Identifying functional loss of ATM gene in patients with advanced cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3629-3629
Author(s):  
Patrick Glen Pilie ◽  
Jinesh S. Gheeya ◽  
Keith Kyewalabye ◽  
Rohit Vivek Goswamy ◽  
Khalida M Wani ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Predictive Biomarker ◽  
Cancer Center ◽  
Precision Oncology ◽  
Cell Nuclei ◽  
Functional Impact ◽  
Unknown Significance ◽  
Atm Protein ◽  
Md Anderson ◽  
Coding Variants

3629 Background: ATM is frequently mutated in cancer, and defects may serve as a putative predictive biomarker. However, the functional impact of most ATM variants is not well known. In this study, we examined the relationship between ATM variants and ATM protein expression to better discern ATM functional defects in patients (pts) with advanced cancer. Methods: We retrospectively identified pts seen at MD Anderson Cancer Center who had ATM variants detected on CLIA-certified next generation sequencing (NGS) assays. ATM immunohistochemistry (IHC) was performed on available tumors. We then prospectively assessed ATM IHC on tumors from pts who were referred for DNA damage repair inhibitor (DDRi) trials. Functional classification of the variants was performed via published in silico tools and/or precision oncology decision support (PODS). An IHC cut-off of 100% loss in tumor cell nuclei defined ATM loss of protein (LOP). Results: Of 1394 ATM-mutant tumors identified retrospectively, ATM alterations were classified as 16% (N = 216) inactivating, 12% (N = 163) potentially inactivating, 71% (N = 993) variant of unknown significance (VUS), and 2% (N = 22) benign. Coding variants were seen across the ATM exonic structure/splice sites, and 20 individual variants were shared in > 10 pts. 263/297 available retrospective tumor samples had interpretable IHC results; 27% (N = 72) had ATM LOP. LOP was most prevalent in tumors with inactivating ATM variants (39/100, 39%); but, importantly, LOP was seen in 20% (N = 33/162) of potentially inactivating/VUS, thus better clarifying their functional impact. In the prospective cohort of 217 pt tumors, 17% (N = 37) had ATM LOP. 29% (N = 62/217) of this cohort also had ATM variants. ATM LOP was seen in 48% of tumors with inactivating variants (N = 14/29), 25% of tumors with potentially/VUS(N = 9/36), and 9% (N = 14/156) of tumors without ATM variants identified. ATM LOP was detected most commonly in colorectal (24%; N = 8/34), cholangiocarcinoma (20%; N = 6/30), prostate (16%; N = 16/104) and pancreatic (9%; N = 1/11) cancers among this cohort of pts referred for DDRi trials. Conclusions: ATM coding variants occurred across the gene, with certain variants shared across tumor types. The functional impact of most ATM variants was VUS, and ATM LOP can help clarify function in up to 25% of these VUS. Also, ATM LOP can be seen even in tumors without ATM variants identified, suggesting epigenetic or post-translational loss. Future prospective studies assessing predictive capability of paired DNA and protein-level profiling of ATM are warranted.

Delirium assessment in patients with advanced cancer presenting to the emergency department of a comprehensive cancer center.

2015 ◽  
Vol 33 (29_suppl) ◽  
pp. 217-217
Author(s):  
Ahmed F. Elsayem ◽  
Alan D. Valentine ◽  
Carla L. Warneke ◽  
Valda D Page ◽  
Eduardo Bruera ◽  
...  
Keyword(s):  
Emergency Department ◽  
Mortality Rate ◽  
Advanced Cancer ◽  
Emergency Departments ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Poor Survival ◽  
Delirium Assessment ◽  
English Speaking ◽  
Md Anderson

217 Background: The exact frequency of delirium among patients with advanced cancer presenting to emergency departments (EDs) is unknown. The purpose of this study is to determine the prevalence of delirium among patients with advanced cancer who present to the ED at MD Anderson Cancer Center. Methods: The exact frequency of delirium among patients with advanced cancer presenting to emergency departments (EDs) is unknown. The purpose of this study is to determine the prevalence of delirium among patients with advanced cancer who present to the ED at MD Anderson Cancer Center. Results: A total of 624 patients were screen for this study, and 243 patients were enrolled. The main reasons for exclusion were: 1) cancer was not advanced, 2) the patient had been in the ED for over 12 hours and 3) the patient was non-English speaking. The median age for all patients enrolled was 62 years (range 19 – 89 years), 167 (69%) were white, and 120(49.4) were female. CAM was positive in 22(9%) of patients. The median MDAS score of CAM positive patients was 14 (range 9 – 22 out of 30). Ten (10%)of 99 patients aged 65 and older were delirious as compared to 12 (8%) of 144 patients younger than 65 years (p = 0.6). Physician correctly predicted delirium in 13 patients (59%). Among the patients who were CAM positive 18 (82%) were admitted to the hospital as compared to 115 (52%) of patients without delirium (p = 0.012). Patients with delirium had higher hospital, and six months mortality rate. Conclusions: Delirium was identified in 9% of patients with advanced cancer visiting an ED, and is associated with more hospitalization and poor survival.

