Advancing precision medicine in clinical oncology: Whole exome paired tumor-normal DNA and RNA sequencing at a single-institution cancer center.

e14006 Background: Next generation sequencing (NGS) allows for reliable, comprehensive and cost-effective identification of clinically actionable genetic and genomic alterations. The increasing adoption of NGS in clinical oncology has increased our ability to identify germline alterations predisposing to cancer development as well as somatic changes enabling prescription of individualized cancer treatment and enhanced clinical trial participation. Here we summarize implementation of an NGS-based precision medicine initiative involving oncology patients from a single institution cancer center. Methods: IRB-approved NGS matched whole exome (WES) germline and solid tumor somatic tumor sequencing together with somatic tumor RNA sequencing (RNA-seq) were performed using germline DNA extracted from peripheral blood lymphocytes and nucleic acids for tumor DNA and RNA sequencing obtained from formalin-fixed, paraffin-embedded tumor specimens. Results of sequencing and analyses were presented to a multi-disciplinary tumor board to establish recommendations for management of germline pathogenic variation, therapeutic drug matching, clinical trials eligibility and molecularly informed patient prognosis. Results: A total of 1,005 patients completed sequencing. Germline and somatic WES exceeded 100X and 250X mean target coverage, respectively; somatic RNA-seq exceeded 200 million mean reads. Patients ranged in age from 17 to 90 years. The study cohort comprised comparable numbers of female (51%) and male (49%) patients. Ethnicities and races were broadly represented with 22% of participants identifying as Hispanic, 14% as Asian, 4% as Black, 55% as Non-Hispanic White and 5% as other. The most common solid tumor histological classification was colorectal (18%), followed by breast (16%), prostate (7%), head and neck (7%), sarcoma (7%), ovarian (5%), melanoma (4%) and lung (3%). Bioinformatic analyses and precision medicine tumor board review established that 12% of patients harbored a germline pathogenic variant and 43% carried clinically actionable genetic/genomic alterations; a majority of patients met molecular requirements for participation in a clinical trial. Conclusions: This study confirms the feasibility and utility of clinical NGS and precision medicine tumor board review in clinical oncology to identify germline genetic pathology, deliver personalized cancer therapeutics, increase clinical trial enrollment and clarify diagnosis and prognosis.

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Yale Cancer Center Precision Medicine Tumor Board: one tumour, multiple targets

The Lancet Oncology ◽

10.1016/s1470-2045(18)30759-9 ◽

2018 ◽

Vol 19 (12) ◽

pp. 1567-1568 ◽

Cited By ~ 1

Author(s):

Tyler Stewart ◽

Karin Finberg ◽

Zenta Walther ◽

Jeffrey L Sklar ◽

Navid Hafez ◽

...

Keyword(s):

Precision Medicine ◽

Tumor Board ◽

Cancer Center ◽

Multiple Targets

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Yale Cancer Center Precision Medicine Tumor Board: new technology, new drugs, and the value of repeat testing

The Lancet Oncology ◽

10.1016/s1470-2045(20)30010-3 ◽

2020 ◽

Vol 21 (3) ◽

pp. 343-344

Author(s):

Navid Hafez ◽

Zenta Walther ◽

Joseph P Eder ◽

Jeffrey L Sklar ◽

Scott N Gettinger ◽

...

Keyword(s):

Precision Medicine ◽

New Technology ◽

New Drugs ◽

Tumor Board ◽

Cancer Center ◽

Repeat Testing

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Tumor genomic profiling (TGP) in metastatic colorectal cancer (CRC): Bridging the community and the tertiary cancer center through genomic consultation (GC).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.538 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 538-538

Author(s):

John M. Kaczmar ◽

Karen S. Gustafson ◽

Yu Ning Wong ◽

Carl J. Minniti ◽

Vijay Krishna Sandilya ◽

...

