Project Details
Description
PROJECT SUMMARY:
Pancreatic ductal adenocarcinoma (PDA) will become the 2nd leading cause of cancer deaths in the
United States by 2030. Most patients with PDA present with nonresectable/metastatic disease, and systemic
chemotherapy is the anchoring treatment in these patients. Surgery is an option in the minority of patients (~30%)
who present with localized disease, though most develop early recurrence after a highly morbid surgery due to
occult metastases. Therefore, neoadjuvant therapy (NAT) is an emerging standard approach, but is only
beneficial if the selected systemic therapy is effective. Indeed, for all patients with PDA, metastatic or otherwise,
the duration of effective systemic therapy is the most important factor in their survival. There is a critical unmet
need for accurate and timely assessment of treatment response in order to 1) get patients on effective systemic
therapy as soon as possible and keep them on it as long as possible, 2) expeditiously discontinue toxic, costly
and ineffective therapies, and 3) facilitate evidence-based personalized clinical decisions regarding curative-
intent surgery. Current management of PDA relies principally on computed tomography (CT) and tumor markers
(CA19-9). However, these tools are not sensitive enough and are too slow for adjudicating benefit in patients
with rapidly lethal metastatic disease, and for identifying suitable candidates most likely to benefit from surgery
after NAT. We now have cutting-edge tools for more precise quantification of disease burden at the molecular
and metabolic levels. We have previously shown that mutant KRAS circulating tumor (ct)DNA can be detected
with high sensitivity in PDA, tends to drop rapidly with effective therapy, and may be a more dynamic predictor
of therapy response than CA19-9. We have also shown that metabolic imaging with hybrid integrated 18-fluoro-
deoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) improves the
detection of subtle metastases that are occult on CT, early response assessment in patients with
nonresectable/metastatic PDA, and prediction of pathological response to NAT in patients who undergo
resection. Building on these promising results, we hypothesize that the appropriate combination of KRAS ctDNA
and PET/MRI biomarkers will enable timely assessment of the clinical utility of therapy in PDA patients. In Aim
1, we will define thresholds for early chemotherapy switch in unresectable/metastatic PDA using dynamic and
quantitative changes in KRAS ctDNA and FDG PET/MRI biomarkers for use in future prospective trials. In Aim
2, we will construct, test and validate a model of surgical benefit or futility for patients with potentially resectable
PDA using dynamic KRAS ctDNA and FDG PET/MRI response data. Our overarching goal is to integrate reliable
biomarkers that can accurately guide therapy and enable precision medicine to improve outcomes of patients
with this deadly disease.
Status | Finished |
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Effective start/end date | 4/1/21 → 3/31/24 |
Funding
- National Cancer Institute: $596,548.00
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