Appraising the Costs of Genomic Testing for Histology-Independent Technologies: An Illustrative Example for NTRK Fusions

Abstract Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

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EPEN-45. NORMALIZING AND FACILITATING GENOMIC TESTING AT DIAGNOSIS IN PEDIATRIC EPENDYMOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.179 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii317-iii317

Author(s):

Emily Owens Pickle ◽

Ana Aguilar-Bonilla ◽

Amy Smith

Keyword(s):

Current Practice ◽

Molecular Classification ◽

Molecular Data ◽

Molecular Profiling ◽

Genomic Testing ◽

Molecular Testing ◽

Newly Diagnosed ◽

Pediatric Ependymoma ◽

Need Support ◽

Almost All

Abstract The current consensus is that diagnosis and treatment of ependymoma should be based upon clinical and molecular classification. As we move into this paradigm, it is important all ependymoma cases undergo tumor collection, preservation, and molecular profiling at diagnosis. Our group of 6 sites gathered data on a cohort of 72 ependymoma cases. Sites were asked to report known molecular findings; 60/68 eligible cases (88%) did not include genetic findings. The low number of cases with molecular findings was surprising and since cases were diagnosed from as early as 2004, we asked collaborators to share their current practice in profiling (e.g., how frequently; in what setting were ependymomas sent for testing) to try and better understand current practice at sites. Since the publication of ependymoma molecular data, sites with a neuro-oncology program report sending almost all newly diagnosed ependymomas for molecular testing, whereas current practices at sites without dedicated neuro-oncology were less consistent. Profiling in the setting of relapse was more frequently reported at all centers. The implementation of molecular testing at diagnosis may need support at sites without dedicated neuro-oncology. Lead investigators for upcoming ependymoma clinical trials will need to think carefully about the logistics of profiling at centers where this is not standard practice at diagnosis.

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Personalized Decision Making on Genomic Testing in Early Breast Cancer: Expanding the MINDACT Trial with Decision-Analytic Modeling

Medical Decision Making ◽

10.1177/0272989x21991173 ◽

2021 ◽

pp. 0272989X2199117

Author(s):

Ewout W. Steyerberg ◽

Liesbeth C. de Wreede ◽

David van Klaveren ◽

Patrick M. M. Bossuyt

Keyword(s):

Breast Cancer ◽

Decision Making ◽

Genetic Testing ◽

Early Stage ◽

Pragmatic Trial ◽

Genomic Signature ◽

Genomic Testing ◽

Analytic Modeling ◽

Clinical Risk ◽

Genomic Test

Background Genomic tests may improve upon clinical risk estimation with traditional prognostic factors. We aimed to explore how evidence on the prognostic strength of a genomic signature (clinical validity) can contribute to individualized decision making on starting chemotherapy for women with breast cancer (clinical utility). Methods The MINDACT trial was a randomized trial that enrolled 6693 women with early-stage breast cancer. A 70-gene signature (Mammaprint) was used to estimate genomic risk, and clinical risk was estimated by a dichotomized version of the Adjuvant!Online risk calculator. Women with discordant risk results were randomized to the use of chemotherapy. We simulated the full risk distribution of these women and estimated individual benefit, assuming a constant relative effect of chemotherapy. Results The trial showed a prognostic effect of the genomic signature (adjusted hazard ratio 2.4). A decision-analytic modeling approach identified far fewer women as candidates for genetic testing (4% rather than 50%) and fewer benefiting from chemotherapy (3% rather than 27%) as compared with the MINDACT trial report. The selection of women benefitting from genetic testing and chemotherapy depended strongly on the required benefit from treatment and the assumed therapeutic effect of chemotherapy. Conclusions A high-quality pragmatic trial was insufficient to directly inform clinical practice on the utility of a genomic test for individual women. The indication for genomic testing may be far more limited than suggested by the MINDACT trial.

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Longitudinal and multi-tissue molecular diagnostics track somatic BRCA2 reversion mutations that correct the open reading frame of germline alteration upon clinical relapse

npj Genomic Medicine ◽

10.1038/s41525-021-00181-0 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Shelly Sorrells ◽

Kelly E. McKinnon ◽

Ashleigh McBratney ◽

Christopher Sumey

Keyword(s):

Disease Progression ◽

Parp Inhibitor ◽

Acquired Resistance ◽

Open Reading Frame ◽

Genomic Testing ◽

Clinical Relapse ◽

Resistance Mutations ◽

Reading Frame ◽

Germline Alteration ◽

Over Time

AbstractBRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.

