scholarly journals Outcomes in Patients With Pancreatic Adenocarcinoma With Genetic Mutations in DNA Damage Response Pathways: Results From the Know Your Tumor Program

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Michael J. Pishvaian ◽  
Edik M. Blais ◽  
Jonathan R. Brody ◽  
Lola Rahib ◽  
Emily Lyons ◽  
...  
Keyword(s):  
Dna Damage ◽  
Overall Survival ◽  
Dna Damage Response ◽  
Median Overall Survival ◽  
Advanced Disease ◽  
Genetic Mutations ◽  
Damage Response ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

PURPOSE Up to 25% of pancreatic adenocarcinomas (PDACs) harbor mutations in the homologous recombination DNA damage response (HR-DDR) pathway. Although known to affect responsiveness to DNA-damaging chemotherapy, the prognostic relevance of these mutations is unclear and outcomes in patients with PDAC who harbor HR-DDR mutations beyond BRCA1/2 remain unexplored. METHODS We evaluated 820 patients with PDAC enrolled in the Know Your Tumor program for whom we had collected comprehensive genomic testing results and longitudinal clinical outcomes. Patients were categorized as having resected versus advanced disease, and as having received platinum-based therapy versus being platinum naïve. Tumor genomic profiles were categorized as HR-DDR mutated (HR-DDRmut) or proficient (pHR-DDR) on the basis of the presence of pathogenic mutations of somatic or germline origin in BRCA1/2 or PALB2 (group 1); ATM/ATR/ATRX (group 2); or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (group 3). Overall survival was measured from the date of diagnosis until death. RESULTS Median overall survival (mOS) was similar in all resected patients irrespective of exposure to platinum-based therapy, whereas for platinum-treated patients with advanced disease, mOS was significantly longer for HR-DDRmut versus pHR-DDR (2.37 years v 1.45 years, respectively). Of importance, no difference was identified in platinum-naïve patients. mOS in patients with mutations in all three HR-DDRmut groups was greater than that for pHR-DDR patients, but this difference was lost in platinum-naïve patients. CONCLUSION Patients with advanced HR-DDRmut have improved mOS when treated with platinum-based therapy compared with pHR-DDR patients. In platinum-naïve patients, there is no mOS difference, which suggests that HR-DDR status has no pure prognostic value. These findings support the need to test all patients with advanced PDAC to ensure that HR-DDRmut patients receive the benefit of treatment with platinum-based therapy.

Outcomes in pancreatic adenocarcinoma (PDA) patients (pts) with genetic alterations in DNA damage repair (DDR) pathways: Results from the Know Your Tumor (KYT) program.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 191-191 ◽  
Author(s):  
Michael J. Pishvaian ◽  
Edik Matthew Blais ◽  
Jonathan Robert Brody ◽  
Davendra Sohal ◽  
Andrew Eugene Hendifar ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Value ◽  
Median Overall Survival ◽  
Advanced Disease ◽  
Treated Group ◽  
Genetic Alterations ◽  
Damage Repair ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

191 Background: Up to 17% of PDAs harbor mutations in the DDR pathway. However, the purely prognostic relevance of these mutations is unclear. Furthermore, outcomes in response to platinum-based therapies in PDA pts harboring mutations in a broad range of DDR genes, particularly beyond BRCA1/2 and PALB2, remain unexplored. Methods: We evaluated PDA pts enrolled in the KYT registry for whom we collected cancer related exome sequencing and clinical outcomes. Pts were categorized as resected and advanced (LAPC and metastatic pts), and tumor genomic profiles were categorized as DDR mutated (DDRmut) based on the presence of pathogenic alterations in BRCA1/2, PALB2 (Group 1), ATM, ATR, ATRX (Group 2), or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (Group 3). Tumors harboring no DDR mutations were labelled DDR proficient (pDDR). Median overall survival (OS) was measured from the date of diagnosis until death. Results: The OS was similar in all resected pts, irrespective of exposure to platinum therapy (see Table). However, for the pts with advanced disease, OS was significantly longer for DDRmut vs. pDDR pts, particularly in the platinum-treated group; but no such difference was identified in the platinum-naïve pts. Detailed outcomes for the 3 Groups will be presented, but in general the OS in pts with mutations in all 3 DDRmut Groups was greater than for the pDDR pts; but again this difference was lost in the platinum-naïve pts. Conclusions: Advanced DDRmut pts have an improved OS when treated with platinums, compared to pDDR pts. But, in the absence of platinum-based therapy, there is no OS difference observed in DDRmut vs. pDDR pts, suggesting that DDR status has no pure prognostic value. These findings support the need to test all pts with advanced PDA, to ensure that DDRmut pts are treated with platinum-based therapy. [Table: see text]

scholarly journals EPID-13. A RETROSPECTIVE ANALYSIS TO STUDY THE SURVIVAL CHARACTERISTICS OF PATIENTS WITH FIRST PROGRESSION OF GLIOBLASTOMA AT THE CLEVELAND CLINIC

