRCC).

745 Background: Tumor comprehensive genomic profiling (CGP) in addition to risk stratification by IMDC criteria may aid in improving risk stratification. The objective of this study was to assess the prognostic impact of somatic mutations in addition to IMDC risk criteria. Methods: All patients with mccRCC treated with first line with VEGFR-TKI with CGP data available through a CLIA certified lab were included. Kaplan-Meier methodology and Cox proportional hazard ratios were used to test the association of overall survival with genomic alterations present in at least 7% of the population in this dataset. Genomic data were correlated with outcome by univariate analysis and subsequent multivariate testing, integrating genomic data with IMDC risk criteria. Results: A total of 58 patients met eligibly. The presence of any mutation in VHL, PBRM1, and MLL2 were prognostic in terms of overall survival (Table). The mutation status for these three prognostic genes was added to the IMDC risk model to test for the prognostic correlation. The mutations status of these 3 genes significantly correlated with overall survival (VHL: 0.32 [95% CI 0.11-0.95], PBRM1: 0.36 [0.14-0.96], and MLL2: 7.60 [1.35-24.6]) independent of the IMDC risk criteria. Conclusions: In mccRCC, VHL, PBRM1, and MLL2 mutations each predict overall survival independent of IMDC criteria. Further studies are warranted to assess alterations with low prevalence in this data set. Upon external validation, these data provide the rationale for integration of mutation status of these three genes in to the IMDC risk criteria.[Table: see text]

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7.

Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).

Impact of somatic mutations on prognosis in resected non‐small‐cell lung cancer: The Japan Molecular Epidemiology for lung cancer study

BackgroundTo report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non‐small‐cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival (RFS) and overall survival (OS).MethodsPatients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations.ResultsOf 876 patients, 172 had ≥2 somatic mutations. Median follow‐up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488‐2.695), age (≥70 vs <70 years, HR = 1.583, 95% CI: 1.229‐2.049), gender (male vs female, HR = 1.503, 95% CI: 1.045‐2.170) and pathological stage (II vs I, HR = 3.386, 95% CI: 2.447‐4.646; ≥III vs I, HR = 6.307, 95% CI: 4.680‐8.476) were significantly associated with RFS, while EGFR mutation (yes vs no, HR = 0.482, 95% CI: 0.309‐0.736), number of coexisting mutations (≥2 vs 0 or 1, HR = 1.695, 95% CI: 1.143‐2.467), age (≥70 vs <70 years, HR = 1.932, 95% CI: 1.385‐2.726), and pathological stage (II vs I, HR = 2.209, 95% CI: 1.431‐3.347; ≥III vs I, HR = 5.286, 95% CI: 3.682‐7.566) were also significant for OS.ConclusionA smaller number of coexisting mutations, earlier stage, and younger age were associated with longer RFS and OS, while EGFR mutations were significantly associated with improved OS.

Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Impact of Somatic Mutations on Outcome in Patients > 60 Years Old with Newly Diagnosed AML Treated with Response-Adapted Sequential Azacitidine and Induction Chemotherapy within the DRKS00004519 Trial (RAS-AZIC) of the East German Study Group of Hematology and Oncology (OSHO)

