scholarly journals Building towards Precision Oncology for Pancreatic Cancer: Real-World Challenges and Opportunities

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1098
Author(s):  
Yifan Wang ◽  
Anna Lakoma ◽  
George Zogopoulos
Keyword(s):  
Real World ◽  
Cancer Susceptibility ◽  
Molecular Profiling ◽  
Ductal Adenocarcinoma ◽  
Precision Oncology ◽  
Sequencing Technologies ◽  
Cancer Susceptibility Genes ◽  
Challenges And Opportunities ◽  
Next Generation Sequencing Ngs ◽  
Insight Into

The advent of next-generation sequencing (NGS) has provided unprecedented insight into the molecular complexity of pancreatic ductal adenocarcinoma (PDAC). This has led to the emergence of biomarker-driven treatment paradigms that challenge empiric treatment approaches. However, the growth of sequencing technologies is outpacing the development of the infrastructure required to implement precision oncology as routine clinical practice. Addressing these logistical barriers is imperative to maximize the clinical impact of molecular profiling initiatives. In this review, we examine the evolution of precision oncology in PDAC, spanning from germline testing for cancer susceptibility genes to multi-omic tumor profiling. Furthermore, we highlight real-world challenges to delivering precision oncology for PDAC, and propose strategies to improve the generation, interpretation, and clinical translation of molecular profiling data.

Assessing real-world outcomes in precision oncology by linking clinical genomic testing to electronic medical records.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18091-e18091
Author(s):  
Debajyoti Datta ◽  
Theodore Goldstein ◽  
Atul Butte
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Patients ◽  
Relational Database ◽  
Real World ◽  
Molecular Profiling ◽  
Genomic Testing ◽  
Precision Oncology ◽  
Clinical Sequencing ◽  
Clinical Genomic ◽  
Generation Sequencing

e18091 Background: With an ever-widening array of targeted therapies for cancer patients, clinical genomic testing has expanded rapidly in recent years. Tumor molecular profiling by next-generation sequencing is now considered a cornerstone of precision oncology, with the potential to offer patients with advanced cancers new therapeutic options. However, the overall impact of this testing remains unclear, and evidence demonstrating improvement in patient outcomes is lacking. The objective of this study is to assess the utility of clinical sequencing on the management of cancer patients. Methods: We present the development of a database that combines results of tumor mutation profiling using various next-generation sequencing panels (both external commercial tests and our institution’s internal sequencing panel), with a variety of data points from a de-identified representation of our institution’s electronic medical record (EMR). Assembling this data from different sources into a common relational database permits efficient retrospective analysis of real-world outcomes in patients with advanced cancers. Results: This study included over 3000 patients seen at UCSF Comprehensive Cancer Center since 2013. With this linked data set we analyzed the rate at which tumor molecular profiling affected clinical decision making, identified barriers to the efficient use of testing, and assessed for disparities in utilization. For example, by measuring patient survival relative to the clinical intervention of genomic testing for the subset of patients with a date of death recorded in our EMR, we found that a small fraction of patients died before results returned and any action could be taken, especially in cases of pancreatic cancer. Conclusions: We demonstrate that a common relational database combining clinical sequencing results with real-world EMR data provides insights into the optimal clinical use of tumor molecular profiling. This provides new opportunities for advancing precision oncology initiatives and improving patient care, such as identifying which cancer patients should get genomic testing and efficiently matching patients to clinical trials.

scholarly journals Hereditary Breast Cancer: The Era of New Susceptibility Genes

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Paraskevi Apostolou ◽  
Florentia Fostira
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Breast Cancer Susceptibility ◽  
Cowden Syndrome ◽  
Susceptibility Genes ◽  
Current Data ◽  
Li Fraumeni Syndrome ◽  
Sequencing Technologies ◽  
Cancer Susceptibility Genes ◽  
New Findings

Breast cancer is the most common malignancy among females. 5%–10% of breast cancer cases are hereditary and are caused by pathogenic mutations in the considered referenceBRCA1andBRCA2genes. As sequencing technologies evolve, more susceptible genes have been discovered andBRCA1andBRCA2predisposition seems to be only a part of the story. These new findings include rare germline mutations in other high penetrant genes, the most important of which includeTP53mutations in Li-Fraumeni syndrome,STK11mutations in Peutz-Jeghers syndrome, andPTENmutations in Cowden syndrome. Furthermore, more frequent, but less penetrant, mutations have been identified in families with breast cancer clustering, in moderate or low penetrant genes, such asCHEK2,ATM,PALB2,andBRIP1. This paper will summarize all current data on new findings in breast cancer susceptibility genes.