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii81-ii81
Author(s):  
Yasmeen Rauf ◽  
Jimmy Yao ◽  
Addison Barnett ◽  
Yanwen Chen ◽  
Brian Hobbs ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Overall Survival ◽  
Cleveland Clinic ◽  
Progression Free Survival ◽  
Free Survival ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary central nervous system malignancy. The median overall survival is 15 to 18 months with treatment and decreases to nine months after first progression. METHODS This is a retrospective study. Data was collected from all patients with first progression of GBM treated at CCF between Jan 2012 to Jan 2020. Eight cohorts of patients were evaluated: Group 1 received cytotoxic chemotherapy, Group 2 received bevacizumab alone, Group 3 received surgical or reirradiation alone, Group 4 were enrolled in clinical trials. Each group was divided into methylated and unmethylated cohorts. RESULTS Median overall survival was 12.4 months for patients with first progression of GBM (n= 248). Among the methlylated patients, the median overall survival was 16.5 months for group 1, 13.4 for group 2, 23.7 for group 3, and 17.3 for group 4. Among the unmethylated patients, the Median overall survival was 8.6 months for group 1, 7.7 months for group 2, 11.7 months for group 3 and 10.7 months for group 4. (p= 0.00016). Progression free survival (PFS) was 4.3 months for all patients with first progression of GBM. Among the unmethlylated patients, the PFS was 3.6 months for group 1, 15.3 months for group 2, 4.8 months for group 3, and 6.1 months for group 4. Among the unmethylated patients, the PFS was 2.3 months for group 1, 3.9 months for group 2, 3.8 months for group 3, and 4.4 months for group 4. (p < 0.0001). CONCLUSION Patients with first progression of GBM had the best overall survival in the cohort that underwent a surgical or reirradiation. The best progression free survival was for patients who were treated with Bevacizumab if they were methylated and those enrolled in clinical trials if they were unmethylated. The study was statistically significant.

Survival characteristics of patients with first progression of glioblastoma at Cleveland Clinic Foundation.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14526-e14526
Author(s):  
Yasmeen Rauf ◽  
Jimmy Yao ◽  
Addison Barnett ◽  
Yanwen Chen ◽  
Brian Hobbs ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Overall Survival ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Free Survival ◽  
Group 4 ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

e14526 Background: Glioblastoma (GBM) is the most common primary central nervous system malignancy, with a median overall survival of 14 to 17 months. First progression refers to progressive disease after initial radiation with or without chemotherapy. The median overall survival of patients with the first progression of GBM is nine months. Currently, there is no standard treatment for progressive GBM. Common treatment options include clinical trials, surgical resection, re-irradiation, stereotactic radiosurgery, cytotoxic chemotherapies, bevacizumab, and tumor treating fields. Methods: This retrospective study reviewed 244 patients with the first progression of GBM who were treated at CCF between Jan 2012 to Jan 2020. Statistical analyses included patients who had biopsy-proven GBM, a known MGMT methylation status, a KPS of more than 70 and presented with the first progression on MRI brain. Four cohorts of patients were evaluated: Group 1 received cytotoxic chemotherapy, Group 2 received bevacizumab alone, Group 3 received surgical or radiation therapy alone, Group 4 received experimental treatments. Results: The median overall survival (OS) and progression-free survival (PFS) was 12.4 months (95% CI: 10.9 to 14.3) and 4.3 months (95% CI: 3.9 to 5.4), respectively. The cohorts demonstrate statistical significant differentiation for PFS (p = 0.021) but not OS (p = 0.19). Second progression was noted at a median interval of 5.6 months in Group 4, 4.3 months in Group 2, 3.8 months Group 3 and 3.2 months in Group 1. Conclusions: Patients with the first progression of GBM had a better progression-free survival on experimental clinical trials than those in other cohorts.

