KRAS and NOTCH1/2 Mutations are Associated With Pathologic and Clinical Outcomes in Localized Pancreatic Cancer Treated With Neoadjuvant Chemotherapy and Stereotactic Body Radiotherapy Followed by Surgical Exploration.

Purpose/Objective(s) The role of radiation for pancreatic cancer remains controversial with heterogeneous clinical response. Characterization of molecular biomarkers that predict radiosensitivity may help select patients for radiation therapy. The purpose of this study was to determine if somatic mutations and mutational frequency are associated with pathologic and survival outcomes in a cohort of patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT) followed by surgical exploration. Materials/Methods Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical exploration from 2017-2019 and who consented to next generation sequencing (NGS) of their primary tumor were included in the study. Tissue samples were obtained with FNA at initial biopsy (n = 5) or from surgical specimen (n = 38). Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and variant allele frequency (VAF) with pathologic and survival outcomes. Local response was defined as achieving complete response, marked response, or moderate response on pathology. Results A total of 43 patients underwent NGS of their primary tumor with either solid tumor panel (n = 35) or Foundation One (n = 8). Neoadjuvant therapy consisted of FOLFIRNOX (n = 36) and/or gemcitabine/abraxane (n = 11) followed by SBRT in 33 Gy in 5 fractions (range, 30-36 Gy/5 fractions). Surgical resection was performed in 35/43 patients and aborted in 8/43. Median follow-up time was 20.4 months. Median OS, PFS, DMFS, and LPFS after SBRT were 21.3 months, 9.7 months, 10.0 months, and 22.0 months, respectively. KRAS mutations were observed in 96% (43/45) of patients. On UVA and MVA, tumors with KRAS G12V mutation demonstrated a higher local response rate to neoadjuvant therapy when compared to tumors with other KRAS mutations (100% vs 68.4%, P = 0.003). On UVA and MVA, alterations in NOTCH1/2 and KRAS VAF > 4.3 were associated with worse OS. The median OS for NOTCH1/2 mutated patients was 14.4 months vs 27.5 months in NOTCH1/2 wild type patients (P = 0.045). The median OS for patients with KRAS VAF > 4.3 was 13.8 months vs 31.3 months for patients with KRAS VAF ≤ 4.3 (P = 0.025). KRAS VAF > 4.3 was also associated with worse DMFS (median, not met vs 8.1 months; P = 0.043) and a trend towards significance with worse PFS (median, 8.1 months vs 13.9 months; P = 0.058). Conclusion Tumors with KRAS G12V mutation demonstrated a greater local response in BRPC and LAPC patients treated with neoadjuvant chemotherapy, SBRT, and surgery. Alterations in NOTCH1/2 and KRAS VAF > 4.3 were associated with worse OS. KRAS VAF > 4.3 was also associated with worse DMFS and PFS. As genetic characterization of pancreatic tumors becomes more universal, further investigation into the association between these mutations and radiation-specific response endpoints should be pursued.