scholarly journals ATM Serine/Threonine Kinase and its Role in Pancreatic Risk

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 108 ◽  
Author(s):  
Neha Nanda ◽  
Nicholas J. Roberts
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Susceptibility ◽  
Ductal Adenocarcinoma ◽  
Ataxia Telangiectasia Mutated ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cancer Susceptibility Genes ◽  
History Of ◽  
Impact Patient Care ◽  
Generation Sequencing

Next-generation sequencing has led to the recent discovery of several novel pancreatic cancer susceptibility genes. These genes include ataxia telangiectasia mutated (ATM), a serine/threonine kinase that is an integral component of DNA repair. Pathogenic germline ATM variants are frequently identified in patients with pancreatic ductal adenocarcinoma (PDAC) with and without a family history of the disease. Loss of ATM is also a frequent somatic event in the development of PDAC. These discoveries have advanced our understanding of the genetic basis of pancreatic cancer risk and will impact patient care through appropriate patient–risk stratification; personalized screening and early detection efforts; and, for some, targeted therapy.

Unselected germline screening in pancreatic adenocarcinoma yields high rates of pathogenic and likely pathogenic variants (PV) in hereditary cancer susceptibility genes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1582-1582
Author(s):  
Carol Cremin ◽  
Michael Lee ◽  
Quan Hong ◽  
Carolyn Hoeschen ◽  
Steve Kalloger ◽  
...  
Keyword(s):  
Hereditary Cancer ◽  
Cancer Susceptibility ◽  
Susceptibility Genes ◽  
Population Substructure ◽  
Ductal Adenocarcinoma ◽  
Familial Pancreatic Cancer ◽  
Research Protocol ◽  
Cascade Screening ◽  
True Incidence ◽  
Cancer Susceptibility Genes

1582 Background: Recent literature cites a germline mutation rate of 3.9-15.1% in patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) depending on breadth of genes tested, pre-selection of high-risk history and population substructure. True incidence of germline mutations in PDAC is unknown in unselected population. Methods: All patients (pts) diagnosed with PDAC in the province of British Columbia, Canada and referred to the Hereditary Cancer Program, were eligible to undergo 30 gene Color saliva kit testing under a research protocol, or clinical multigene testing if they met existing local criteria regardless of whether they signed on to the protocol. Any healthcare provider or patients themselves could refer. Results: 243 pts were referred between August 2016 and October 2018 but 25.1% (61) declined and 9.1% (22) died before testing. Of the 141 pts who consented to research protocol and completed germline testing, median age was 64 (46.1-81.0), 68.8% were European, 1.4% Ashkenazi Jewish heritage, 42% male, 61% non-smoker, 24.1% had personal history of a second cancer and 39% had metastatic disease. Baseline characteristics were similar between the PV positive and uninformative group. 20/25 PV were in known PDAC susceptibility genes with cascade screening implications (ATM (9), BRCA2 (4), BRCA2/ATM (1), CDKN2A (4), and MSH2 (2)). Excluding the 3 PV identified through carrier testing (1) and prior research identification (2), the rate of PV in unselected, unrelated PDAC cohort is 22/138 (15.9%). Utilizing previous NCCN criteria for BRCA1/BRCA2 testing or for familial pancreatic cancer did not appear to select for patients with higher risk of PV positive (12/65 (18.4%) PV positive rate versus 13/76 (17.1%) in those that didn’t meet criteria). Previous criteria would have missed 52% (13/25) PV in ATM (6), BRCA2/ATM (1), BRCA2 (2), MSH2 (2), NBN (1), CHEK2 (1). To date, a third of families with PV identified have accessed cascade testing in 38 relatives. Conclusions: Given the high incidence of 15.9% PV in hereditary cancer susceptibility genes, our data support recommendations for universal germline genetic testing of PDAC pts.

Precision Oncology: Who, How, What, When, and When Not?

