Germline BRCA1/2, PALB2, and ATM mutations in 3,030 patients with pancreatic adenocarcinoma: Survival analysis of carriers and noncarriers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 280-280
Author(s):  
Pashtoon Murtaza Kasi ◽  
Fergus Couch ◽  
William R Bamlet ◽  
Chunling Hu ◽  
Steven Hart ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Pancreatic Adenocarcinoma ◽  
Final Analysis ◽  
Parp Inhibitors ◽  
P Value ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Before And After ◽  
Brca1 Brca2

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.

scholarly journals CASAS: Cancer Survival Analysis Suite, a web based application

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 919 ◽  
Author(s):  
Manali Rupji ◽  
Xinyan Zhang ◽  
Jeanne Kowalski
Keyword(s):  
Survival Analysis ◽  
Cancer Survival ◽  
Univariate Analysis ◽  
Multiple Cancer ◽  
Web Based ◽  
Survival Analyses ◽  
Link Type ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
One Stop

We present CASAS, a shiny R based tool for interactive survival analysis and visualization of results. The tool provides a web-based one stop shop to perform the following types of survival analysis:  quantile, landmark and competing risks, in addition to standard survival analysis.  The interface makes it easy to perform such survival analyses and obtain results using the interactive Kaplan-Meier and cumulative incidence plots.  Univariate analysis can be performed on one or several user specified variable(s) simultaneously, the results of which are displayed in a single table that includes log rank p-values and hazard ratios along with their significance. For several quantile survival analyses from multiple cancer types, a single summary grid is constructed. The CASAS package has been implemented in R and is available via http://shinygispa.winship.emory.edu/CASAS/. The developmental repository is available at https://github.com/manalirupji/CASAS/.

Analysis of real-world (RW) data for metastatic breast cancer (mBC) patients (pts) with somatic BRCA1/2 (sBRCA) or other homologous recombination (HR)-pathway gene mutations (muts) treated with PARP inhibitors (PARPi).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10512-10512
Author(s):  
Felipe Batalini ◽  
Russell Madison ◽  
Dean C. Pavlick ◽  
Ethan Sokol ◽  
Tamara Snow ◽  
...  
Keyword(s):  
Cox Regression ◽  
Gene Mutations ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Free Survival ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Pathway Gene ◽  
Comprehensive Genomic Profiling

10512 Background: PARPi are approved for treatment of pts w/ HER2-negative mBC and germline BRCA1/2 (g BRCA) pathogenic or likely pathogenic variants (muts); however, clinical benefit has also been demonstrated in mBC pts w/ sBRCA or other HR-pathway gene muts. Using a RW Clinico-Genomic Database (CGDB), we assessed outcomes for pts w/ gBRCA muts compared to pts w/ either s BRCA or other HR-pathway muts treated w/ PARPi. Methods: 6,329 mBC pts from ̃280 US cancer clinics were included in the Flatiron Health (FH) -Foundation Medicine (FM) CGDB, which includes comprehensive genomic profiling (CGP) linked to de-identified, electronic health record (EHR)-derived clinical data. Eligible pts had mBC, received care in the FH network from 1/1/2011-9/1/2020, and had tissue CGP by FM. Pts classified as gBRCA: positive germline result in EHR and BRCA mut predicted germline per FM’s somatic, germline, zygosity algorithm (SGZ) (Sun et al PMID 29415044). Non-g BRCA: negative germline results in EHR and a somatic BRCA (s BRCA) mut per SGZ or BRCA wild-type w/ another HR mut per CGP result. Pts w/o a documented gBRCA result in EHR, unknown FM BRCA SGZ result, or conflicting results were excluded. RW overall survival (rwOS) and RW progression-free survival (rwPFS) from start of PARPi for pts w/ gBRCA and non- gBRCA mBC were compared using Kaplan-Meier analysis and Cox regression adjusted for mBC line number, prior platinum, age at PARPi initiation, race, and receptor status. Results: Among pts who received PARPi in the mBC setting, 44 had gBRCA and 18 had non -gBRCA: 9 s BRCA (5 BRCA1, 4 BRCA2), 4 PALB2, 2 ATM, and 1 each of ATM+CDK12, BARD1+FANCF+RAD54L, and CHEK2. Of HR muts 76% were confirmed biallelic: 33/44 gBRCA (11 unknown), 8/9 sBRCA, 3/4 PALB2, and 3/5 other (1 unknown). Neither median rwPFS nor rwOS from start of PARPi were significantly different between the non-g BRCA and g BRCA cohorts (rwPFS: 7.0 [4.6-11.3] vs 5.5 [4.3-7.2] months (mos), aHR: 1.19 [0.57 – 2.43]; rwOS: 15.0 [7.95-16.3] vs 11.5 [9.46-NA] mos, aHR: 0.85 [0.36-1.98]). For 9 pts w/ sBRCA mut, median rwPFS was 7.1 mos (range 1.4-12.4) and all pts had progressed by data cut off. Conclusions: Despite small pt numbers and limitations from RW data, our results suggest that pts w/ biallelic non-g BRCA mBC may derive similar benefit from PARPi when tumor CGP detects a s BRCA mut or germline or somatic mut in other HR-pathway genes. These findings are consistent w/ the results from TBCRC-048 (Tung et al PMID 33119476) and support further randomized trials exploring the efficacy of PARPi in this population.[Table: see text]

ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 138-138
Author(s):  
Ellen Jaeger ◽  
Elisa Marie Ledet ◽  
Marcus W. Moses ◽  
Charlotte Manogue ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Cancer Center ◽  
Small Subset ◽  
Published Data ◽  
Pathogenic Variants ◽  
Recombination Repair ◽  
Brca1 Brca2 ◽  
Allelic Fraction ◽  
Germline Testing

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.

scholarly journals Mechanical Dispersion as a powerful echocardiographic predictor of outcomes after Myocardial Infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J.P De Sousa Bispo ◽  
P Azevedo ◽  
P Freitas ◽  
N Marques ◽  
C Reis ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Survival Analysis ◽  
Primary Endpoint ◽  
Longitudinal Strain ◽  
Univariate Analysis ◽  
Global Longitudinal Strain ◽  
P Value ◽  
Peak Strain ◽  
Kaplan Meier

Abstract Introduction Several studies have addressed the importance of transthoracic echocardiography (TTE) in risk prediction of subsequent adverse events after ST elevation myocardial infarction (STEMI). While several traditional echo parameters have a well-established prognostic value, data derived from 2D-Speckle Tracking Echocardiography (2DSTE) needs further investigation. Objectives To determine if 2DSTE parameters provide additional information beyond conventional echocardiography to predict long-term adverse outcomes in patients admitted with STEMI Methods Retrospective, single-center study, that included all patients without previous cardiovascular events admitted with STEMI (who underwent primary coronary angioplasty) between 2015 and 2017. Patients with poor acoustic windows, severe valvular disease, irregular heart rhythm, and those who died during hospital stay were excluded. We reviewed all pre-discharge TTE to assess conventional parameters of LV systolic and diastolic function and data obtained by 2DSTE: global longitudinal strain (GLS) and peak strain dispersion (PSD), an index that is the standard deviation from time to peak strain of all segments over the entire cardiac cycle. Demographic and clinical data was obtained through electronic hospital records. Minimum follow-up was 2 years. The primary endpoint was a composite of all-cause mortality and cardiovascular re-admission at follow-up. Survival analysis was used to determine independent predictors of the primary endpoint. Results 377 patients were included, mean age 62±13 years, 72% male. Mean LVEF was 50±10% with 19% of patients having LVEF &lt;40%. Mean indexed left atrium volume (LAVi) was 33±10 ml/m2, mean GLS was −14±4%, and PSD was 60±22 msec. Average follow-up was 36±11 months, with a combined endpoint of mortality and hospitalization of 27% (n=102) Univariate analysis of echocardiographic variables revealed an association between heart rate, LVEF, indexed LV end-systolic volume, indexed stroke volume, LAVi, GLS and PSD with the endpoint. However, on multivariate analysis only LAVi [HR 1.030 (95% CI 1.009 - 1.051), p-value = 0.005] and PSD [HR 1.011 (95% CI 1.002 - 1.020), p-value = 0.012] remained independent predictors of the primary endpoint. We determined that a PSD value higher than 52 msec has a sensitivity of 76% and a negative predictive value of 83% for mortality and hospitalization, and that this cut-off point discriminates patients at a higher risk of events in Kaplan-Meier Survival analysis with a Log-Rank p-value=0.001. Conclusion PSD derived by longitudinal strain analysis is a promising prognostic predictor after STEMI. PSD outperformed conventional echocardiographic parameters in the risk stratification of STEMI patients at discharge. Kaplan-Meier Survival Curves Funding Acknowledgement Type of funding source: None