Keyword(s):

Higher Education ◽

Clinical Trial ◽

Remote Access ◽

Tumor Board ◽

Cancer Center ◽

Trial Participation ◽

Community Patterns ◽

High Expectations ◽

Improve Life Expectancy ◽

Tertiary Center

538 Background: TGP of cancers is increasingly accessible to oncologists (MDs) and patients (pts). Despite efforts to provide clinical interpretation and decision support within TGP reports, results are complex and their interpretation remains fraught with uncertainty. In an ongoing pilot, we provide community MDs access to a 50-gene next generation sequencing (NGS)-based TGP assay and expert guidance through remote access to genomic tumor board (GTB) resources via telephone-based GC. Our goal is to explore how access to GTB expertise impacts community patterns of care. In parallel, we examine MDs and pts perceptions of TGP with a focus on awareness and expectations. Methods: MDs from 4 community practices participated. Participating MDs and their pts with metastatic unresectable CRC receiving 2nd line or beyond chemotherapy provide informed consent and complete baseline and follow-up surveys. Adequate tumor samples are tested with the Fox Chase 50-gene NGS-based TGP assay. All results are presented at a bi-monthly GTB or are reviewed with the GTB chair. MDs have a ~10 min GC by telephone with the PI to summarize findings and convey GTB recommendations. Results: 9 MDs have enrolled 22 pts and TGP has been completed on 15 samples (4 additional in process and 3 insufficient for TGP). Pts report diverse ancestry (24% Hispanic or non-White) and SES (33% income < $25K). To date, all completed TGPs have reported > 1 mutation. Of 11 pts who have received TGP results, 1 has sought consultation at a tertiary center for a clinical trial. Pts with higher education were more aware of TGP (p = 0.05). Most (80%) pts felt TGP would improve their MD’s ability to treat their cancer. Male sex and higher education were associated with stronger belief that TGP will improve life expectancy. Conclusions: A partnership with community MDs to provide TGP and GTB expertise through GC is feasible. Pts exhibit high expectations of TGP, despite limited data to support improved outcomes from TGP-guided treatment. Further research into optimizing partnership between community MDs and tertiary centers is valuable to guide treatment and clinical trial participation based on TGP results.

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Precision oncology for the treatment of salivary gland tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17577 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17577-e17577

Author(s):

Damian Tobias Rieke ◽

Mario Lamping ◽

Serge Leyvraz ◽

Theo Daniel Kim ◽

Lutz Brinkmann ◽

...

Keyword(s):

Salivary Gland ◽

Rna Sequencing ◽

Salivary Gland Tumors ◽

Tumor Board ◽

Molecular Testing ◽

Precision Oncology ◽

Rna Seq ◽

Mixed Response ◽

Antiandrogen Therapy ◽

Panel Sequencing

e17577 Background: Salivary gland tumors (SGT) represent a rare and heterogeneous group of malignancies. No standard treatment exists in the advanced situation and the prognosis is poor. We here report characteristics and clinical outcomes of patients with SGT discussed at the Charité molecular tumor board (MTB). Methods: Patients with advanced cancer and no curative treatment option were discussed at the Charité MTB. Eligible patients underwent fresh tissue sampling and subsequent whole exome (WES) and RNA sequencing (RNA-seq) and immunohistochemical analyses (EGFR, HER2, AR as well as validation tests) or panel sequencing. Results from molecular testing were discussed at the MTB and patients were followed-up after recommendations were made. Results: 24 patients (median age 56 years, 13 male, 11 female) with advanced SGT were presented at the MTB between 2016 and 2019 (9 adenoidcystic carcinomas, 5 adenocarcinomas, 3 mucoepidermoid, 2 carcinosarcoma, 5 miscellaneous). WES/RNA sequencing was performed on tumor tissue from 16 patients. 2 patients were not included in the sequencing program and WES/RNA-Seq was ongoing for another 4 patients at the time of analysis. For another 2 patients, panel sequencing and IHC analysis, respectively was done. Results from analyses were discussed and a median of 2 recommendations, ranked by priority according to prespecified evidence levels, were made for 17 patients, each. Most commonly proposed treatment options by the MTB were FGFR inhibitors in 6 patients, mTOR or PARP inhibitors in 5 each, EGFR, HDAC inhibitors or antiandrogen therapy in 4, each. Treatments following MTB recommendations were initiated in 8 patients, 1 of which received a second recommended therapy after progression (antiandrogen therapy in 4, EGFR inhibitor in 2, a PDGFR, mTOR and PARP inhibitor in 1, each). A clinical benefit (CR = 1; Mixed Response = 1, SD = 3) was achieved in 5 patients, including a complete response in a patient with a metastatic adenocarcinoma of the parotid gland, treated with antiandrogen therapy. Conclusions: Precision oncology represents a feasible treatment strategy in patients with advanced SGT and shows early evidence of activity in a subset of patients. These results suggest further exploration of personalized therapy in these hard-to-treat tumors.