2017 ◽  
pp. 160-169 ◽  
Author(s):  
Lee Schwartzberg ◽  
Edward S. Kim ◽  
David Liu ◽  
Deborah Schrag
Keyword(s):  
Cost Effective ◽  
Molecular Profiling ◽  
Molecular Testing ◽  
Precision Oncology ◽  
High Quality ◽  
Tissue Samples ◽  
Development Of Resistance ◽  
Target Drug ◽  
Number Of Patients ◽  
Next Generation Sequencing Ngs

Precision oncology, defined as molecular profiling of tumors to identify targetable alterations, is rapidly developing and has entered the mainstream of clinical practice. Genomic testing involves many stakeholders working in a coordinated fashion to deliver high-quality tissue samples to high-quality laboratories, where appropriate next-generation sequencing (NGS) molecular analysis leads to actionable results. Clinicians should be familiar with the types of genomic variants reported by the laboratory and the technology used to determine the results, including limitations of current testing methodologies and reports. Interpretation of genomic results is best undertaken with multidisciplinary input to reduce uncertainty in clinical recommendations relating to a documented variant. Non–small cell lung cancer has emerged as a prototype disease where genomic data from at least several well-documented alterations with approved targeted agents are essential for optimal treatment from diagnosis of advanced disease. Due to the development of resistance to targeted therapies, resampling and retesting of tumors, including using liquid biopsy technology after clinical progression, may be important in making treatment decisions. The value of molecular profiling depends on avoiding both underutilization for well-documented variant target-drug pairs and overutilization of variant-drug therapy without proven benefit. As techniques evolve and become more cost effective, the use of molecular testing may prove to add more specificity and improve outcomes for a larger number of patients.

scholarly journals ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 687 ◽  
Author(s):  
Nicholas R. Jette ◽  
Mehul Kumar ◽  
Suraj Radhamani ◽  
Greydon Arthur ◽  
Siddhartha Goutam ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Precision Oncology ◽  
Ataxia Telangiectasia Mutated ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Cancer Susceptibility Genes ◽  
Potential Applications

Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes

2021 ◽  
Author(s):  
Anna M Varghese ◽  
Isha Singh ◽  
Rituraj Singh ◽  
Siddharth Kunte ◽  
Joanne F Chou ◽  
...  
Keyword(s):  
Early Onset ◽  
Pancreas Cancer ◽  
Cancer Susceptibility ◽  
Ductal Adenocarcinoma ◽  
Molecular Characteristics ◽  
Wild Type ◽  
Entire Cohort ◽  
Cancer Susceptibility Genes ◽  
Germline Variant ◽  
Germline Testing

Abstract Background Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC). Methods Institutional databases were queried for demographics, treatment history, genomic results and outcomes. Overall survival (OS) from date of diagnosis was estimated using Kaplan-Meier method. Results Four hundred and fifty patients with EOPC were identified at Memorial Sloan Kettering between 2008 and 2018. Median OS was 16.3 months (95% confidence interval [CI] = 14.6 to 17.7 months) in the entire cohort and 11.3 months (95% CI = 10.2 to 12.2 months) for patients with stage IV disease at diagnosis. One hundred and thirty-two (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1 and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. One hundred and thirty-eight (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV) and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a pathogenic germline variant. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared to patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95%CI = 0.26 to 0.69). Conclusions PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.

scholarly journals STAMPede: A Precision Oncology Catalogue of Solid Tumors

2020 ◽  
Author(s):  
Jessica W. Chen ◽  
Haik Kalantarian ◽  
Christian A. Kunder ◽  
James L. Zehnder ◽  
Henning Stehr ◽  
...  
Keyword(s):  
Healthcare Providers ◽  
Genetic Data ◽  
Molecular Profiling ◽  
Precision Oncology ◽  
Summary Statistics ◽  
Sequencing Data ◽  
Web Based ◽  
Cancer Types ◽  
Tumor Sequencing ◽  
Insight Into

ABSTRACTMolecular profiling of tumor specimens is a key contributor in the application of precision medicine toward patient care in oncology. The presence of genetic mutational data may provide insight into the etiology of the cancer and inform about the available therapeutic options for patients diagnosed with various cancer types. However, the ability to centrally organize, structure, and visualize this genetic data can be hindered by the lack of necessary computational infrastructure. Here we present a somatic tumor data visualization portal titled STAMPede that utilizes tumor sequencing data from an in-house solid tumor oncology sequencing panel at Stanford Health Care. STAMPede is intended to provide Stanford healthcare providers and clinical researchers an easy to navigate web-based portal to query and display gene-, variant-, and cancer-level summary statistics.