Incidence and characterization of venous thromboembolic events (VTE) in patients with pancreatic cancer: Effect of timing of VTE on survival.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4037-4037
Author(s):  
Maithili A Shethia ◽  
Aparna Hegde ◽  
Xiao Zhou ◽  
Michael J. Overman ◽  
Saroj Vadhan-Raj
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Survival Analysis ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
One Year ◽  
The Impact

4037 Background: Patients (pts) with pancreatic cancer are at high risk for VTE, and the occurrence of VTE can affect pts’ prognosis. The purpose of this study was to evaluate the incidence of VTE and the impact of timing of VTE (early vs. late) on survival. Methods: Medical record of 260 pts with pancreatic cancer, newly referred to UT MDACC during one year period from 1/1/2006 to 12/31/2006, were reviewed for the incidence of VTE during a 2-year follow-up period from the date of diagnosis. All VTE episodes were confirmed by radiologic studies. Survival analysis was conducted using Kaplan-Meier analysis and Cox proportional hazard models. Results: Of the 260 pts, 47 pts (18%) had 51 episodes of VTE during the 2-year follow-up. The median age of the pts with VTE was 61 years (range: 28-86) and 53% were males. Of the 47 pts with VTE, 27 (57%) had PE, 19 (40%) had DVT and 1 had concurrent PE/DVT. Three pts had recurrent VTE during the study period. Median follow-up time for OS was 192 days (range: 1-1652 days). Kaplan-Meier Survival analysis showed that those who developed VTE earlier (within 30 or 90 days) had shorter median overall survival (OS) compared with those who had VTE beyond these time points. The hazard ratios, 95% CI, and median OS at 1 year are summarized in the table below. Conclusions: The incidence of VTE is high in pts with pancreatic cancer. The timing of VTE had a significant impact on OS; pts who had an early development of VTE had a shorter overall survival. [Table: see text]

Real-world outcome analysis of EGFR-mutated lung adenocarcinoma with brain metastases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13588-e13588
Author(s):  
Feng-Che Kuan ◽  
Wei-Hsun Yang ◽  
Hung-Yi Lai ◽  
Chun-Chieh Huang ◽  
Cheng-Ta Yang ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Lung Adenocarcinoma ◽  
Egfr Mutations ◽  
Outcome Analysis ◽  
P Value ◽  
Research Database ◽  
Poor Prognostic Factor ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Egfr Mutated

