WGS Implementation in standard cancer Diagnostics for Every cancer patient

By tailoring treatment towards individual patient and tumor characteristics
using biomarkers that predict clinical efficacy, *precision oncology* can
ensure each patient receives the right treatment at the right time. The rapid
increase in the number of new biomarkers in oncology has led to a large variety
of diagnostic platforms, such as targeted next generation sequencing (NGS)
panels, RNA-based NGS fusion analysis, Sanger sequencing, RT-PCRs, FISH and
IHC. All these platforms address a small part of the diagnostic spectrum and
are often performed in an iterative way to reduce costs, however, at cost of
valuable time and tissue. In addition, when new biomarkers are added, often
another assay is added to this list or an existing test needs to be expanded
and (re-)validated for the new biomarker, which takes a substantial amount of
time and resources and complicates reporting.
We need a comprehensive diagnostic pipeline that optimally uses the available
tumor tissue in an acceptable turnaround time. This comprehensive test needs to
keep up with the pace of the rapidly changing current oncology landscape with
respect to new biomarkers and clinical trials and should result in a
comprehensive, yet comprehendible, diagnostic report.
Whole Genome Sequencing (WGS) is a next generation NGS technology that can map
the complete genetic composition and practically all of the aforementioned
biomarkers of a tumor in a single assay. WGS is efficient with respect to
tissue-consumption, as it requires relatively low amounts of input material.
Simultaneously, costs for WGS are steadily decreasing and therefore WGS is
becoming an attractive alternative for standard molecular diagnostics. WGS
thereby allows simplifying laboratory logistics with a *one-size-fits-all* test
instead of multiple different stand-alone tests that need validation for every
new indication.
Despite the potential of WGS, the actual value and feasibility in a routine
diagnostic setting has not yet been demonstrated.

The WIDE project aims to investigate if implementation of WGS in molecular
diagnostics is feasible in routine practice at the Netherlands Cancer Institute
(NKI).

observational diagnostic consecutive cohort study

Main objectives:
- stepwise confirm the feasibility of WGS in routine clinical cancer care;
- clinically validate WGS in a consecutive prospective diagnostic cohort in the
NKI.
- compare the costs and benefits associated with WGS and the SOC pathology
diagnostics.

Secondary objectives:
- explore differences in the annotation and interpretation of variants using
WGS reporting vs SOC reporting;
- identify additional potential treatment options revealed by WGS that cannot
be identified using SOC diagnostic assays;
- explore the effect/benefit of WGS availability on the decision-making process
by the treating physicians;
- expand the HMF database of clinically annotated and WGS analysed patients for
future research purposes

- A fresh or fresh-frozen tumor material of the metastatic or primary lesion
will be obtained as part of routine standard of care (SOC) diagnostic
procedures. Tumor material means resection, biopsy or body fluid containing
tumor cells, such as pleural fluid or ascites. In case of a biopsy, multiple
tumor biopsies are obtained from all patients as part of the routine SOC
diagnostic procedure. There will be no additional biopsy taken for WIDE, thus
there will be no extra burden for the patient.
- A 10ml blood sample will be drawn once. This blood draw will by preference be
done during a regular blood draw needed for routine care. The risk of a blood
draw is negligible.
- Actionable (treatment-relevant) germline mutations (eg BRCA1 / 2) will be
reported to the patient if the patient chooses to receive these findings. This
can lead to information about hereditary predisposition to cancer, which may
also have consequences for family members of the patient. The patient can
indicate on the consent form whether she wants to be informed of these changes
in the germline DNA.
- Results from WGS diagnostics will be used to support clinical decision making
and care, which could identify additional treatment options. These subsequent
therapies will be SOC or patients will be included in experimental studies: in
regular clinical studies with experimental agents or in the Drug Rediscovery
Protocol (DRUP), for all of which a separate informed consent will be asked.
Therefore, no experimental intervention will be implemented in the current
project and the workflow will parallel current diagnostic and treatment
strategies.