Cancer DNA Screening Pilot Study (CANDACE)
Condition: Circulating Tumor Cells
MeSH terms: Neoplastic Cells, Circulating
Study type: Interventional

Summary: 
      The investigators have developed an assay that can sensitively and specifically detect DNA
      mutations circulating in human plasma that may be indicators of the presence of a solid
      tumor. This study is a pilot study to measure positive and negative predictive values of this
      assay as an indicator of the presence of a tumor in normal subjects
    

Detailed description: 
      Participants consenting for the study will be requested to consent for an initial collection
      of two vials of blood (~ 20 ml total) and to answer questions regarding aspects of their
      medical history and lifestyle that are relevant to cancer risk. Participants in the study
      will also be asked to provide consent for follow-up blood samples, and if the confirmatory
      tests show a positive result, follow-up PET/CT scans and other investigations.

      1,000 participants between the ages of 55 and 75 will be enrolled through BC Generations
      Project. This is a invite-only study.

        -  Respondents who provide consent and choose to be enrolled in the study will then be
           directed to an online questionnaire where they will be asked to answer questions
           regarding their lifestyle and medical history.

        -  The consent form and questionnaire results will be electronically received at the UBC
           study site.

        -  Once participant information has been received at UBC, it will be entered into a
           password protected spreadsheet on a UBC server. At that point, participants will be sent
           a requisition form directing them to one of several possible blood collection sites
           (LifeLabs), where two 10mL blood draws will be collected by a phlebotomist. Blood
           collections will be paid for by Boreal through a contract with LifeLabs, and will be
           performed in Streck stabilized cfDNA blood collection tubes (capable of storing blood at
           room temperature for over a week).

        -  Once collected, the two blood tubes will be delivered by LifeLabs to BC Cancer Research
           Center within 24-48 hrs of collection. The tubes will be collected by study staff
           (within 5 days of the initial blood draw) and transported to UBC, where they will be
           de-identified and assigned a random identifier (UBC study number). Any personal
           identification on the tubes will be completely removed, by abrasion if necessary.
           Identifying information will be entered in a password protected spreadsheet (on a UBC
           server) linking the participant information to the UBC study number. From this point on,
           the blood samples, and subsequent fractions and results, will only be identified by the
           study number. The de-identified tubes will be transported to Boreal Genomics where they
           will be separated into plasma and cellular fraction including erythrocytes and buffy
           coat. The non-plasma components of the blood samples will be pooled and subsequently
           discarded. The plasma fraction will be placed in a separate tube and frozen for
           subsequent analysis. The original blood tubes (now empty), will be destroyed.

        -  Frozen plasma samples, now de-identified, will be delivered to Pathway Genomics (San
           Diego, CA) where DNA content will be analyzed with a circulating tumor DNA assay
           employing the UBC/Boreal Genomics enrichment technology. All of the participants' plasma
           will be sent to Pathway, where it will be used up in the assay. Any plasma not consumed
           in the assay will be destroyed. No plasma, blood or other samples will be stored at
           either Pathway Genomics or UBC, beyond any temporary storage (1-2 weeks) required to
           perform the assay.

        -  Circulating tumor DNA assay results (raw sequencing data) from Pathway Genomics will be
           returned to UBC and analyzed for the presence of cancer mutations. Any samples showing
           activating mutations above the assay's technical Limit of Detection (LOD) will be called
           positive. One exception will be made for TP53 mutations that are known to exist in some
           normal individuals at low levels. For these mutations, a level of 0.1% will be set,
           above which the sample will be called positive.

        -  Once the data is analyzed, participants with a negative result will be sent an email
           thanking them for their participation and informing them of the negative result.

        -  Participants whose sample provided a positive result will be contacted immediately by
           telephone by an oncologist co-investigator and concurrently sent a letter by mail
           informing them of the result and asking them to return for a second blood draw. The
           investigators expect that this communication will happen with about a month of the
           original blood draw. The letter will include contact information for the study team and
           the oncologist co-investigators, in case the participant has any questions or concerns
           at this stage. A requisition form will be sent with the letter. Two 10mL tubes of blood
           will be drawn at the blood collection visit, to allow repeat testing and confirmation
           that the mutation is present consistently.

        -  Samples from the additional draw will be treated as described above for the initial
           samples, with two exceptions. One, the samples will be processed at Boreal Genomics
           instead of being shipped to Pathway Genomics. Two, some buffy coat DNA (germline DNA)
           will also be tested for the 96 cancer mutations present on the Boreal panel to detect
           rare cases where the circulating tumor DNA signal derives from low level germline
           mutations instead of tumor DNA. This testing will be done at Boreal Genomics and any
           remaining buffy coat or DNA not consumed in the test will be discarded. Data from the
           circulating tumor DNA assay and buffy coat test will be returned to UBC and compared to
           the initial blood result.