e13588 Background: BM represent a common problem in EGFR-mutated lung adenocarcinoma. The updated Lung-molGPA elucidates the survival in patients with non-small-cell lung cancer and BM by incorporating the effect of EGFR gene alterations. However, the nature history and differences of prognostic implication between common and uncommon EGFR mutations remain unsolved. Methods: By retrospective analysis of Chang-Gung Research Database (CGRD), patients with EGFR-mutated lung adenocarcinoma and BM were included into analysis of PFS and OS. EGFR mutations were categorized into exon 19 deletions (Del19), exon 21 Leu858Arg substitution (L858R) and uncommon mutations. Kaplan-Meier method was used to estimate survival, and multivariate Cox proportional hazard models was performed to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI). The p-value was set to be statistically significant at 0.05 or less. Results: From April 1, 2014 to June 30, 2015, 269 out of 818 patients with EGFR-mutated lung adenocarcinoma and BM were included, of which 115 patients with Del19, 131 patients with L858R, and 23 patients with uncommon EGFR mutations. The baseline characteristics were balanced in age, gender, KPS, ECM, number of BM, and timing of BM. In comparison with those with L858R, uncommon mutations is a poor prognostic factor for PFS (HR 2.24, 95% CI: 1.34-3.75, p = 0.002). The median PFS of Del 19, L858R, and uncommon EGFR mutations were 10.4, 10.0, and 3.2 months, respectively (log-rank p = 0.03). Besides, the median OS of Del 19, L858R, and uncommon EGFR mutations were 18.1, 17.4, and 12.5 months, respectively (log-rank p = 0.05). In comparison with those treated with gefitinib, afatinib treatment is a good prognostic factor for PFS and OS (PFS, HR 0.57, 95% CI: 0.35-0.94, p = 0.03; OS, HR 0.48, 95% CI: 0.26-0.91, p = 0.03). The median PFS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 11.0, 8.5, and 10.3, respectively (log-rank p = 0.63). In addition, the median OS of those treated with sequential WBRT, concurrent WBRT and TKI alone were 18.7, 15.2, and 18.2 months, respectively (log-rank p = 0.50). Conclusions: Among patients with EGFR-mutated adenocarcinoma, common and uncommon EGFR mutations have distinct natural history and prognostic implications in patients with BM.

Survival analysis

2017 ◽  
Author(s):  
Janet L. Peacock ◽  
Sally M. Kerry ◽  
Raymond R. Balise
Keyword(s):  
Survival Analysis ◽  
Cox Regression ◽  
Logrank Test ◽  
Kaplan Meier ◽  
Hazard Ratios

Chapter 11 covers survival analysis, and includes Kaplan–Meier estimates, and the logrank test. Cox regression is used to do multifactorial analyses with results reported as adjusted hazard ratios. The chapter includes analyses using Stata, SAS, SPSS, and R.

Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 283-283
Author(s):  
Panagiotis J. Vlachostergios ◽  
Jyothi Manohar ◽  
Muhammad Junaid Niaz ◽  
Aileen Lee ◽  
Amy Hackett ◽  
...  
Keyword(s):  
Single Gene ◽  
Brca2 Gene ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Somatic Alterations ◽  
Brca1 Brca2 ◽  
Tissue Specimens ◽  
The Impact

283 Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.

Significance of scores generated by a cancer therapy matching engine for patient outcomes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15099-e15099
Author(s):  
Eden Romm ◽  
Emiliya Davtyan ◽  
Kevin Bush ◽  
Ramsay Sutton ◽  
Itamar Patek ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Progression Free Survival ◽  
Sampling Bias ◽  
P Value ◽  
Cancer Drugs ◽  
Sequencing Data ◽  
Ampullary Adenocarcinoma ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Suitable Treatment

e15099 Background: Oncologists need effective precision medicine tools to navigate the myriad of therapeutic options to best address each patient’s unique tumor profile. Described here is a digital solution, which analyzes tumor data (NGS, other), scores and ranks known and novel matching combinations of cancer drugs with molecular-level precision for decision support. Methods: All data was acquired through the published supplement of the I-PREDICT study (NCT 02534675). Patients with available progression-free survival (PFS) and sequencing data who received <3 matched non-experimental cancer drugs in combination were evaluated (n=77). To determine each patient’s score (represented as %), the system used expert-curated content integrated within an artificial intelligence (AI) reasoning framework that computed how well the therapy each patient received matched their tumor’s genomic profile. The dataset was binarized at 36 possible thresholds, which split the data into higher vs. lower score bins. Relationship with PFS and the degree of separation between bins were evaluated with Kaplan-Meier plots and assessed in terms of p-value, hazard ratios and related confidence intervals (Table). To prevent sampling bias at high and low thresholding extremes of this dataset, a limit was imposed of >25 patients per bin. Results: Significant separation between high and low scoring bins was observed in >73% of evaluable thresholds. The mean p-value was 0.044 (range, 0.011-0.13). The hazard ratio was consistently ̃2 (mean, 1.81, range, 1.50-2.08). A similar level of statistical significance was observed for all thresholds up to and including bracketing of 60% (Table). Despite the small size of this dataset and the disparity between sample counts per bin seen at the end of the range, significant p-values of <0.05 were achieved. Ex., a 68-year-old female with an ampullary adenocarcinoma harboring ERBB2, CDK6 and other alterations, received a combination of pertuzumab and trastuzumab scoring 56%. The PFS was 745+ days. However, had palbociclib, ribociclib, or abemaciclib been added to this combination, the resulting 3-drug options would have scored even higher due to also targeting CDK6. Conclusions: Our study indicates that therapies with higher scores were predictive of better PFS, while lower scores were predictive of worse PFS. The results will be validated on larger datasets but are already demonstrative of the utility of this system in providing digital guidance to oncologists in selecting the most suitable treatment. [Table: see text]