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Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study—An Asian Tertiary Cancer Center Experience

JCO Precision Oncology ◽

10.1200/po.20.00261 ◽

2021 ◽

pp. 859-875

Author(s):

Amanda O. L. Seet ◽

Aaron C. Tan ◽

Tira J. Tan ◽

Matthew C. H. Ng ◽

David W. M. Tai ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Tumor Tissue ◽

Molecular Profiling ◽

Tumor Board ◽

Cancer Center ◽

Precision Oncology ◽

Molecular Tumor Board ◽

Tumor Types ◽

Tertiary Cancer Center

PURPOSE Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.

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Burkitt Lymphoma Genome Sequencing Project (BLGSP): Introduction

Blood ◽

10.1182/blood.v128.22.1760.1760 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1760-1760 ◽

Cited By ~ 1

Author(s):

Daniela S Gerhard ◽

Bruno Grande ◽

Nicholas Griner ◽

Corey Casper ◽

Sarah E. Gerdts ◽

...

Keyword(s):

Rna Sequencing ◽

Molecular Characterization ◽

Genome Sequencing ◽

Burkitt Lymphoma ◽

Research Funding ◽

Somatic Mutations ◽

Rna Seq ◽

Dna And Rna ◽

Pathology Review

Abstract Introduction: Burkitt Lymphoma (BL) is an aggressive B-cell lymphoma with a translocation involving MYC and immunoglobulin(Ig) loci. It is most common in children, but also affects adults, and occurs in sporadic, endemic and HIV-associated forms. The Epstein-Barr virus (EBV)-associated endemic subtype is the most common pediatric cancer in equatorial Africa, but also occurs in other parts of the world, for example in the rain forest of Brazil. Intensive chemotherapy is effective, but the associated toxicity requires supportive care that is not readily available in resource-poor regions. Previously published molecular characterization of small numbers of tumors indicated that the mutation profiles of endemic and sporadic cases are similar, but not identical. One goal of the BLGSP is to conduct comprehensive molecular characterization of BL by sequencing DNA and RNA from a large BL cohort - including endemic, sporadic, pediatric and adult cases - in order to define the genetic and phenotypic features that drive these cancers. These data will be analyzed with an intent toward developing new therapeutic strategies that can be deployed worldwide. Methods: The goal is to collect 160 BL cases, of which 50% will be endemic, 38% sporadic (pediatric and adult) and 12% from HIV+ patients. For the discovery phase, each tumor requires case-matching normal DNA as well as treatment, outcome and other clinical information. The optimal source of tumor DNA and RNA is from frozen tissue with at least 50% tumor nuclei, but FFPE immobilization is also accepted. Accrual locations include Africa, Brazil, Europe and the US. The BLGSP has developed extensive standard operating procedures for tissue collection, pathology review and tissue processing to reduce the variation associated with these parameters in the interpretation of the results (see https://ocg.cancer.gov/programs/cgci/projects/burkitt-lymphoma). The project also established procedures that allow sharing of all clinical and sample information through the National Cancer Institute Genomic Data Commons (https://gdc.cancer.gov). Molecular characterization includes whole genome sequencing of tumor and normal DNA (80X and 40X coverage, respectively), RNA-sequencing (RNA-seq) and micro-RNA sequencing. These data will enable the BLGSP to identify chromosomal rearrangements, chromosomal copy number alternations, somatic mutations (single nucleotide, insertions, deletions), viral insertions, expression signatures, viral expressions and miRNA regulation of transcripts. Results: To date we have accrued 80 cases of BL of which 75% passed diagnostic pathology review. There was an additional 25% attrition at the tissue processing stage, either due to low quality nucleic acids or low percent tumor nuclei. We have completed sequencing for 45 cases, all but one of which have a MYC translocation involving one of the 3 Ig loci; one case has a MYC rearrangement by FISH analysis that is being characterized further. We have identified recurrent mutations in ID3, DDX3X, ARID1A, FOXO1, TP53, SMARCA4 and other genes. Most mutations are supported by the RNA-seq data, which is also useful in defining the pattern of EBV genome transcription. Preliminary unsupervised hierarchical clustering and principal component analysis of gene expression data defined sample clusters that do not correspond to mutation status or EBV infection, warranting further investigation. Some genes accumulated somatic mutations in a BL subtype-specific fashion. Discussion: BLGSP is an ongoing international collaborative project that will provide a comprehensive molecular portrait of BL subtypes when completed, with the potential to suggest new molecular targets for therapy that can eventually lead to effective treatments that are less toxic than the current regimens. Disclosures Casper: Janssen: Consultancy, Research Funding; Roche: Consultancy, Other: Travel, Accommodation, Expenses; TempTime: Consultancy, Other: Travel, Accommodation, Expenses; Up to Date: Patents & Royalties; GSK: Other: Travel, Accommodation, Expenses. Abramson:Kite Pharma: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Noy:Pharmacyclics, LLC, an AbbVie Company: Other: travel, accommodations, expenses, Research Funding.

