SMAD4-tailored neoadjuvant therapy for pancreatic cancer that can be surgically removed

Inclusion Criteria:

* Patients must have histologically confirmed pancreas ductal adenocarcinoma

  * Most recent cross-sectional imaging of the chest, abdomen and pelvis will be used to rule out distant metastases (this will have been completed within standard of care timelines which will typically fall within 90 days of registration)
* Patients must have undergone next generation sequencing (NGS) testing on the pre-treatment tumor tissue and must have either SMAD4 mutant or SMAD4 wild-type mutation identified before consenting for this study

  * Note: Before consenting to this study, standard of care NGS procedure will be performed on pre-treatment tumor biopsies that are routinely collected through endoscopic biopsy specimens (in-house Oncomine Precision NGS). The results will be documented for this study from clinic notes
* Patients must have resectable/borderline-resectable disease

  * Note: National Comprehensive Cancer Network (NCCN) definitions of resectability will be used
* Patients must be treatment-naïve and clinically fit and eligible for either FOLFIRINOX or gemcitabine/nab-paclitaxel chemotherapy regimens (per treating physician's determination)
* Patients must be ≥ 18 years of age
* Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Patients must have adequate organ and bone marrow function as determined by the treating physician to be considered to be clinically fit for the physician-determined chemotherapy regimen
* Patients must agree to use adequate contraception: (e.g. hormonal or barrier method of birth control for a patient of child-bearing potential (POCBP), prior to study entry, and for the duration of study participation. Should a female patient, or a female partner of a patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician and study doctor immediately. Male patients with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the study starting with the screening visit through the time period indicated for standard of care drugs , after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner. Note: A POCBP is any patient (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) with an egg-producing reproductive tract who meets the following criteria:

  * Has not undergone a hysterectomy or bilateral oophorectomy
  * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)
* POCBP must have a negative pregnancy test prior to registration on study
* Patients must have the ability to understand and the willingness to sign a written informed consent document and comply with the study requirements

Exclusion Criteria:

* Patients with the presence of any of the following genetic or molecular abnormalities:

  * Mismatch repair (MMR)-deficiency/Lynch syndrome
  * High-frequency microsatellite instability (MSI-H)
  * Homologous recombination deficiency (HRD)
* Patients who are currently participating in another study and receiving a study drug
* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia, neuropathy and other non-significant adverse events per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 6.0
* Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen (per treating physician's determination)
* Patients who are pregnant or nursing
* Patients who have an uncontrolled intercurrent illness (as determined by treating physician), including, but not limited to any of the following:

  * Hypertension that is not controlled on medication
  * Active infection requiring treatment
  * Symptomatic congestive heart failure
  * Unstable angina pectoris
  * Cardiac arrhythmia
* Patient with presence of any concurrent medical or psychiatric condition/social situations which would make them inappropriate candidates for entry into this study or that would limit compliance with study requirements, or would compromise the patient's safety or study endpoints, in the treating investigator's judgment