Tumor testing in men with prostate cancer to predict for germline DNA-damage repair mutations.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 229-229
Author(s):  
Maria Isabel Carlo ◽  
Yelena Kemel ◽  
Kelsey Breen ◽  
Karen Anne Cadoo ◽  
Michael Francis Walsh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Germline Mutation ◽  
Cancer Susceptibility ◽  
Germline Mutations ◽  
Founder Mutations ◽  
Cancer Susceptibility Genes ◽  
Damage Repair ◽  
Next Generation Sequencing Ngs ◽  
Current Guidelines ◽  
Germline Testing

229 Background: Current guidelines recommend genetic testing for patients (pts) who have BRCA1/2 mutations on tumor-only testing, where germline is not subtracted. The clinical utility of this approach, and possible inclusion of other DDR genes associated with cancer susceptibility, has not been examined in men with prostate cancer. Methods: Pts with mostly advanced prostate cancer were prospectively enrolled to a matched tumor-germline DNA sequencing protocol and consented for disclosure of germline results. Germline analysis was done with an institutional, CLIA-certified next generation sequencing (NGS) platform (MSK-IMPACT) and analyzed for likely pathogenic or pathogenic germline mutations in at least 76 cancer susceptibility genes. Clinical data was retrieved from the medical record. We report on the frequencies in the germline and in the tumor of a subset of DDR genes. Results: 1243 men had analysis of both germline and tumor. Median age 64 (range 35-90). 12% had a second malignancy and 40% reported a relative with prostate cancer. 19% were of Ashkenazi Jewish (AJ) descent. 330 (27%) had any mutation in BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, MSH2, MSH6, MLH1, PMS2. 127 (10%) had a germline mutation, of which 36% were AJ founder mutations. For each gene, the percentage of mutations found in germline and tumor is shown in the table. Conclusions: Of prostate cancer pts found to have any DDR mutation on tumor-germline testing, 29% had a germline mutation. Proportion of germline mutations was highest for PALB2, CHEK2 and BRCA2. These findings not only support germline testing when BRCA1/2 mutations are found tumor-only sequencing, but also support germline testing when other DDR mutations are seen. Clinical trial information: NCT01775072. [Table: see text]

scholarly journals Clinical Significance of Germline Cancer Predisposing Variants in Unselected Patients with Pancreatic Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 198
Author(s):  
Elena Fountzilas ◽  
Alexia Eliades ◽  
Georgia-Angeliki Koliou ◽  
Achilleas Achilleos ◽  
Charalambos Loizides ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Significant Proportion ◽  
Disease Stage ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes ◽  
Mutational Status ◽  
Predictive Role

Our aim was to determine the prevalence, prognostic and predictive role of germline pathogenic/likely pathogenic variants (P/LPVs) in cancer predisposing genes in patients with pancreatic ductal adenocarcinoma (PDAC). Germline testing of 62 cancer susceptibility genes was performed on unselected patients diagnosed from 02/2003 to 01/2020 with PDAC, treated at Hellenic Cooperative Oncology Group (HeCOG)-affiliated Centers. The main endpoints were prevalence of P/LPVs and overall survival (OS). P/LPVs in PDAC-associated and homologous recombination repair (HRR) genes were identified in 22 (4.0%) and 42 (7.7%) of 549 patients, respectively. P/LPVs were identified in 16 genes, including ATM (11, 2.0%) and BRCA2 (6, 1.1%), while 19 patients (3.5%) were heterozygotes for MUTYH P/LPVs and 9 (1.6%) carried the low-risk allele, CHEK2 p.(Ile157Thr). Patients carrying P/LPVs had improved OS compared to non-carriers (22.6 vs. 13.9 months, p = 0.006). In multivariate analysis, there was a trend for improved OS in P/LPV carriers (p = 0.063). The interaction term between platinum exposure and mutational status of HRR genes was not significant (p-value = 0.35). A significant proportion of patients with PDAC carries clinically relevant germline P/LPVs, irrespectively of age, family history or disease stage. The predictive role of these P/LPVs has yet to be defined. ClinicalTrials.gov Identifier: NCT03982446.

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