Introduction: Old age and unfavorable cytogenetics are well-established adverse prognostic factors for outcome in patients (pts) with AML. Recently, high-throughput sequencing techniques have identified multiple somatically acquired driver mutations (muts) with a strong prognostic impact in AML. We explored the relative contribution of baseline molecular genetics versus a response-based sequential treatment approach on response and overall survival (OS) at two years in pts &amp;gt;60 years (y) with newly diagnosed AML treated within the multicenter RAS-AZIC study of the OSHO. Patients and methods: In the RAS-AZIC trial, 112 pts received priming with Azacitidine (AZA) followed by a day (d) 15 bone marrow (BM) blast count-adapted sequential treatment with AZA or intensive chemotherapy (IC). Pts with d15 blasts ≥45% received IC. If the count was &amp;lt;45%, AZA was continued at d28. The second treatment adaptation was based on d56 response. If no complete remission (CR) or CR with incomplete recovery (CRi) were documented, IC was applied followed by AZA maintenance or allogeneic hematopoietic stem cell transplantation if a remission was achieved on d90. Conventional cytogenetics, NPM1, and FLT3 mutational screening were used for genetic risk stratification following the 2010 ELN recommendations. Response [CR/CRi/Partial remission (PR)] and treatment-related mortality on d90, the two-year OS, event-free survival (EFS), and relapse-free survival (RFS) were previously presented (Jaekel N, et al; ASH 2018). Baseline BMs of 77 pts who signed the translational informed consent were analyzed by NGS using the NEOmyeloid panel of NEO New Oncology (Siemens Healthineers Company, Germany). This hybrid capture-based assay comprises 43 genes and detects point muts, small insertions and deletions in 30 genes as well as gene fusions in 18 genes. Molecular results were correlated to outcome data. Results: Median age was 70y. Secondary AML was present in 39%. Genetic risk was int-II and adverse in 25% and 27% respectively. Response on d90 was 67% (CR/CRi 58%, PR 9%). A median of 3 muts per pt were found. Mutations in DNA methylation-related-, spliceosome complex-, and chromatin-modifying-genes were 62%, 39%, and 30% respectively. Overall, muts in DNMT3A (34%), ASXL1 (25%), RUNX1 (24%), SRSF2 (23%), and TET2 (23%) were the most frequently detected (fig. 1). As expected, 72% of SRSF2 muts were associated with ASXL1 and/or RUNX1 muts. CR/CRi in the favorable and int-I 2010 ELN genetic risk groups was 81% and 57.5% in int-II and adverse risk pts. With the exception of muts in spliceosome complex-related genes, the mutational status (including the FLT3 status) seemed to have no impact on response in this cohort (table 1). In the presence of splicing factor gene muts a trend towards an inferior response of 53% compared to 77% in pts without such a mut was observed. High risk muts such as ASXL1, RUNX1, and TP53 muts which were included in the 2017 ELN adverse risk stratification were present in 20/32 (63%) of pts with favorable and int-I genetic risk. Yet, only 5/32 (16%) did not achieve a response. Similarly, CR/CRi was achieved in 7/9 (78%) pts with TP53 mut which was associated with an adverse karyotype in 8 pts. Likewise, OS tended to be similar across all molecular classes with the exception of KMT2A gene fusions with their well-known negative impact on outcome. The presence of such a fusion (n=4) was associated with a median survival time of only 8 compared to 16 months in pts without a detectable KMT2A fusion. These KMT2A gene fusions also correlated with a shorter EFS and RFS. The presence of myeloid transcription factor gene muts such as in RUNX1 (24%) and BCOR (13%) tended to be associated with an inferior EFS, while cohesin complex- (STAG2 8%), tumour suppressor-, and DNA-methylation-related gene muts with a negative RFS (table 1). Conclusions: This explorative analysis with a limited number of patients describes the pattern of genetic mutations in elderly AML treated with a response-based sequential approach that integrates epigenetic and chemotherapeutic treatments and their association with outcome. Whether such a response-based treatment mitigates the negative impact of (some) high risk mutations on outcome needs to be addressed in a much larger trial. Disclosures Jaekel: Celgene: Other: travel grant. Siebolts:Merck: Honoraria; Boehringer Ingelheim: Honoraria; MSD: Honoraria; Pfizer: Honoraria; AstraZeneca: Honoraria; Roche: Honoraria; Novartis: Honoraria; BMS: Honoraria. Pazaitis:Novartis: Consultancy. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Hänel:Amgen: Honoraria; Roche: Honoraria; Novartis: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Heukamp:NEO New Oncology GmbH: Employment. Menon:NEO New Oncology GmbH: Employment. Bertrand:NEO New Oncology GmbH: Employment. Wickenhauser:BMS: Honoraria; Merck-Serono: Honoraria; MSD: Honoraria; Böhringer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Roche: Honoraria. Brosteanu:University Leipzig: Employment. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

