scholarly journals Outcomes in patients with DNA-damage repair related pancreatic cancer

2019 ◽  
Author(s):  
Sarah Macklin ◽  
Stephanie L. Hines ◽  
Pashtoon M. Kasi
Keyword(s):  
Dna Damage ◽  
Cancer Patients ◽  
Clinical Outcomes ◽  
Pancreas Cancer ◽  
Locally Advanced ◽  
Predictive Marker ◽  
Parp Inhibitors ◽  
Prior History ◽  
Increased Sensitivity ◽  
Platinum Chemotherapy

Abstract Background: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNA-damage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. Methods: Pancreas cancer patients with either a somatic or germline BRCA1/2 or other DDR genes were identified retrospectively through review of medical records (medical genetics/oncology), germline and tumor-based genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. Results: A total of 11 patients with pancreas cancer were identified. Pathogenic DDR-variants detected were within BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Seven out of 11 patients were still alive at time of data review. Survival in the 3 patients who had died in the metastatic/advanced cohort was 23.5, 25.8 and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. Conclusions: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDR-subset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.

Association of "DNA damage signature" with poor outcome in early prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 13-13
Author(s):  
Mahesh Iddawela ◽  
Carmel Pazaro ◽  
Mitchell Lawrence ◽  
Luc Furic ◽  
Renea Taylor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Prognostic Marker ◽  
Disease Free Survival ◽  
Predictive Marker ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Early Prostate Cancer ◽  
Poor Outcome

13 Background: Whole genome and matching normal tissue analyses in prostate cancer patients have shown that widespread genomic changes occur in multiple distant regions of the genome simultaneously (Baca et al., Cell. 2013). The inherent genomic instability in prostate cancers causes activation of pathways involved in DNA damage, which could be a prognostic and potentially predictive marker for treatment with agents impacting DNA repair (e.g. PARP inhibitors). Using a published dataset, a “DNA damage signature” was generated to test its role as a potential prognostic marker. Methods: A 10-gene signature was generated, using the top 9 genes (MXD3, ZMYND19, BANF1, TOMM40, UBE2S, SNRPF, RPP21, CDK2AP2 and H2AFX) correlated with H2AFX expression, which is known to be unregulated upon DNA damage. TP53 was added due to its significant role in this pathway. This signature was then assessed in The Cancer Genome Atlas dataset (TCGA, unpublished data at NCI) as a discovery set and then validated in the MSK dataset (Taylor et al., 2010) using mutation, copy number, mRNA and proteomic data. Results: Genes in the signature were altered in 31% (77/246) of patients, by amplification and over expression compared to normal. The most frequent alterations were found in TP53 (15%), MXD3 (7%), BANF1 (7%), UBE28 (7%) and CDK2AF2 (7%). Analysis of protein changes associated with alteration in genomic signature showed upregulation of FOXO3, BCL2L1, BAK1 and PCNA (P<0.05). There were significant correlations between the signature and Gleason score (p=0.0015), PTEN (p=0.003) & RAD51 gene expression (p<0.001), but not with ERG,PSA, PIK3CA or BRCA2. Patients with alterations were associated with poor disease free survival (DFS) (p=0.002). When expression was assessed in the validation set, 73%(62/85) samples showed altered gene signatures and those with alterations also had poor DFS (p=0.003). Conclusions: The DNA damage signature can be used to define a group of patients with poor outcome and has the potential to be used as prognostic marker in treatment decisions in early prostate cancer patients.

scholarly journals Radiation induced apoptosis and initial DNA damage are inversely related in locally advanced breast cancer patients

2010 ◽  
Vol 5 (1) ◽  
pp. 85 ◽  
Author(s):  
Beatriz Pinar ◽  
Luis Henríquez-Hernández ◽  
Pedro C Lara ◽  
Elisa Bordon ◽  
Carlos Rodriguez-Gallego ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Advanced Breast Cancer ◽  
Cancer Patients ◽  
Locally Advanced Breast Cancer ◽  
Locally Advanced ◽  
Advanced Breast ◽  
Breast Cancer Patients ◽  
Radiation Induced ◽  
Induced Apoptosis

scholarly journals Arsenic compound sensitizes homologous recombination proficient ovarian cancer to PARP inhibitors