        -  Participants who are found to have a cancer-associated germline mutation during the
           foregoing testing will be informed by the oncologist co-investigators and will be
           offered a consultation with the Hereditary Cancer Program at the BC Cancer Agency where
           they can meet with a medical geneticist for a consultation. If they wish it, these
           participants would have access to clinically validated retesting for the germline
           mutation.

        -  Participants for which the additional blood sample does not yield positive results for
           cancer mutations, will be contacted by telephone to explain the results.

        -  Participants for whom the additional blood sample yields a positive result for the same
           cancer mutations seen in the first blood draw will be contacted by telephone by an
           oncologist co-investigator, to explain the results and next steps. They will also be
           sent a letter. The investigators expect this communication to happen within about a week
           of the second blood draw. Pending oncological evaluation of the participant (see below)
           and study results, a PET-CT scan with fluorodeoxyglucose (FDG) agent, and possibly other
           tests will be requested. Unless the oncological exams suggest otherwise, the default
           follow-up will be a full body PET-CT. The participants undergoing medical imaging scans
           will be given a requisition form and directed to have the requested scan, which will be
           paid for by the study sponsor (Boreal Genomics).

        -  Recognizing that being advised of an abnormal DNA test may cause participants distress,
           the investigators have committed to (a) complete testing and to contact the participant
           about the result of 2nd test within 14 days of the blood being drawn; (b) notification
           of 2nd result (abnormal or normal) being done by phone by the study oncologist (c)
           pre-booking the follow-up oncological evaluation appointment and offering the
           participant two options when phoned to advise of the 2nd abnormal result (d) completing
           the oncological evaluation within 3 weeks of the patient being advised that the 2nd test
           is abnormal.

        -  The oncological evaluation will be performed at the Vancouver Centre of the BC Cancer
           Agency and is likely to include:

             -  A full history, including risk factors for cancer and a review of systems to seek
                symptoms that could be from cancer.

             -  A physical examination of:

                - Head and neck, thorax, abdomen, skin, neurological system lymphatic system and
                rectum. In men: prostate examination. In women: breast and gynecological
                examinations

             -  A whole-body PET-CT scan

             -  Standard age-appropriate cancer screening investigations such as the fecal
                immunochemical test (FIT) for colorectal cancer, Papanicolaou test for cervix
                cancer and mammography for breast cancer, if they have not been completed, are due,
                or are overdue.

             -  Additional investigations will be guided by the history, physical examination,
                whole-body PET-CT and standard screening investigations.

             -  Investigations may include: complete blood count, liver enzymes, tumour markers,
                urinalysis, contrast-enhanced MRI, contrast-enhanced CT, as well as endoscopy of
                the head and neck, bronchi, bladder, upper GI tract and lower GI tract.

        -  Results of these tests will be returned to the oncologist investigators and to Dr.
           Marziali and then entered into the study database. The results will be communicated to
           the participant in writing as well as in person or by phone. The oncologist will refer
           participants for additional testing and to appropriate clinicians for follow up for
           additional investigations. The oncologist will also offer a referral of participants to
           supportive counseling at this stage.

        -  The results will be communicated to the participant's family physician, if the
           participant has one, by an oncologist investigator.

        -  Participants whose investigations detect a potentially malignant mass will have a
           biopsy, either with imaging guidance, or through referral to an appropriate specialist.

        -  Participants, whose investigations do not detect a potentially malignant mass, will be
           informed in writing, as well as in person or by phone that the circulating tumor DNA
           test gave a false positive result and will be advised to continue with appropriate
           cancer screening for their age and family history.

        -  Participants with positive circulating tumor DNA results who are unwilling to undergo
           further testing including possible PET-CTs will still be offered a follow up visit with
           the oncologist co-investigator to discuss the results and to offer supportive counseling
           as described above.

        -  A year following the initial blood draw, participants will be contacted by email to
           determine if a cancer diagnosis has been made during that time. For non-responding
           participants, they will be telephoned and their family physicians will be sent a letter
           inquiring whether the participant was diagnosed with cancer.

      Data collected in this study will be provided to BC Generations Project.
    

Intervention name(s): Circulating tumor DNA assay
Intervention type(s): Genetic
Intervention description(s): Blood samples will be separated into plasma and cellular fraction including erythrocytes and buffy coat.The plasma fraction will be placed in a separate tube and frozen for subsequent analysis. Frozen plasma samples, de-identified, will be delivered to Pathway Genomics where DNA content will be analyzed with a circulating tumor DNA assay employing the UBC/Boreal Genomics enrichment technology. All of the participants' plasma will be sent to Pathway, where it will be used up in the assay. Circulating tumor DNA assay results (raw sequencing data) from Pathway Genomics will be returned to UBC and analyzed for the presence of cancer mutations. Any samples showing activating mutations above the assay's technical Limit of Detection (LOD) will be called positive. One exception will be made for TP53 mutations that are known to exist in some normal individuals at low levels. For these mutations, a level of 0.1% will be set, above which the sample will be called positive.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Intervention model description: Blood test screening for all who wish to participant. Additional screening test for those who test positive twice.
Masking: None (Open Label)
Primary purpose: Screening