comprehensive genomic profiling
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2021 ◽  
pp. 1-10
Author(s):  
David M. Thomas ◽  
Joanne M. Hackett ◽  
Stjepko Plestina

<b><i>Objectives:</i></b> “Personalized healthcare” is generating new approaches to disease management by considering inter-individual variability in genes, environment, and lifestyle. Technologies such as comprehensive genomic profiling (CGP) are drivers of this shift. Here, we address the significant hurdles to the equitable implementation of CGP into routine clinical practice. <b><i>Methods:</i></b> This article draws on published evidence on the value of genomic profiling, as well as interviews with nine academic and clinical experts from six different countries to validate findings and test policy proposals for reforms. <b><i>Results:</i></b> The potential benefits of CGP extend beyond direct patient outcomes, to healthcare systems with societal and economic impacts. Among key barriers impeding integration into routine clinical practice are the lack of infrastructure to ensure reliable clinical testing and the limited understanding of genomics among healthcare personnel. In addition, the absence of health economic evidence supporting broader use of CGP is creating concerns for payers regarding the systemic benefits and affordability of this technology. <b><i>Conclusion:</i></b> Policy proposals that aim to improve equitable patient access to CGP will need to consider new funding models, health technology assessment processes that capture both patient and systemic benefits, and appropriate regulatory standards to determine the quality of genomic profiling tests.


2021 ◽  
pp. candisc.0669.2021
Author(s):  
Shinichi Yachida ◽  
Yasushi Totoki ◽  
Michael Noe ◽  
Yoichiro Nakatani ◽  
Masafumi Horie ◽  
...  

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260089
Author(s):  
Jeffrey M. Conroy ◽  
Sarabjot Pabla ◽  
Sean T. Glenn ◽  
R. J. Seager ◽  
Erik Van Roey ◽  
...  

Timely and accurate identification of molecular alterations in solid tumors is essential for proper management of patients with advanced cancers. This has created a need for rapid, scalable comprehensive genomic profiling (CGP) systems that detect an increasing number of therapeutically-relevant variant types and molecular signatures. In this study, we assessed the analytical performance of the TruSight Oncology 500 High-Throughput assay for detection of somatic alterations from formalin-fixed paraffin-embedded tissue specimens. In parallel, we developed supporting software and automated sample preparation systems designed to process up to 70 clinical samples in a single NovaSeq 6000TM sequencing run with a turnaround time of <7 days from specimen receipt to report. The results demonstrate that the scalable assay accurately and reproducibly detects small variants, copy number alterations, microsatellite instability (MSI) and tumor mutational burden (TMB) from 40ng DNA, and multiple gene fusions, including known and unknown partners and splice variants from 20ng RNA. 717 tumor samples and reference materials with previously known alterations in 96 cancer-related genes were sequenced to evaluate assay performance. All variant classes were reliably detected at consistent and reportable variant allele percentages with >99% overall accuracy and precision. Our results demonstrate that the high-throughput CGP assay is a reliable method for accurate detection of molecular alterations in support of precision therapeutics in oncology. The supporting systems and scalable workflow allow for efficient interpretation and prompt reporting of hundreds of patient cancer genomes per week with excellent analytical performance.


Author(s):  
Michael R Clay ◽  
Emilia M Pinto ◽  
Lauren Fishbein ◽  
Tobias Else ◽  
Katja Kiseljak-Vassiliades

Abstract Context Adrenocortical carcinoma (ACC) is a rare endocrine malignancy that affects patients across the age spectrum. Although the overall survival in patients with ACC is poor, there is significant heterogeneity in terms of outcomes, presentation, and underlying genetic drivers. Evidence Acquisition This review is based on the evidence collected from primary research studies, expert reviews, and published guidelines. The studies were identified through PubMed search with key words “adrenocortical carcinoma”, “prognosis”, “pathology” and “genetics”. The PubMed search was complemented by authors’ expertise, research, and clinical experience in the field of ACC. Evidence Synthesis Identification of biomarkers has been critical to gain better insight into tumor behavior and to guide therapeutic approach to patients. Tumor stage, resection status and Ki67 are pathological tumor characteristics that have been identified as prognosticators in patients with ACC. Cortisol excess also correlates with worse prognosis. Clinical and histopathological characteristics help stratify patient outcomes, yet still up to 25% of patients have a different outcome than predicted. To bridge this gap, comprehensive genomic profiling studies have characterized additional profiles that correlate with clinical outcomes. In addition, studies of clinically applicable molecular markers are underway to further stratify outcomes in patients with ACC tumors. Conclusions Clinical predictors in combination with pathological markers play a critical role in the approach to patients with ACC. Recent advances in genetic prognosticators will help extend the stratification of these tumors and contribute to a personalized therapeutic approach to patients with ACC.


