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Clinical and molecular features of patients with KRAS wild-type pancreatic adenocarcinoma
Background
KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC). However, 8-10% of patients harbor KRAS wild-type tumors (WT). The objectives of this study were to describe the clinical and molecular features of WT pancreatic tumors.
Methods
A retrospective chart review was performed in patients with PDAC who were found to have no KRAS mutation (e.g KRAS-WT) on tumor molecular profiling as part of routine care (on tumor tissue with in-house panel (35%) or FoundationOne Medicine® (15%), or liquid biopsy with FoundationOne Liquid® (50%)). Data on demographics, risk factors, systemic therapy, radiographical response, progression free survival (PFS), and overall survival (OS) were collected.
Results
Out of 270 tested PDAC patients, 34 patients (12%) with KRAS-WT PDAC were included. The median age was 63 years (IQR = 56-68), 22 patients (65%) were female and 48% of patients had a smoking history. At diagnosis, 10 pts (29%) had resectable or borderline disease, 6 had locally-advanced disease (25%) and 17 (50%) had metastatic cancer. Median CA19/9 at diagnosis was 124 U/mL (IQR = 93.2-2010). Eight patients underwent upfront primitive surgical resection of after neoadjuvant chemotherapy. Nine pts (26%) had metachronous metastases. Liver was the most frequent metastatic site at diagnosis (64%) and at relapse in case of metachronous disease (29%). One patient had a somatic BRCA2 mutation. Molecular alterations were found in 71% of patients. The most common genes altered were in TP53 (26%), CDKN2A (12%), BRAF mutation (8.8%) and BRCA1/2 (6%). Among patients with available data, median tumor mutational burden was 2.52 (n=7) with 1 had a TMB >10, and 3 patients had a MSI tumor (of 19 patients with MSI status). ESCAT classification of molecular alterations were: I (17%), II (4%), III (17%), IV (8%), X (54%). A putative therapeutic target was identified in 11 pts (32%) (ESCAT I to IV) of patients. Among the 26 patients who received palliative systemic therapies, 5 (19%) patients received a treatment targeting the molecular anomaly of interest (MEK inhibitor (n=2), FGFR2 inhibitor (n=1), CDK2 inhibitor (n=1), and a combination of PARP inhibitor and ATR inhibitor (n=1)). For the 17 (65%) patients who received FOLFIRINOX as first-line palliative systemic therapy, median PFS was 13.4 months [95%CI: 10-31.3] and the overall response rate (ORR) by RECIST v1.1 was 34.6%. Among the 7 patients who received a Gemcitabine-based regimen as first line therapy, the median PFS was 8 months [95%CI: 2.4-NR]. In the overall population, the median OS from ti.me of initial diagnosis was 34.4 months [95%CI: 27.8-NR]. Median overall survival from time of metastatic disease was 28.8 months [95% CI: [25.2-NR].
Conclusions
Patients with KRAS-WT PDAC were found to have a longer median OS (24.4 months) and PFS under FOLFIRINOX (8 months) than KRAS mutated PDAC compared to historical controls. Among KRAS-WT PDAC, more than one third of the patients had a potentially actionable molecular alteration and 15% received a treatment targeting a molecular anomaly of interest. Patients without KRAS mutations should be eligible for broad molecular screening in a precision medicine approach.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
A. Hollebecque: Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: AstraZeneca. All other authors have declared no conflicts of interest.