Association between germline DNA damage repair-related genes mutation and tumor mutational burden in lung cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21163-e21163
Author(s):  
Wei Nie ◽  
Hua Zhong ◽  
Ding Zhang ◽  
Shiqing Chen ◽  
Baohui Han
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Gene Mutations ◽  
Related Gene ◽  
Mutational Burden ◽  
Damage Repair ◽  
Tumor Mutational Burden ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P < 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.

scholarly journals Alterations of DNA damage response genes correlate with response and overall survival in anti‐PD‐1/PD‐L1‐treated advanced urothelial cancer

2020 ◽  
Vol 9 (24) ◽  
pp. 9365-9372
Author(s):  
Monika Joshi ◽  
Petros Grivas ◽  
Amir Mortazavi ◽  
Paul Monk ◽  
Steven K. Clinton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Overall Survival ◽  
Dna Damage Response ◽  
Urothelial Cancer ◽  
Damage Response ◽  
Advanced Urothelial Cancer

The Majority of Myeloma Patients Are Hypogonadal but This Is Not Associated with High Risk Cytogenetics

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5329-5329
Author(s):  
Beau Snoad ◽  
Samantha Hudzik ◽  
Douglas W Sborov ◽  
Nita Williams ◽  
Desiree Jones ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Serum Testosterone ◽  
Clinic Visit ◽  
Total Testosterone ◽  
Testosterone Levels ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Introduction: Hypogonadism, i.e. low total testosterone, is present in approximately a quarter of men older than 70 years (Harman SM et al, J. Clin Endo & Met, 2001, PMID 11158037 and Wu FCW et al, J Clin Endo & M et, 2008, PMID 18270261). Myeloma patients are known to suffer from fatigue and decreased functional performance, mood disturbances, and anemia; similar trends have been found in people with hypogonadism. Cytogenetically high risk myeloma characterized by the amplification of 1q21 is associated with increased serum levels of soluble IL-6 receptor (sIL-6r) (Stephens OW, Blood, 2012, PMID 22072558). We hypothesized that total testosterone levels will be associated with overall survival from the time of diagnosis, presence of 1q21 amplification by CD138-selected FISH, anemia, and anti-depressant use. Methods: The Buckeye Myeloma Registry (OSU 10115) opened in 2011 to enroll any patient with a plasma cell dyscrasia. Serum total testosterone was measured at the time of the initial clinic visit to the myeloma group at Ohio State. Less than 325 ng/dL was defined as the hypogonadal range, and testosterone was divided into <100 (group 1), 100-240 (group 2), 240-325 (group 3), and greater than 325 ng/dL (group 4), although normal testosterone decreases with age. Female patient testosterone levels were also analyzed and divided into <10 (group 1), 10-60 ng/dL (group 2), and >60 ng/dL (group 3). A retrospective chart review was initiated to review all myeloma patients with a serum testosterone drawn at the time of their initial clinic visit to OSU. Results: Among 418 male MM patients, median age was 65 y.o. (range 24-95), 86% were Caucasian and 14% African-American, and the distribution of ISS stage was 32% stage 1, 22% stage 2, and 19% stage 3 with 28% missing staging data. Cytogenetic data was missing from 28% of patients. Out of 418 male MM patients, 29 (7%) had serum testosterone <100, 202 (48%) with testosterone 100-240, 79 (19%) with testosterone 241-325, and 108 (26%) > 325 ng/dL. Out of 172 female MM patients, 44 (26%) had an undetectable serum testosterone, 120 (70%) with testosterone 10-60, and 8 (5%) with testosterone > 60. Among male MM patients, log-rank [Mantel-Cox] analysis of overall survival with serum testosterone including all 4 groups demonstrated no significant differences (p=0.917) with only 80 events. Among 275 male MM patients with cytogenetic information available, there was no correlation between presence of 1q21 trisomies or tetrasomies and overall survival (r=0.0714, p=0.238). There was a strong and expected correlation between testosterone and BMI (r=0.14, p=0.00468). Among 161 total female MM patients, log-rank analysis with serum testosterone including all 3 groups also demonstrated no differences (p=0.416) with only 29 events in total. Among 101 females with cytogenetic information, there was also no correlation with 1q21 amplification (r=0.0895, p=0.373). Conclusion: The majority of male MM patients (74%) have secondary hypogonadism and approximately half have total testosterone levels <240 ng/dL. Cox proportional hazards analyses of survival adjusted for significant univariate covariates will be presented at the meeting. Correlations with anemia and medication use (specifically opiates and anti-depressants) will also be presented at the meeting. Disclosures No relevant conflicts of interest to declare.

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.

