Impact of <i>KRAS</i> Mutations and Co-mutations on Clinical Outcomes in Pancreatic Ductal Adenocarcinoma

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Abstract

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 PDAC patients (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p<0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRAS ^G12R had a similar OS (median 34 months), while patients with KRAS ^Q61 and KRAS ^G12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2–3.0, p=0.006] and 22 months [HR: 1.7, 95% CI 1.3–2.3, p<0.001], respectively). There was enrichment of KRAS ^G12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2–2.4, p=0.001) and enrichment of KRAS ^G12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05–2.99, p=0.04). Similar findings were observed in the external validation cohort (PanCAN’s Know Your Tumor ^® dataset, n=408).

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Maftools: efficient and comprehensive analysis of somatic variants in cancer

Anand Mayakonda, De-Chen Lin, Yassen Assenov … (2018)

Numerous large-scale genomic studies of matched tumor-normal samples have established the somatic landscapes of most cancer types. However, the downstream analysis of data from somatic mutations entails a number of computational and statistical approaches, requiring usage of independent software and numerous tools. Here, we describe an R Bioconductor package, Maftools, which offers a multitude of analysis and visualization modules that are commonly used in cancer genomic studies, including driver gene identification, pathway, signature, enrichment, and association analyses. Maftools only requires somatic variants in Mutation Annotation Format (MAF) and is independent of larger alignment files. With the implementation of well-established statistical and computational methods, Maftools facilitates data-driven research and comparative analysis to discover novel results from publicly available data sets. In the present study, using three of the well-annotated cohorts from The Cancer Genome Atlas (TCGA), we describe the application of Maftools to reproduce known results. More importantly, we show that Maftools can also be used to uncover novel findings through integrative analysis.

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FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

Thierry Conroy, Françoise Desseigne, Marc Ychou … (2011)

Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer. We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001). As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).

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Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

Daniel Von Hoff, Thomas Ervin, Francis Arena … (2013)

In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

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Journal

Journal ID (nlm-ta): Res Sq

Journal ID (publisher-id): ResearchSquare

Title: Research Square

Publisher: American Journal Experts

Publication date (Electronic): 10 August 2023

Electronic Location Identifier: rs.3.rs-3195257

Affiliations

[1 ]Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[2 ]Pancreatic Cancer Action Network, Manhattan Beach, Los Angeles, CA, USA

[3 ]Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[4 ]Department of Data Engineering & Analytics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[5 ]Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[6 ]Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

[7 ]Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Author notes

Author contributions:

D.Z. and J.P.S. conceptualized the paper, provided oversight, contributed to patient enrollment and treatment, patient assessment, data interpretation, and writing the manuscript. A.Y., M.Y. conceived and designed the study, contributed to literature search, data acquisition, data analysis, data interpretation, and manuscript writing. J.W., M.O. and S.K contributed to patient enrollment, treatment, assessment, and data interpretation. K.A., S.D., L.M. contributed to data acquisition, data analysis, data interpretation. M.K., P.E., S.C., J.P. and R.S., contributed to the statistical analysis and writing of the manuscript. All authors read, reviewed the manuscript, and approved the final version of the manuscript.

Corresponding Author: Dan Zhao, MD, PhD, MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 0426, Houston, TX 77030, Phone: 832 750 5964, dzhao3@ 123456mdanderson.org

Author information

Abdelrahman Yousef http://orcid.org/0000-0001-7761-8149

Saikat Chowdhury http://orcid.org/0000-0002-0783-3959

Mark Knafl http://orcid.org/0000-0002-3953-2173

Paul Edelkamp http://orcid.org/0000-0001-5881-8292

Brandon G. Smaglo http://orcid.org/0000-0002-8814-8004

Jason Willis http://orcid.org/0000-0001-8238-8552

John Paul Shen http://orcid.org/0000-0003-4588-2775

Dan Zhao http://orcid.org/0000-0001-7066-9058

Article

Other ID: 10.21203/rs.3.rs-3195257

DOI: 10.21203/rs.3.rs-3195257/v1

PMC ID: 10441514

PubMed ID: 37609177

SO-VID: 27cf1cab-d4d1-45e5-b7d1-add218790e93

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This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.

Impact of KRAS Mutations and Co-mutations on Clinical Outcomes in Pancreatic Ductal Adenocarcinoma

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Most cited references 76

Maftools: efficient and comprehensive analysis of somatic variants in cancer

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.

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