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Clinical utility of molecular testing to select therapy in relapsed/refractory non-Hodgkin lymphoma: Mayo Clinic Center for Individualized Medicine experience.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11571 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11571-11571

Author(s):

Nabila Nora Bennani ◽

Stephen Maxted Ansell ◽

Thomas E. Witzig ◽

Andew L. Feldman ◽

Tammy M McAllister ◽

...

Keyword(s):

Clinical Trial ◽

Targeted Therapy ◽

Precision Medicine ◽

Mayo Clinic ◽

Individualized Medicine ◽

Tumor Board ◽

Current Therapy ◽

Molecular Profile ◽

Molecular Testing ◽

Molecular Alterations

11571 Background: Relapsed/refractory (R/R) non-Hodgkin lymphomas (NHL) have a poor prognosis with limited treatment options. Our expanding knowledge of molecular alterations seen in R/R NHL allows identification of patients that potentially may benefit from a precision medicine approach. However, experience in routine clinical implementation of precision medicine has been limited. Here, we summarize our clinical experience in molecular characterization of RR NHL targeted therapy (TT) using next-generation sequencing (NGS), and selection of targeted therapy (TT) based on molecular profile. Methods: We conducted a prospective study in RR NHL through the Center for Individualized Medicine at Mayo Clinic. Consenting patients underwent NGS using FoundationOne Heme panel from biopsies done at time of relapse. Results of NGS were discussed at the Genomic Tumor Board and recommendations for TT were given based on matching specific molecular alteration(s) with potential agent(s) predicted to be active based on NGS. The agents could include FDA-approved, off-label use and clinical trial therapies. Results: 28 cases were enrolled: 18 aggressive NHL, 10 follicular lymphoma (FL). Molecular alterations were present in all cases. In aggressive B-cell NHL, CDKN2A/B gene cluster alterations were seen in 73% (8/11), while seen in only 1/7 T-cell lymphomas (TCL), and 1/10 FL. TP53 deletions were second most common genomic alterations in DLBCL (57%) and seen in 40% FL. JAK-STAT and ERBB pathways were altered in TCL (2/7 each). IGH-BCl-2 gene rearrangement were common in FL (70%), followed by MLL gene alterations (50%). Targetable mutations were present in 86% (24/28) of cases. A TT was recommended in all 24 cases, but received by 2 patients only. Remaining patients did not due to benefit from current therapy (10/24), ineligibility or lack of clinical trial (7/24) or interim clinical deterioration (5/24). Conclusions: Targetable mutations were identified in most cases of RR NHL with TT recommended for all cases. However, access to TT limits potential clinical benefit of molecular-based matching strategy. More studies are needed to assess impact on clinical outcomes.

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A virtual tumor board-driven synaptic knowledge network.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.8_suppl.89 ◽

2017 ◽

Vol 35 (8_suppl) ◽

pp. 89-89

Author(s):

Laurence J. Heifetz ◽

Ahrin B. Koppel ◽

Elaine Melissa Kaime ◽

Daphne Palmer ◽

Thomas John Semrad ◽

...