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Junfen Xu ◽  
Yuanming Shen ◽  
Conghui Wang ◽  
Sangsang Tang ◽  
Shiyuan Hong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Cancer Patients ◽  
Parp Inhibitors ◽  
Ovarian Cancer Cells ◽  
Therapeutic Effects ◽  
Arsenic Compound ◽  
Antitumor Effects ◽  
Sequential Administration

AbstractThe poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors show survival benefits in ovarian cancer patients with BRCA1/2 mutation or homologous recombination (HR) deficiency, but only limited efficacy in HR-proficient ones. Another drug, arsenic trioxide (ATO) or arsenic drug (RIF), exerts antitumor effects via inducing DNA damage. Here, we investigated the combined therapeutic effects of the PARP inhibitors and the arsenic compound in HR-proficient ovarian cancer. The combined treatment of niraparib, olaparib, or fluazolepali with ATO showed a significant suppression in tumor cell viability and colony formation. The drug treatment also induced synergistic inhibition of cell proliferation and DNA damage, and acceleration of cell apoptosis in two HR-proficient ovarian cancer cell lines SKOV3 and CAOV3, either by simultaneous or sequential administration. The mechanism underlying these synergistic effects were reflected by the significantly increased ratio of cleaved-PARP/total PARP and decreased ratio of p-AKT/total AKT. Consistently, the combination of olaparib with RIF synergistically reduced the tumor growth in mouse xenograft models. In conclusion, the arsenic compound greatly sensitizes HR-proficient ovarian cancer cells to the PARP inhibitors, and our findings provide an evidence for the clinical treatment development of this combination in HR-proficient ovarian cancer patients.

Correlation of peripheral blood markers of DNA damage and immune response with chemoradiation response in patients with locally advanced rectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15109-e15109
Author(s):  
Sanjeevani Arora ◽  
Elena Demidova ◽  
Vladimir Avkshtol ◽  
Randy Lesh ◽  
Amanda J Browne ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Dna Damage ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Treatment Options ◽  
Locally Advanced ◽  
Peripheral Blood Lymphocytes ◽  
Poor Responders ◽  
Predictive Capacity ◽  
Crt Response

e15109 Background: Approximately 60% of newly diagnosed rectal cancers are locally advanced. The standard of care for these malignancies is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. Unfortunately, only approximately 20% of patients experience a complete response, but all are at risk for toxicity. There are no biomarkers to predict who will derive the greatest benefit from CRT. We hypothesized that inherent DNA damage recognition and repair (DNA-DRR) capacity contributes to CRT response in rectal cancer. Methods: We used primary peripheral blood lymphocytes (pPBLs) from rectal cancer patients to study differences in DNA-DRR capacity. The blood samples used were either drawn prior to nCRT or post a standard course of ~5.5 weeks of nCRT. We used immunofluorescence and Luminex-based multianalyte approaches to study DNA-DRR capacity in pPBLs. To determine if the tested biomarkers correlated with CRT response, we segregated patients by neoadjuvant rectal (NAR) score, a validated surrogate endpoint in rectal cancer. Results: Using pPBLs, we found that a subset of patients had elevated phosphorylated histone H2AX (γ-H2AX) foci, a well-described marker of DNA double strand breaks. We found that poor responders (PoR; NAR score > 14; n = 21) had lower γ-H2AX foci then complete responders (CR; NAR score < 1; n = 21) (P < 0.0001, Kruskal-Wallis test). We also did not observe any significant differences in γ-H2AX foci from pPBLs drawn prior to CRT versus post nCRT (p = 0.519, n = 11, Wilcoxon rank sum test). Next, by multianalyte testing, we found that a combined score derived from six DNA-DRR markers (ATR, MDM2, phosphorylated forms of H2AX (γ), p53, Chk1, Chk2) strongly correlated with CR (p < 0.001). Finally, by multianalyte testing, we also detected a serum signature of inflammatory markers that significantly correlated with CRT response (p < 0.05). Conclusions: Our data suggest that rectal cancer patients who differ in their response to CRT differ in global, inherent DNA-DRR capacity, suggesting that DNA-DRR capacity in pre-treatment pPBLs can form the basis of a predictive biomarker. This predictive capacity may reflect underlying epigenetic or genetic differences, or inflammatory state. Validation and further development of this novel assay is warranted, as it has the capacity to substantially improve patient selection in an era with growing treatment options for these patients.

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