Primary pancreatic adenocarcinoma (PPDA) and metastatic pancreatic adenocarcinoma (MPDA): Are they genomically distinct?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16226-e16226
Author(s):  
Sunny R. K. Singh ◽  
Shravan Leonard-Murali ◽  
Ruicong She ◽  
Chun-Hui Lin ◽  
Jonathan Freaney ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Progression Free Survival ◽  
P Value ◽  
Genetic Changes ◽  
Immune Infiltrate ◽  
Genomic Changes ◽  
Kaplan Meier ◽  
Dismal Prognosis ◽  
Tumor Mutational Burden ◽  
Frequent Mutations

e16226 Background: PDA is an aggressive disease with a dismal prognosis. Advances in next-generation sequencing (NGS) have enabled targeted therapies, revolutionizing treatments of several solid tumors. Their role in the management of PDA is limited, in part due to the paucity in our understanding of targetable genomic events. We sought to evaluate genomic differences between PPDA and MPDA in the tumor and tumor immune microenvironment (TIME). The genomic changes after chemotherapy (CTX) administration were also evaluated. Methods: NGS data derived from tumor samples of 150 unique patients was analyzed. Targeted 648 gene DNA sequencing was performed using the Tempus xT and xO assays. Patients were allocated into 2 cohorts: PPDA (n = 75) and MPDA (n = 75), which were overall similar in terms of their demographics. The frequencies of somatic mutations were compared. The immune infiltrate was imputed from RNAseq. Proportions of immune cells (IC), and the tumor mutational burden (TMB) relative to the proportion of IC in the TIME, were also analyzed. Kaplan Meier Survival estimates for most frequent mutations and TMB were calculated. Results: The most frequently mutated genes amongst the 150 study subjects were: KRAS (92.7%), TP53 (76.7%), CDKN2A (45.3%), SMAD4 (31.3%), ATM (12.7%) and ARID1A (10.7%). Patients in the MPDA cohort had a higher rate of mutation in several genes when compared to PPDA, most notably in TP53 (85.3% vs 68.0%, p = 0.010), ARID1A (16.0 vs 5.3%, p = 0.037) CDKN2A (49.3 vs. 41.3%, p = 0.3) and SMAD4 (33.3 vs. 29.3 p = 0.7). We also evaluated if the genetic changes between PPDA and MPDA are associated with alterations in the TMB and differences in the TIME. A higher TMB was seen amongst patients in the MPDA vs PPDA cohort (2.73 vs 1.73 Mut/Mb, p = 0.008). TMB was also significantly increased after CTX (2.22 vs 1.63 Mut/Mb p = 0.049). TMB ≥ 3 was associated with decreased odds of progression free survival ≥ 12 months (OR 0.26 95% CI 0.078-0.822, p = 0.023). Regarding immune infiltrate, the proportion of CD4 and CD8 T cells were higher in the PPDA cohort. Macrophages and NK cells were more prevalent the MPDA cohort. TMB had a positive correlation with the degree of macrophage infiltration in the TIME (Multivariate estimate: 1.70, p value 0.01). Conclusions: PPDA and MPDA are biologically dissimilar entities with genomic disparity. Associated differences were observed in TMB and TIME. There is a differential increase in the spectrum of mutations in MPDA as compared to PPDA, specifically in p53, ARID1A, CDKN2A and SMAD4. The burden of increased mutations in MPDA is associated with an increase in the TMB and tumor associated macrophages. The role of serial NGS in the management of PDA both in early and late disease should be investigated further to identify evolving genomic changes that correlate with outcome.

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