Correlation of pathogenic POLE mutations with clinical benefit to immune checkpoint inhibitor therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
Benjamin Garmezy ◽  
Jinesh S. Gheeya ◽  
Kyaw Zin Thein ◽  
Patrick Glen Pilie ◽  
Wanlin Wang ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Cancer Center ◽  
Chi Square ◽  
Dna Polymerase Epsilon ◽  
Number Variation ◽  
Md Anderson ◽  
Chi Square Analysis

3008 Background: Mutations in DNA polymerase epsilon ( POLE) may induce DNA replication errors, increasing neoantigen load and potentially enhancing clinical benefit to immune checkpoint inhibitors (ICI). We present a clinicopathologic analysis of patients (pts) with advanced cancers harboring POLE mutations and their response to ICI therapy at MD Anderson Cancer Center. Methods: We used targeted exome sequencing via CLIA-certified next generation sequencing assays to identify pts with POLE-aberrant tumors and their co-occurring mutations. The pathogenicity of each POLE mutation was annotated utilizing InterVar and ClinVar databases. Chi-square analysis was performed. Results: Tumors from 12,947 pts were analyzed and 448 (3.5%) pts had a mutation or copy number variation in POLE (3.5%), comparable to the TCGA PanCancer Atlas (4.0%). Clinical data were available for 293 pts; the most common cancers were colorectal (14.7%), non-small cell lung (13.7%), cholangiocarcinoma (13.3%) and melanoma (10.2%). There were 267 unique co-mutations, including KRAS (23.0%), ARID1A (21.5%), BRCA2 (18.7%), ATM (18.4%), CDKN2A (17.5%), BRAF (15.3%), EGFR (15.3%), ATRX (12.6%), CREBBP (11.7%), APC (11.3%), ATR (11.0%), BRCA1 (11.0%) and CDK12 (10.4%). POLE variants were annotated in all pts: pathogenic/likely pathogenic (n = 34, 11.6%), benign/likely benign (61, 20.8%), and variant of unknown significance (198, 67.6%). 104 (35.8%) of 293 pts with POLE mutations received PD-1/L1 inhibitors as monotherapy or in combination. 93 (88.4%) of 104 pts were evaluable for response: Radiological CR 4.3% (n = 4), PR 26.9% (n = 25), SD 22.6% (n = 21), PD 46.2% (n = 43), for a clinical benefit rate (CR + PR + SD) of 53.8%. Pathogenic status of POLE mutation was associated with clinical benefit to PD-1/L1 inhibitors (p = 0.04). TMB (p = 0.44), PD-L1 (p = 0.11), and MSI (p = 0.66) status were not associated with pathogenic status. MSI-H status was not over-represented in pts with ICI clinical benefit (p = 0.36). Conclusions: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutations as a predictive biomarker. Multiple co-occurring DNA damage response mutations were found, which may contribute to ICI clinical benefit.

scholarly journals L6.5 Personalized Medicine: An Update on 1,985 Patients with Advanced Cancer at Md Anderson Cancer Center

2012 ◽  
Vol 23 ◽  
pp. v10
Author(s):  
A.M. Tsimberidou ◽  
D.S. Hong ◽  
J.J. Wheler ◽  
Y. Ye ◽  
S. Fu ◽  
...  
Keyword(s):  
Personalized Medicine ◽  
Advanced Cancer ◽  
Cancer Center ◽  
Md Anderson

Outcomes of patients ≥65 years old with advanced cancer treated on phase I trials at MD ANDERSON CANCER CENTER

2016 ◽  
Vol 140 (1) ◽  
pp. 208-215 ◽  
Author(s):  
Ishwaria M. Subbiah ◽  
Jennifer J. Wheler ◽  
Kenneth R. Hess ◽  
David S. Hong ◽  
Aung Naing ◽  
...  
Keyword(s):  
Phase I ◽  
Advanced Cancer ◽  
Cancer Center ◽  
Phase I Trials ◽  
Md Anderson

657 Interleukin-6 receptor blockade for management of immune checkpoint inhibitor related adverse events in patients with melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A694-A694
Author(s):  
Chantal Saberian ◽  
Faisal Fa’ak ◽  
Jean Tayar ◽  
Maryam Buni ◽  
Sang Kim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Activity ◽  
Median Time ◽  
Interleukin 6 ◽  
Immune Checkpoint ◽  
Activity Index ◽  
Critical Role ◽  
Cancer Center ◽  
Interleukin 6 Receptor ◽  
Md Anderson