1997 ◽  
Vol 15 (5) ◽  
pp. 1858-1869 ◽  
Author(s):  
B Fisher ◽  
S Anderson ◽  
D L Wickerham ◽  
A DeCillis ◽  
N Dimitrov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Total Dose ◽  
Primary Breast Cancer ◽  
National Surgical Adjuvant Breast ◽  
Significant Difference ◽  
Bowel Project ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

PURPOSE The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-22) to determine if intensifying but maintaining the total dose of cyclophosphamide (Cytoxan, Bristol-Myers Squibb Oncology, Princeton, NJ) in a doxorubicin (Adriamycin, Pharmacia, Kalamazoo, MI)-cyclophosphamide combination (AC), or if intensifying and increasing the total dose of cyclophosphamide improves the outcome of women with primary breast cancer and positive axillary nodes. PATIENTS AND METHODS Patients (N = 2,305) were randomized to receive either four courses of standard AC therapy (group 1); intensified therapy, in which the same total dose of cyclophosphamide was administered in two courses (group 2); or intensified and increased therapy, in which the total dose of cyclophosphamide was doubled (group 3). The dose and intensity of doxorubicin were similar in all groups. Disease-free survival (DFS) and overall survival were determined using life-table estimates. RESULTS There was no significant difference in DFS (P = .30) or overall survival (P = .95) among the groups through 5 years. At 5 years, the DFS of women in group 1 was similar to that of women in group 2 (62% v 60%, respectively; P = .43) and to that of women in group 3 (62% v 64%, respectively; P = .59). The 5-year survival of women in group 1 was similar to that of women in group 2 (78% v 77%, respectively; P = .86) and to that of women in group 3 (78% v 77%, respectively; P = .82). Grade 4 toxicity increased in groups 2 and 3. Failure to note a difference in outcome among the groups was unrelated to either differences in amount and intensity of cyclophosphamide or to dose delays and intervals between courses of therapy. CONCLUSION Intensifying or intensifying and increasing the total dose of cyclophosphamide failed to significantly improve either DFS or overall survival in any group. It was concluded that, outside of a clinical trial, dose-intensification of cyclophosphamide in an AC combination represents inappropriate therapy for women with primary breast cancer.

Prognostic role of apolipoprotein and lactate dehydrogenase levels in resectable colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15541-e15541
Author(s):  
Yifei Ma ◽  
Ping Lu ◽  
Xinjun Liang ◽  
Shaozhong Wei
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Lactate Dehydrogenase ◽  
Cox Regression ◽  
Prognostic Role ◽  
Free Survival ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

e15541 Background: Apolipoprotein b (apob), apolipoprotein a1 (apoa1), and lactate dehydrogenase (LDH) levels are circulating biomarkers that relate to tumor inflammation. This study aimed to evaluate the prognostic role of apob/apoa1 and LDH in resectable colorectal cancer (CRC). Methods: 513 patients of colorectal cancer (CRC) from Hubei cancer hospital were included finally, and we collected the pre-operative laboratory results within a week before surgery. We combined the two indicators and divided them into three groups (group 1: apob/apoa1-LDH low; group 2: apob/apoa1 or LDH high; group 3: apob/apoa1-LDH high). Kaplan-Meier survival analysis, univariate COX regression and multivariate COX regression were used to assess the prognoses of colorectal cancer patients. Results: The median follow-up was 35 months. Our study found that the prognosis of group 1 was better than group 2 in both overall survival (88.2% vs. 75.4% vs. 61.9%) (P≤0.001) and diseases-free survival (77.4% vs. 64.7% vs. 42.8%) (P≤0.001), and group 3 was the worst. By multivariate analysis, the new predictive marker obtained by combining apob/apoa1 and LDH could independently predict outcomes in CRC [overall survival: (HR: 1.487; 95% CI, 1.074-2.061); diseases-free survival (HR: 1.381; 95% CI, 1.045-1.827)]. Conclusions: New marker based on apob/apoa1 and LDH is useful for predicting the prognosis of patients with CRC. However, more research is needed in the future.

scholarly journals CD40L/IL-4–stimulated CLL demonstrates variation in translational regulation of DNA damage response genes including ATM

2018 ◽  
Vol 2 (15) ◽  
pp. 1869-1881 ◽  
Author(s):  
Larissa Lezina ◽  
Ruth V. Spriggs ◽  
Daniel Beck ◽  
Carolyn Jones ◽  
Kate M. Dudek ◽  
...  
Keyword(s):  
Dna Damage ◽  
Overall Survival ◽  
Dna Damage Response ◽  
Translational Regulation ◽  
Damage Repair ◽  
Key Points ◽  
Damage Response ◽  
Baseline Levels ◽  
Repair Genes ◽  
11Q Deletion

Key Points CD40L/IL-4 responses mediate translational regulation of DNA damage repair genes, including ATM, and associate with baseline levels of ATM. Lower levels of baseline ATM, independent of 11q deletion, associate with reduced overall survival.

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