Abstract 573: Mutations found by targeted next generation sequencing is associated with intra-tumor immune profile and may predict response to anti-PD1 therapy in lung adenocarcinoma

Abstract Purpose: the immune environment of cancer is the target of immunotherapies with programmed cell death 1 (PD-1) therapeutic antibodies. However, factors that can robustly predict long-lasting responses are still needed. Previous studies showed a role of cancer cells on immune response setting, but the impact of somatic mutations on the composition of the immune stroma is not fully characterized. Experimental Design: We characterized the immune profile of 221 lung adenocarcinomas using immunohistochemistry (CD8 T cells, Macrophages, neutrophils, PD-L1) and compare to tumor mutational status using targeted next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort of 31 lung carcinomas according to tumor mutational profiles and to tumor cell PD-L1 expression. Results: We report that distinct combinations of STK11, EGFR and TP53 mutations, allows the identification of immune cells combination and prediction of PD-L1 expression on tumor cells. Lung adenocarcinomas with the highest CD8 T cell density and PD-L1 expression were those with TP53 mutations without co-occurring STK11or EGFR alterations (TP53-mut/STK11-EGFR-WT), and independently of KRAS status. Interestingly in TP53-mut/STK11-EGFR-WT tumors, pathways related to T cell chemotaxis, immune cell cytotoxicity, and antigen processing were up-regulated. In accordance with these results we found a prolonged progression-free survival (PFS: HR=0.32; 95% CI, 0.16-0.63, p&amp;lt;0.001) in anti-PD-1 treated patients harboring TP53-mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Conclusions: Our study reveals that mutations in lung adenocarcinoma impact intra-tumor immune profile and predict response to PD-1 blockade. Citation Format: Audrey Lupo, Jerome Biton, Marco Alifano, Diane Damotte, Jennifer Arrondeau, Pascaline Boudou, François Goldwasser, Karen Leroy, Marie Wislez, Pierre Laurent-Puig, Isabelle Cremer, Helène Blons, Ronald Herbst. Mutations found by targeted next generation sequencing is associated with intra-tumor immune profile and may predict response to anti-PD1 therapy in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 573.

Abstract 2443: Predicting the impact of somatic mutations on chromatin conformation using deep learning

Abstract DNA in eukaryotes is packed into hierarchical layers of loops resulting in the 3D structure of the genome. 3D genome organization plays vital roles in many biological processes of the cell such as gene regulation, cell division and stem cell differentiation and its disruption can lead to gene dysregulation and diseases, including cancer. We developed a deep learning model to predict the impact of single nucleotide variants, indels and structural variants on 3D chromatin loop structures of the genome. We first built a deep convolutional neural network to learn DNA sequence patterns of boundaries of 3D chromatin loops. The learned patterns of boundaries are then used to train another neural network to learn if two boundaries are likely boundaries of a chromatin loop given their DNA sequences. The model produces a probability indicating the likelihood of the two boundaries to form a chromatin loop (loop probability). It is trained with DNA sequence only, and therefore, it can detect effects of DNA variants on 3D chromatin loops as changes in loop probabilities. We trained our model with 80% of 3D chromatin loop from the cell line GM12878. Our model to predict boundaries of loops can distinguish DNA sequences of boundaries from random sequences with AUC of 0.96 on a balanced test-set from the cell line GM12878 and also performs well on data from the K562 cells with AUC of 0.93. Our result shows that variants in lymphoblastoid cells GM12878 do not change loop probabilities as much as variants in leukemia cells K562 do, consistent with the greater disruptive role of tumorigenic variants in the cancer cells. We next applied our model on whole-genome sequences of 240 malignant lymphoma patients to identify loop-disrupting variants that may act as drivers of cancer. We find that genes in predicted altered loops show more differential expression in tumor samples compared to genes in unchanged loops. Our method can be applied on large cohorts of patients with whole-genome sequences to analyze the chromatin conformation changes caused by somatic variants. Citation Format: Tuan Trieu, Ekta Khurana. Predicting the impact of somatic mutations on chromatin conformation using deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2443.