2021 ◽  
Author(s):  
Richard Wood ◽  
Daniel Rayson ◽  
Thomas Arnason ◽  
Ryan C DeCoste ◽  
Daniel Gaston ◽  
...  

Abstract Background Comprehensive genomic profiling (CGP) is an essential tool in precision medicine, providing diagnostic, prognostic, and predictive (therapeutic) information that enables personalized optimal care for cancer patients. We present the case of a 54-year-old woman with stage IV large-cell neuroendocrine carcinoma (LCNEC) of the colon with liver and nodal metastases with complete response to therapy and demonstrate the value of CGP in identifying potential targets for treatment in these tumors. Results CGP performed on the tumor showed pathogenic mutations in multiple oncogenes and tumor suppressor genes including BRCA1, BAP1, and BRAF, high tumor mutation burden (TMB), and high microsatellite instability (MSI-H). Treatment with platinum-based therapy resulted in a complete radiographic response of the metastases, with no evidence of recurrence after 6.5 years. Assessment by Medical Genetics did not identify any evidence of hereditary cancer syndrome. The dramatic response to therapy is likely due to loss of BRCA1 and/or BAP1 function, as deleterious mutations in both genes predict response to platinum-based therapy through exploitation of deficient homologous recombination repair (HRR). The information provided by CGP also suggested potential tumor sensitivity to poly(ADP-Ribose) polymerase inhibitors (PARPi), immunotherapy (IT) and BRAF/MEK inhibitor therapy, should the tumor recur. Conclusion This case highlights the value of CGP in guiding diagnosis and management of rare and aggressive tumors.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A661-A661
Author(s):  
Samuel Schellenberg ◽  
Leeseul Kim ◽  
Young Kwang Chae

BackgroundImmune checkpoint inhibitors have revolutionized care for a number of different cancer types. For colorectal cancer (CRC), a leading cause of cancer-related death in the United States, programmed cell death protein 1 (PD-1) inhibition is a treatment option for certain subsets of patients. High microsatellite instability (MSI-H) tumors are immunogenic, and thus PD-1 inhibition is first-line treatment. Anti-PD-1 therapy is generally not utilized for microsatellite stable (MSS) patients. Tumor mutational burden (TMB) is another predictive biomarker for immunotherapy response in all solid tumors. Here we present the case of a patient with MSS, TMB-H CRC resistant to multiple lines of chemotherapy, who responded to anti-PD-1 monotherapy.MethodsCase presentation.ResultsA 64-year-old man with a family history significant for colon cancer was diagnosed with colorectal cancer, revealed to be moderately differentiated mucinous adenocarcinoma (stage IIIC) on biopsy. A tissue-based comprehensive genomic profiling of the cancer showed KRASG12D and ERBB2 amplification, microsatellite-stable, and TMB of 11mut/mB (FoundationOne). The patient progressed on multiple lines of therapy with multiple metastatic sites, and was briefly put under home hospice with diffuse abdominal pain and weight loss. The patient was started on pembrolizumab monotherapy, around 3.5 years after initial presentation. After five months on pembrolizumab, imaging showed significant improvement in pulmonary, hepatic, adrenal, and retroperitoneal metastases and the patient demonstrated partial response to treatment according to RECIST 1.1 criteria. The patient's carcinoembryonic antigen (CEA) levels had decreased from 45 ng/mL at treatment initiation to 2.8 ng/mL, and ctDNA analysis showed a blood TMB decrease from 31.58 mut/mB at treatment initiation to .96 mut/mB (figure 1), accompanied by decreases in the variant allele frequencies of the five most prevalent variants at the time of treatment initiation (Guardant 360). The patient's pain had nearly resolved by this point and pain medications were tapered off.ConclusionsThis case demonstrates the existence of a subset of CRC patients who are MSS but TMB-H and may respond to immune checkpoint blockade. Comprehensive genomic profiling must be utilized in order to not miss this subset of patients. The mechanism of response in this subset of patients is unknown but warrants further exploration. Further studies should clarify the mechanism and likelihood of response to immunotherapy in MSS, TMB-H CRC patients, as this is critical to providing effective treatment for this subset.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 631 Figure 1Carcinoembryonic antigen (CEA) and blood tumor mutational burden (TMB) levels through six cycles of treatment with pembrolizumab


