NANETS2022 15th Annual Multidisciplinary NET Medical Symposium NANETS 2022 Clinical – Chemo/SSA/Biologics (13 abstracts)
Correlation of MEN1 and DAXX Mutational Status with Response to Capecitabine and Temozolomide (CAPTEM) in Pancreatic Neuroendocrine Tumors
Patrick C Lee 1 , Edik M Blais 2 , Jun Gong 1 , Arsen Osipov 1 , Natalie Moshayedi 1 , Shant Thomassian 1 , Camille Ng 1 , Jennifer Chuy 3 , Lynn M Matrisian 4 , Emanuel F Petricoin III 2 , Michael J Pishvaian 5 & Andrew E Hendifar 1
1Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Perthera, Inc, McLean, VA, USA; 3NYU Langone Health, New York, NY; 4The Pancreatic Cancer Action Network, Manhattan Beach, CA; 5Johns Hopkins University, Baltimore, MD.
Background: Capecitabine and temozolomide (CAPTEM) is a common regimen for the treatment of metastatic, well-differentiated pancreatic neuroendocrine tumors (PNETs). However, it is unknown whether certain genomic profiles predict response to CAPTEM. PNETs often contain mutations in MEN1, ATRX, DAXX, and the PI3K/AKT/mTOR pathway. We sought to determine whether the mutational status of these genes may correlate with progression-free survival (PFS) on CAPTEM.
Methods: A retrospective cohort of PNET cases seen at Cedars-Sinai Medical Center or from Perthera’s Real-World Evidence (RWE) Database (n=95) included 25 patients who were treated with first- or second-line CAPTEM and had tumor next-generation sequencing (NGS) performed. Relationships between commonly altered PNET genes and PFS on CAPTEM were analyzed using Perthera’s RWE analytics tools. Differences in PFS outcomes by MEN1mut/DAXXwt status and potential confounders (e.g., line of therapy) were analyzed using univariate and multivariate Cox regression.
Results: We analyzed 25 PNET patients, 4 (16%) of whom had documented functional tumors. We identified MEN1 mutations as positively associated with CAPTEM response, but this effect was less pronounced for the subset with co-occurring DAXX mutations, which are commonly found alongside MEN1 alterations. With and without accounting for line of therapy, we found that PFS on CAPTEM was significantly longer in MEN1-mutated, DAXX-wildtype tumors compared to other mutation profiles (P< 0.01, see Table 1). ATRX and PTEN alterations were also enriched in the MEN1-mutated/DAXX-wildtype subset; however, other PI3K/AKT/mTOR alterations were common across all MEN1-mutated cases.
| PFS Strata (n=25) | Univariate Cox Significance (p) | Hazard Ratio (HR) [95% Conf. Interval] | Multivariate Cox Significance (p) | Hazard Ratio (HR) [95% Conf. Interval] |
| MEN1mut/DAXXwt vs Other NGS Profiles | P=0.0094 | HR=0.16 [0.04-0.64] | P=0.0097 | HR=0.16 [0.04-0.64] |
| 1st Line CAPTEM vs 2nd Line CAPTEM | P=0.68 | HR=0.8 [0.27-2.34] | P=0.86 | HR=0.91 [0.32-2.58] |
Conclusions: We describe a novel, exploratory genomic signature (MEN1-mut/DAXX-wt) that correlates with relative PNET response to CAPTEM. Prospective validation of these associations is warranted while taking into account other therapies, histopathologic factors, and other genomic correlates.
Abstract ID 21454
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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