BackgroundManagement of certain immune mediated adverse events (irAEs) can be challenging and may require prolonged/chronic immune suppression with corticosteroids or other immunosuppressant which could compromise and even reverse the efficacy of immune checkpoint inhibitors (ICI). While the exact immunobiology of irAEs is not fully understood there is enough evidence that IL-6 induced Th-17 that may play critical role in the pathogenesis. Herein, we describe our clinical experience using interleukin-6 receptor (IL-6R) blockade in management of irAEs in melanoma patients.MethodsWe searched MD Anderson databases to identify cancer patients who had received ICIs between January 2004 and March 2020. Of 11,391 ICI-treated patients, 21 patients with melanoma who received IL-6R blockade after ICI infusion were identified and their medical records were reviewed.ResultsMedian age was 61 years (41–82), 52% were females, 90% received anti-programmed cell death-1 antibodies. Fourteen patients (67%) had de novo onset irAEs (11 had arthritis, and 1 each with polymyalgia rheumatica, oral mucositis, and CNS vasculitis), and 7 patients (33%) had flare of their pre-existing autoimmune diseases (5 had had rheumatoid arthritis, and 1 each with myasthenia gravis and Crohn’s disease). Median time from ICI initiation to irAEs was 91 days (range, 1–496) and to initiation of IL-6R blockade was 6.6 months (range, 0.6–24.3). Median number of IL-6R blockade was 12 (range, 1–35), and 16 patients (76%) were concomitantly receiving corticosteroids of median dose of 10 mg (range, 5–20 mg). Of the 21 patients, irAEs improved in 14 (67%) (95% CI: 46%-87%). Of 13 evaluable patients with arthritis, 11 (85%) achieved remission or minimal disease activity as defined by the clinical disease activity index. Median time from initiation of IL-6R blockade till improvement of irAEs was 2.9 months (range, 1.5–36.9). Nineteen patients tolerated well IL-6R blockade, while two patients stopped treatment due to abdominal pain and sinus tachycardia. The median CRP levels at irAEs was 84 mg/L (0.6–187) and decreased to 1.9 mg/L (0.56–12) at 10 weeks after initiation of IL-6R blockade (P=0.02). Of the 17 evaluable patients, the overall tumor response rate by RECIST-1.1 criteria was similar before and after IL-6R blockade initiation (41% vs. 53%).ConclusionsOur data demonstrated that IL-6R blockade could be an effective therapy for irAEs management without dampening the efficacy of ICIs. Prospective clinical trials with longitudinal blood, tumor, and inflamed tissue biopsies are planned to accurately validate these findings and better study the immunobiology of irAEs.Ethics ApprovalThe study was approved by The University of Texas MD Anderson Cancer Center intuition’s Ethics Board, approval number PA19-0089

scholarly journals Changes in fatigue, barriers, and predictors towards physical activity in advanced cancer patients over a period of 12 months—a comparative study

2021 ◽  
Author(s):  
J. Frikkel ◽  
M. Beckmann ◽  
N. De Lazzari ◽  
M. Götte ◽  
S. Kasper ◽  
...  
Keyword(s):  
Physical Activity ◽  
Cancer Patients ◽  
Advanced Cancer ◽  
Physical Functioning ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Advanced Cancer Patients ◽  
Psychological Conditions ◽  
Patient Reported

Abstract Purpose Physical activity (PA) is recommended to improve advanced cancer patients’ (ACP) physical functioning, fatigue, and quality of life. Yet, little is known about ACPs’ attitude towards PA and its influence on fatigue and depressiveness over a longer period. This prospective, non-interventional cohort study examined ACPs’ fatigue, depression, motivation, and barriers towards PA before and after 12 months of treatment among ACP Methods Outpatients with incurable cancer receiving treatment at a German Comprehensive Cancer Center reporting moderate/severe weakness/tiredness during self-assessment via MIDOS II were enrolled. Fatigue (FACT-F), depression (PHQ-8), cancer-related parameters, self-assessed PA behavior, motivation for and barriers against PA were evaluated (T0). Follow-up data was acquired after 12 months (T1) using the same questionnaire. Results At follow-up, fatigue (p=0.017) and depressiveness (p=0.015) had increased in clinical relevant extent. Physically active ACP did not show significant progress of FACT-F (p=0.836) or PHQ-8 (p=0.799). Patient-reported barriers towards PA remained stable. Logistic regression analyses identified motivation as a positive predictor for PA at both time points (T0, β=2.152, p=0.017; T1, β =2.264, p=0.009). Clinically relevant depression was a negative predictor for PA at T0 and T1 (T0, β=−3.187, p=0.044; T1, β=−3.521, p=0.041). Conclusion Our findings emphasize the importance of psychological conditions in physical activity behavior of ACP. Since psychological conditions seem to worsen over time, early integration of treatment is necessary. By combining therapy approaches of cognitive behavioral therapy and exercise in interdisciplinary care programs, the two treatment options might reinforce each other and sustainably improve ACPs’ fatigue, physical functioning, and QoL. Trial registration German Register of Clinical Trials, DRKS00012514, registration date: 30.05.2017

scholarly journals Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance

2017 ◽  
Vol 10 (5) ◽  
Author(s):  
Bian Li ◽  
Jeffrey L. Mendenhall ◽  
Brett M. Kroncke ◽  
Keenan C. Taylor ◽  
Hui Huang ◽  
...  
Keyword(s):  
Functional Impact ◽  
Variants Of Unknown Significance ◽  
Unknown Significance
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