Radiat Oncol J.  2021 Dec;39(4):304-314. 10.3857/roj.2021.00815.

Impact of somatic mutations on clinical and pathologic outcomes in borderline resectable and locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and stereotactic body radiotherapy followed by surgical resection

• Reddy AV
• Hill CS
• Sehgal S
• Ding D
• Hacker-Prietz A
• He J
• Zheng L
• Herman JM
• Meyer J
• Narang AK

• KMID: 2523733
• DOI: http://doi.org/10.3857/roj.2021.00815

Abstract

Purpose
The purpose of this study was to determine if somatic mutations are associated with clinical and pathologic outcomes in patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who were treated with neoadjuvant chemotherapy and stereotactic body radiotherapy (SBRT).
Materials and Methods
Patients treated with neoadjuvant chemotherapy and SBRT followed by surgical resection from August 2016 to January 2019 and who underwent next generation sequencing of their primary tumor were included in the study. Next-generation sequencing was performed either in-house with a Solid Tumor Panel or with FoundationOne CDx. Univariate (UVA) and multivariable analyses (MVA) were performed to determine associations between somatic mutations and pathologic and clinical outcomes.
Results
Thirty-five patients were included in the study. Chemotherapy consisted of modified FOLFIRINOX, gemcitabine and nab-paclitaxel, or gemcitabine and capecitabine. Patients were treated with SBRT in 33 Gy in 5 fractions. On UVA and MVA, tumors with KRAS G12V mutation demonstrated better pathologic tumor regression grade (TRG) to neoadjuvant therapy when compared to tumors with other KRAS mutations (odds ratio = 0.087; 95% confidence interval [CI], 0.009–0.860; p = 0.036). On UVA and MVA, mutations in NOTCH1/2 were associated with worse overall survival (hazard ratio [HR] = 4.15; 95% CI, 1.57–10.95; p = 0.004) and progression-free survival (HR = 3.61; 95% CI, 1.41–9.28; p = 0.008). On UVA, only mutations in NOTCH1/2 were associated with inferior distant metastasis-free survival (HR = 3.38; 95% CI, 1.25–9.16; p = 0.017).
Conclusion
In BRPC and LAPC, the KRAS G12V mutation was associated with better TRG following chemotherapy and SBRT. Additionally, NOTCH1/2 mutations were associated with worse overall survival, distant metastasis-free survival, and progression-free survival.

Keyword

Pancreatic cancer; Stereotactic body radiation therapy; Somatic mutations; NOTCH1/2; KRAS; G12V