Under informed consents, patients undergo tissue sampling (radiologic, endoscopic or
surgical excision). DNA is extracted from tissue and sent for whole-exome sequencing
(WES), organoid culture and drug testing. DNA mutations in PDO models will be determined
using whole-exome sequencing (WES). Mutational burden and driver genes profile will be
assessed for similarities to those identified in primary cancers. The genetic data
generated will be interpreted for response to FDA-approved molecular targeting drugs.
Investigators would study PDO cultures resistant to available chemotherapeutic options.
They would be of exceptional value to study sensitivity to targeted agents, providing
alternative treatment options for chemo-refractory diseases. Based on past experience,
project team has developed a Standard Operational Protocol (SOP) in the area and
establish pipeline in integrative analysis with genome data. PDO Culture and
Genome-guided Drug Screen.To ensure clinical usefulness of our platform, investigators
aim to deliver drug options of each PDO within a meaningful timeframe. In this framework
of typically 4-6 weeks, investigators shall generate organoids, study their molecular
profile and undertake ex vivo drug screening that would allow us to individualize therapy
for each patient. Eligible patients are seen in an MDT board where patients' case
history, laboratory and radiologic results are reviewed. With informed consent to trial
participation, the patient undergoes tissue sampling to his tumor (by radiologic,
endoscopic, or surgical methods). Sampled tumors are then subjected to DNA extraction for
whole exome sequencing, organoid culture, and drug screen. This takes between 2- 4 weeks.
In the interim period, the patient is allowed to receive a chemotherapy agent, a target
agent or hormone therapy between the time of the biopsy and the availability of drug
screen results. An MDT will review the drug screen results and recommend the use of a
drug with a response in a PDO. When several drugs are shown to be efficacious, the
referring oncologist has the final discretion on the choice of chemo- or targeted agent.
Tumor assessments will be performed at baseline, every 8 weeks. Investigators report all
adverse events and serious adverse events (SAE) based on the definitions in NCI CTCAE.
Investigators report all SAEs to the Joint NTEC-CUHK CREC within 24 hours of their
occurrence. Senior physicians at CREC adjudicated all SAEs.
Investigators aim to determine clinical efficacy of NGS/ PDO drug screen guided treatment
in patients with inoperable/ advanced solid tumors refractory to conventional
chemotherapy. Investigators correlate PDO drug response ex vivo to clinical response in
these patients. Our hypothesis is that WES and PDO drug screen can accurately identify
candidate drugs that will reduce tumor size and confer benefits in these patients.
Investigators assume a treatment response with standard treatment be around 10%. A PDO
and NGS guided treatment will likely improve the response rate to about 30% or more. In
the first stage, 10 patients will be accrued, If there is one or fewer response, in these
10 patients, the study will be stopped. Otherwise an additional 19 patients will be
accrued for a total of 29. The null hypothesis will be rejected if 6 or more responses
are observed in 29 patients. This design yields a type 1 error rate of 0.05 and a power
of 80%. Investigators plan to enrol 40 or more patients over a period of 2 years, with
the assumption that in about 20% of patients, PDO culture is unsuccessful.