2021 ◽  
Author(s):  
B Manning-Geist ◽  
S Gordhandas ◽  
A Da Cruz Paula ◽  
B Weigelt ◽  
Y Liu ◽  
...  

2021 ◽  
pp. 1475-1482
Author(s):  
Natalja Eigeliene ◽  
Jatta Saarenheimo ◽  
Viktor Wichmann ◽  
Pia Österlund ◽  
Antti Jekunen

In the era of personalized medicine, systemic treatment with chemotherapy in combination with targeted drugs, tailored according to <i>RAS</i> and <i>BRAF</i> status, has improved the survival of patients with metastatic colorectal cancer (mCRC), but curative resection of metastases provides the only chance of cure. Here, we present a 40-year-old male with rectal adenocarcinoma and multiple bilateral synchronous liver metastases who has achieved long-term remission with multimodal treatment without resection of all metastatic lesions. This case emphasizes the need of repeated multidisciplinary team assessments and change of treatment intent if extraordinary responses are seen. The initial therapy consisted of short-course radiotherapy and surgery of the primary tumor followed by oxaliplatin-based combination chemotherapy and panitumumab with disease control intent. A complete radiologic response in &#x3e;20 liver metastases in segments II–VIII was obtained. A biopsy-verified relapse of 3 liver metastases occurred at 9 months of treatment pause. Subsequently, major liver resection of 8 lesions was performed (4 with adenocarcinoma and 4 with cicatrix showing the challenge of disappearing lesions), followed by 6 months of adjuvant-like therapy. No relapse in MRI, PET, or CT has been noted since liver resection 6 years ago. Comprehensive genomic profiling of the primary tumor and liver metastases had similar driver mutations representing a low level of gene alteration and low diversity, possibly explaining the exceptional treatment response.


Oncotarget ◽  
2021 ◽  
Vol 12 (21) ◽  
pp. 2169-2176
Author(s):  
Subotheni Thavaneswaran ◽  
Mandy Ballinger ◽  
Phyllis Butow ◽  
Bettina Meiser ◽  
David Goldstein ◽  
...  

Author(s):  
Toshi Ghosh ◽  
Patricia T. Greipp ◽  
Darlene Knutson; ◽  
Sara Kloft-Nelson; ◽  
Sarah Jenkins ◽  
...  

Context.— Comprehensive genomic profiling has demonstrated that approximately 20% of pancreatic carcinomas with acinar differentiation harbor potentially targetable BRAF fusions that activate the MAPK pathway. Objectives.— To validate the above finding by BRAF break-apart fluorescence in situ hybridization (FISH) in a large series of pure acinar cell carcinomas (ACCs), evaluate tumors for the presence of BRAF V600E mutations, and compare clinicopathologic features of tumors with BRAF rearrangements with those without. Design.— Thirty cases of pure ACC and 6 cases of mixed acinar-neuroendocrine carcinoma (ACC-NEC) were retrieved. A break-apart FISH probe was used to detect BRAF rearrangements. Immunohistochemistry for BRAF V600E was performed. Results.— BRAF rearrangements by FISH were found in 6 of 36 cases (17%), 5 of which were pure ACC and 1 was a mixed ACC-NEC. Follow-up was available in 29 of 36 (81%). The median survival was 22 months for BRAF-rearranged cases and 16 months for BRAF-intact cases; the 2-year overall survival was 50% for BRAF-rearranged cases and 35% for BRAF-intact cases. No significant clinicopathologic differences were identified in cases with BRAF rearrangement compared with those without BRAF rearrangement. BRAF V600E mutation was identified in 2 of 34 cases (6%), both of which were pure ACC and were BRAF-intact by FISH. Conclusions.— This study supports the finding that BRAF rearrangements are present in approximately 20% of cases and identified BRAF V600E mutations in approximately 5% of cases. These cases may benefit from targeted therapy.


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