Keyword(s):

Clinical Trial ◽

Rural Areas ◽

Cancer Care ◽

Knowledge Network ◽

Tumor Board ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Hospital District ◽

Number Of Patients ◽

Tumor Boards

89 Background: In 2006, Tahoe Forest Hospital District—a 25-bed hospital in Truckee, CA, a mountain resort community one hour from regional and two hours from academic cancer services—designed and implemented an oncology program utilizing effective telecommunications with a committed academic partner, the UC Davis Comprehensive Cancer Center in Sacramento. Methods: The UC Davis Cancer Care Network was established with four remote cancer programs, enabling participation in daily virtual tumor boards, clinical trial enrollment, and quality assurance assistance. (Richard J. Bold, et. al., Virtual tumor boards: community-university collaboration to improve quality of care. Community Oncol 10(11):310-315, November 2013.; Laurence J. Heifetz, MD, et. al., A Model for Rural Oncology. J Oncol Pract, 7:168-171, May 2011.). An increasing number of patients were observed to in-migrate to Truckee from even more remote rural areas in the mountains. In 2013, the now Gene Upshaw Memorial Tahoe Forest Cancer Center developed four remote telemedicine clinics to allow even more physically distant patients the capacity to be followed locally. Results: Since we opened the remote telemedicine clinics, our Sullivan-Luallin patient satisfaction scores have averaged 4.82/5.00 for “overall satisfaction with the practice” and 4.90/5.00 for “recommending your provider to others”; our in-migration rate of patients from outside our primary catchment area increased from 43% to 52%: and clinical trial accrual rate averaged 10%. Conclusions: Reducing cancer health disparities is an ASCO mission. (cover, ASCO Connection, July 2014; Laurence J. Heifetz, MD. Country Docs with City Technology Can Address Rural Cancer Care Disparities. Oncol, 29(9):641-644, September 2015.). We believe this synaptic knowledge network effectively addresses that mission for rural communities. This model can be scaled in many configurations to address the inherent degradation of quality care as a function of physical distance to an academic center that rural doctors and patients deal with on a daily basis. The key is to insist on a cultural shift – Do something smart at lunch every day. Attend a virtual tumor board.

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Precision Medicine for Relapsed Multiple Myeloma on the Basis of an Integrative Multiomics Approach

JCO Precision Oncology ◽

10.1200/po.18.00019 ◽

2018 ◽

pp. 1-17 ◽

Cited By ~ 7

Author(s):

Alessandro Laganà ◽

Itai Beno ◽

David Melnekoff ◽

Violetta Leshchenko ◽

Deepu Madduri ◽

...

Keyword(s):

Multiple Myeloma ◽

Precision Medicine ◽

Rna Sequencing ◽

Plasma Cells ◽

Treatment Options ◽

Drug Repurposing ◽

Precision Oncology ◽

Dna Mutation ◽

Dna And Rna ◽

Disease Marker

Purpose Multiple myeloma (MM) is a malignancy of plasma cells, with a median survival of 6 years. Despite recent therapeutic advancements, relapse remains mostly inevitable, and the disease is fatal in the majority of patients. A major challenge in the treatment of patients with relapsed MM is the timely identification of treatment options in a personalized manner. Current approaches in precision oncology aim at matching specific DNA mutations to drugs, but incorporation of genome-wide RNA profiles has not yet been clinically assessed. Methods We have developed a novel computational platform for precision medicine of relapsed and/or refractory MM on the basis of DNA and RNA sequencing. Our approach expands on the traditional DNA-based approaches by integrating somatic mutations and copy number alterations with RNA-based drug repurposing and pathway analysis. We tested our approach in a pilot precision medicine clinical trial with 64 patients with relapsed and/or refractory MM. Results We generated treatment recommendations in 63 of 64 patients. Twenty-six patients had treatment implemented, and 21 were assessable. Of these, 11 received a drug that was based on RNA findings, eight received a drug that was based on DNA, and two received a drug that was based on both RNA and DNA. Sixteen of the 21 evaluable patients had a clinical response (ie, reduction of disease marker ≥ 25%), giving a clinical benefit rate of 76% and an overall response rate of 66%, with five patients having ongoing responses at the end of the trial. The median duration of response was 131 days. Conclusion Our results show that a comprehensive sequencing approach can identify viable options in patients with relapsed and/or refractory myeloma, and they represent proof of principle of how RNA sequencing can contribute beyond DNA mutation analysis to the development of a reliable drug recommendation tool.

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