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Toward the diagnosis of rare childhood genetic diseases: what do parents value most?

European Journal of Human Genetics ◽

10.1038/s41431-021-00882-1 ◽

2021 ◽

Author(s):

Samantha Pollard ◽

Deirdre Weymann ◽

Jessica Dunne ◽

Fatemeh Mayanloo ◽

John Buckell ◽

...

Keyword(s):

Focus Groups ◽

Genetic Disease ◽

Diagnostic Yield ◽

Management Strategies ◽

Health Benefit ◽

Sampling Technique ◽

Evidence Base ◽

Current Evidence ◽

Genomic Testing ◽

Current Evidence Base

AbstractGenomic testing is becoming routine for diagnosing rare childhood genetic disease. Evidence underlying sustainable implementation is limited, focusing on short-term endpoints such as diagnostic yield, unable to fully characterize patient and family valued outcomes. Although genomic testing is becoming widely available, evidentiary and outcomes uncertainty persist as key challenges for implementation. We examine whether the current evidence base reflects public tolerance for uncertainty for genomics to diagnose rare childhood genetic disease. We conducted focus groups with general population parents in Vancouver, Canada, and Oxford, United Kingdom, to discuss expectations and concerns related to genomic testing to diagnose rare childhood genetic disease. Applying a purposive sampling technique, recruitment continued until thematic saturation was reached. Transcripts were analysed using thematic analysis. Thirty-three parents participated across four focus groups. Participants valued causal diagnoses alongside management strategies to improve patient health and wellbeing. Further, participants valued expanding the evidence base to reduce evidentiary uncertainty while ensuring security of information. Willingness to pay out of pocket for testing reflected perceived familial health benefit. Diagnostic yield fails to fully capture valued outcomes, and efforts to resolve uncertainty better reflect public priorities. Evaluations of genomic testing that fully integrate valued endpoints are necessary to ensure consistency with best practices and public willingness to accept the uncertain familial benefit.

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Direct-to-Consumer Genetic and Genomic Testing: Preparing Nurse Practitioners for Genomic Healthcare

The Journal for Nurse Practitioners ◽

10.1016/j.nurpra.2010.06.007 ◽

2010 ◽

Vol 6 (8) ◽

pp. 585-594 ◽

Cited By ~ 5

Author(s):

Jennifer T. Loud

Keyword(s):

Nurse Practitioners ◽

Genomic Testing ◽

Direct To Consumer

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Identification and management of pathogenic mutations in BRCA1, BRCA2, and PALB2 in a tumor-only genomic testing program.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10528 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10528-10528

Author(s):

Brittany L. Bychkovsky ◽

Tianyu Li ◽

Jilliane Sotelo ◽

Nabihah Tayob ◽

Joanna Mercado ◽

...

Keyword(s):

