This is an open-label, phase II study in patients with resectable and borderline resectable pancreatic cancer.

The study intervention involves molecular profiling Purity Independent Subtyping of Tumors (PurIST) subtyping of pretreatment Endoscopic Ultrasound Fine Needle Aspiration (EUS/FNA) samples to determine pancreatic cancer subtype. Neoadjuvant therapy is directed based on the molecular subtype (classical vs. basal). Patients with classical subtype will receive a standard chemotherapy (mFOLFIRINOX) and patients with basal subtype will receive an alternative standard therapy (gemcitabine/nab-paclitaxel).

Inclusion Criteria (for Screening)

1. Have suspicion of pancreas adenocarcinoma and plan for endoscopic biopsy.
2. Plan for endoscopic biopsy or agreeable to an additional EUS/FNA for research purposes, otherwise plan to obtain archival tissue for PurlST testing.

Inclusion Criteria (for Treatment)

1. Be 18 years of age or older.

2. Be able to understand and provide written informed consent or have a legally authorized representative (LAR).

3. Have documentation of histologically confirmed adenocarcinoma.

4. Have an Eastern Cooperative Group (ECOG) performance status < 2.

5. Have clinical stage consistent with resectable, borderline resectable adenocarcinoma of the pancreas, based on CT or MRI findings.

6. Have adequate organ and bone marrow function, as defined by

   • total leukocytes >3 x103/μL.
   • absolute neutrophil count (ANC) >1.5x 103/μL.
   • hemoglobin >9 g/dL.
   • platelets >100 x 10e3/μL.
   • creatinine clearance >60 mL/min or creatinine <1.5 mg/dL.
   • bilirubin: may be enrolled with an elevated total bilirubin providing current elevated total bilirubin is shown to be in decline following a stent placement and is judged low enough to safely to begin their assigned chemotherapy regimen by the treating medical oncologist
   • aspartate transaminases (AST/SGOT) and alanine transaminases (ALT/SGPT) <3 x upper limit of normal (ULN). At two weeks from biliary decompression, if the subject's serum AST/ALT remains greater 3x ULN, but has demonstrated a progressive decline, the subject may be enrolled into the trial and appropriate modification and dose adjustments will be made to the assigned regimen. Eligibility of subjects whose AST/ALT remain elevated 3x ULN, without demonstrating a downward trend, will be determined at the discretion of the trial PIs.

7. Female patients must be postmenopausal (absence of menses for > 1 year), surgically sterile or have a negative pregnancy test and use at least one form of contraception for four weeks prior to Day 1 of the study, during study treatment and during the first four months after study treatment is discontinued. Male patients must be surgically sterile or use barrier contraception during the study and for four months after the last dose of any study drug.

Definitions of Clinical Stages of PC Resectable PC

To include:

• No evidence of extrapancreatic disease.
• No evidence of tumor-arterial abutment (celiac, SMA [superior mesenteric artery] or HA [hepatic artery]).
• If tumor-induced narrowing of the SMV [superior mesenteric vein], PV [portal vein] or SMV-PV [superior mesenteric-portal vein] confluence is present, it must be < 50% of the diameter of the vessel.
• CA 19-9 < 5000.

Borderline Resectable PC

To include at least one of the following:

• Tumor abutment <180⁰ of the SMA or celiac axis.
• Tumor abutment or encasement (>180⁰) of a short segment of the HA.
• > 50% narrowing of SMV, PV or SMPV.
• Short-segment occlusion of the SMV, PV or SMV-PV with a suitable anatomy for reconstruction.
• CT or MRI findings suspicious for, but not diagnostic of, metastatic disease (based on multidisciplinary assessment).
• Radiographically suspicious or biopsy-proven N1 disease (regional lymph nodes involved) from prereferral biopsy or EUS-guided FNA.
• CA 19-9 >5000 when bilirubin is < 2 mg/dL or >2 mg/dL and declining.

Locally Advanced Type A PC

To include at least one of the following:

• Between 180⁰-270⁰ encasement of SMA or
• > 180⁰ encasement of the celiac artery without extension to aorta and amenable to celiac resection or
• >180⁰ encasement of the hepatic artery with extension to the celiac artery and amenable to vascular reconstruction

Exclusion Criteria:

1. Has received chemotherapy and/or radiation within three years prior to study enrollment.
2. Has any previous history of another malignancy (other than cured basal or squamous cell carcinoma of the skin or cured in situ carcinoma of the cervix or localized prostate cancer with normal prostate specific antigen) within three years of study enrollment.
3. Uncontrolled comorbidities including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina, unstable cardiac arrhythmias, psychiatric illness, excessive obesity (BMI >55) or situations that would limit compliance with the study requirements or the ability to willingly give written informed consent.
4. Known HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
5. Pregnant or breastfeeding patients or any patient with childbearing potential not using contraception four weeks prior to treatment.