ASCO GU 2022: Next-Generation Sequencing: Discussing Results With Patients

( In this presentation, Dr. Faltas offered his perspective on how to navigate sequencing results from patients in the clinic. He first laid out several concepts that are important to understand about genomic sequencing tests:


  1. The type of sequencing – Is this a targeted DNA sequencing panel, or covering the exome sequences of presumed coding genes, or is it whole genome sequencing? Is this DNA or RNA sequencing, and is it adequate to identify genomic items of interests like mutations or fusions or copy number alterations?
  2. Is germline DNA directly sequenced or is it computationally inferred from tumor-only sequencing results
  3. Similar to item 1, which regions of DNA or RNA are covered by the sequencing test
  4. Depth of sequencing and the limits of detection of the assay
  5. The computational analysis pipeline
  6. The possibility of sequencing artifacts which could confound results
  7. The grade of sequencing – is it clinical grade test conducted in a CLIA-certified environment or is it research grade?

Then it is important to be able to read the report. These reports come in different formats depending on the institution or company used. The written report only captures a fraction of the information generated by the sequencing data, and it may ultimately be important to have access to deeper layers of detailed information to interpret results more fully.

Any genomic variant is typically annotated for its presumed functional impact. The level of evidence supporting this annotation varies based on scientific studies and available data at the time the annotation database was created. Dr. Faltas showed his institution’s version of an annotation database, and commented that it is important to understand if the functional annotation is based on computational prediction, preclinical data, or clinical data. 

Because there are multiple layers of information in genomic or transcriptomic data, a multi-discplinary molecular tumor board is essential to interpreting results and deciding how they may be applied to a patient. These tumor boards should ideally consist of all the providers who have input into the care of a patient.

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ASCO and the College of American Pathologists have released consensus recommendations for interpreting and reporting sequence variants in cancer. It divides the actionability of tumor variants into four tiers based on how relevant they may be from either a diagnostic, prognostic or therapeutic perspective.

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Dr. Faltas then described several challenges that have been identified in implementing precision medicine guided by tumor sequencing, as well as potential solutions for each one.

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Germline testing is an important consideration in genomic testing for several reasons. One is that some germline DNA alterations are clinically actionable, most notably the presence of germline alterations in DNA damage repair proteins. However, germline testing is not always performed with institutional or company sequencing platforms either for logistical or cost reasons.

Dr. Faltas discussed which patients with urothelial cancers should have dedicated germline testing. These include:

  1. All patients who meet the Amsterdam/Bethesda criteria or Hereditary breast and ovarian cancer/BRCA guidelines or have a close relative who would have met these guidelines
  2. All patients with MSI-H or MMR-deficient tumors
  3. Patients with early onset diagnosis prior to 45 years of age, which is outside the 5% confidence interval of median age of onset for UC.

Patients who have tumor only testing that identifies potential inherited mutations should also have genetic counseling as this may trigger cascade testing of first-degree relative.

Communicated sequencing results to patients requires first assessing the baseline understanding that patients have of the test, assisting with their interpretation of these results, streamline the process of communicating results, and subsequently providing support around the impact of the results.

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Presented by: Bishoy Morris Faltas, MD, medical oncologist at Weill Cornell Medicine, New York, NY

Written by: Alok K. Tewari, MD, PhD, medical oncologist at Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022

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