Cancer Patients ◽

Familial Cancer ◽

Clinical Indication ◽

Genomic Testing ◽

Tumor Type ◽

Nccn Guidelines ◽

Somatic Alterations ◽

Prostate Cancers ◽

Brca1 Brca2 ◽

Germline Testing

10528 Background: Tumor-genomic testing is increasingly used to guide treatment decisions in cancer patients. Although tumor-only testing cannot definitively distinguish between germline versus somatic alterations, the identification of pathogenic or likely pathogenic (P/LP) variants in certain genes should prompt consideration of germline testing. Germline P/LPs in BRCA1, BRCA2 and PALB2 ( B1B2PAL) are associated with hereditary cancer syndromes. Methods: We reviewed tumor-only genomic data (Dana-Farber Oncopanel) between 10/2016 and 6/2018 to examine the prevalence of P/LPs in BRCA1, BRCA2, PALB2 among adult cancer patients at Dana-Farber Cancer Institute/Brigham and Women’s Hospital. We characterized the frequency of P/LPs by primary tumor type, confirmation by germline testing before or within 12 months after Oncopanel testing or not, and factors associated with germline testing. Results: Among 7,575 patients, the median age was 62 (range 18-99); 53.9% were female. A total of 272 (3.6%) had P/LPs in BRCA1 (n = 90), BRCA2 (n = 162) and/or PALB2 (n = 29). P/LPs in B1B2PAL were detected in 5.3% (38/712) of breast, 11.9% (34/285) of ovarian, 6.6% (18/272) of pancreatic, and 5.1% (12/234) of prostate cancers. P/LPs in B1B2PAL were also detected in other neoplasms (12.9% (8/62) of non-melanoma skin, 5.0% (43/855) of colorectal, 7.6% (20/264) of endometrial, and 4.6% (10/216) of head and neck cancers). Of 169 patients who had not had prior germline testing, 29/169 (17.2%) completed germline testing within 12 months after Oncopanel; 13 (7.7%) referred for testing declined or did not complete testing within 12 months, 14 (8.3%) died before or within 3 months of the Oncopanel results, and 113 (66.9%) had no documented germline testing within 12 months. Among 132 patients who had germline testing, 117 (88.6%) had a clinical indication based on personal or family history compared to 66/140 (47.1%) who did not undergo germline testing. Among 132/272 (48.5%) germline-tested patients, 70.5% were positive for a germline mutation in B1B2PAL; the remainder had somatic B1B2PAL mutations only. Germline testing was more often performed in patients with B1B2PAL-associated tumors (breast, ovarian, pancreatic and prostate cancers) or other clinical indications for germline testing. Conclusions: A low but clinically meaningful rate of P/LPs in BRCA1, BRCA2 and PALB2 was detected by tumor-only genomic testing in diverse malignancies. Given the implications of B1B2PAL alterations on treatment and familial cancer risk, our data support current NCCN guidelines recommending germline testing among patients with cancer and P/LPs in B1B2PAL detected on tumor-genomic testing and highlights the need for systems to ensure germline testing when indicated.

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Improving time to molecular testing results in patients with newly diagnosed, metastatic non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.244 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 244-244

Author(s):

Stephanie Ossowski ◽

Elad Neeman ◽

Charles Borden ◽

Amy Ying Ju Lin ◽

Raymond Liu

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Turnaround Time ◽

Small Cell ◽

Pathological Diagnosis ◽

Genomic Testing ◽

Newly Diagnosed ◽

Small Cell Lung ◽

First Line ◽

Metastatic Nsclc

244 Background: Next generation sequencing (NGS) is a crucial component of evaluation of newly diagnosed patients with metastatic non-small cell lung cancer (NSCLC) to determine appropriate first line treatment. Delays in NGS can lead to psychologic distress for patients and can affect choices in first line therapy, especially for patients with underlying targetable mutations. While more data is needed to benchmark turnaround time for NGS results, guidelines and expert consensus suggest time from diagnosis to treatment should be 15 days and turnaround time for genomic testing 10-14 days. This study was aimed at reducing time to NGS results in a large integrated health care system. Methods: Through the ASCO Quality Training Program, we reviewed electronic medical records of 25 patients with newly diagnosed, untreated metastatic NSCLC from 12/2018 to 9/2020 and determined number of days from pathological diagnosis to NGS results. We reviewed process maps for oncology, pathology, the internal data management division, and a genomic testing company to determine factors leading to significant preventable delays. Since 11/2020, we created an automated weekly report using CoPath to identify new pathological diagnoses of potential metastatic NSCLC. The oncology department reviewed these cases weekly and NGS orders were placed for patients with metastatic NSCLC. Eleven additional patients with newly diagnosed metastatic NSCLC were included in the prospective cohort. Results: Demographic characteristics are noted in Table. Our intervention reduced median time from pathological diagnosis to NGS results from 24 to 19 days. Median time from biopsy results to NGS order was reduced from 7 to 1 day. Time from specimen being sent from pathology to NGS vendor was a median of 6 days in both cohorts. Total time from pathological diagnosis to appropriate treatment was reduced from a median of 33 to 25 days. Conclusions: Delays in time to NGS results can be reduced by improved communication between departments and simple, automated interventions to ensure results are efficiently released to an oncologist. Additional Plan-Do-Study-Act cycles are currently being developed to further reduce time from biopsy results to NGS results. [Table: see text]

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