Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations
Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecul...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/9/2569 |
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| author | Anthony Tarabay Alice Boileve Cristina Smolenschi Leony Antoun Marine Valery Alina Fuerea Audrey Perret Pascal Burtin Simona Cosconea Hichem Belkhodja David Malka Valérie Boige Antoine Hollebecque Michel Ducreux |
| author_facet | Anthony Tarabay Alice Boileve Cristina Smolenschi Leony Antoun Marine Valery Alina Fuerea Audrey Perret Pascal Burtin Simona Cosconea Hichem Belkhodja David Malka Valérie Boige Antoine Hollebecque Michel Ducreux |
| author_sort | Anthony Tarabay |
| collection | DOAJ |
| description | Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years with histologically confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP). Results: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly <i>BRCA1</i> or <i>BRCA2</i> (5 (18%)), <i>HER2</i> (5 (18%)), <i>MTAP</i> (5 (18%)), and <i>FGFR</i> (3 (11%)). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (<i>n</i> = 12 (11.8%)), 14 months in patients with actionable GAs treated with standard therapies (<i>n</i> = 17 (16.7%)), and 17 months in patients without actionable GAs treated with standard therapies (<i>n</i> = 73 (71.5%); <i>p</i> = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, <i>p</i> = 0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. Interpretation: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome. |
| first_indexed | 2024-03-10T23:00:03Z |
| format | Article |
| id | doaj.art-26a3fb018c8542f2bb1c09dce554c516 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T23:00:03Z |
| publishDate | 2023-09-01 |
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| series | Biomedicines |
| spelling | doaj.art-26a3fb018c8542f2bb1c09dce554c5162023-11-19T09:43:09ZengMDPI AGBiomedicines2227-90592023-09-01119256910.3390/biomedicines11092569Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable MutationsAnthony Tarabay0Alice Boileve1Cristina Smolenschi2Leony Antoun3Marine Valery4Alina Fuerea5Audrey Perret6Pascal Burtin7Simona Cosconea8Hichem Belkhodja9David Malka10Valérie Boige11Antoine Hollebecque12Michel Ducreux13Gustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceGustave Roussy, Département d’Innovation Thérapeutique et d’Essais Précoces, 94805 Villejuif, FranceGustave Roussy, Département de Médecine, 94805 Villejuif, FranceBackground: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years with histologically confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP). Results: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly <i>BRCA1</i> or <i>BRCA2</i> (5 (18%)), <i>HER2</i> (5 (18%)), <i>MTAP</i> (5 (18%)), and <i>FGFR</i> (3 (11%)). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (<i>n</i> = 12 (11.8%)), 14 months in patients with actionable GAs treated with standard therapies (<i>n</i> = 17 (16.7%)), and 17 months in patients without actionable GAs treated with standard therapies (<i>n</i> = 73 (71.5%); <i>p</i> = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, <i>p</i> = 0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. Interpretation: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome.https://www.mdpi.com/2227-9059/11/9/2569PDACprecision medicinegene alterationsmolecular profilingmolecular targeted therapies |
| spellingShingle | Anthony Tarabay Alice Boileve Cristina Smolenschi Leony Antoun Marine Valery Alina Fuerea Audrey Perret Pascal Burtin Simona Cosconea Hichem Belkhodja David Malka Valérie Boige Antoine Hollebecque Michel Ducreux Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations Biomedicines PDAC precision medicine gene alterations molecular profiling molecular targeted therapies |
| title | Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations |
| title_full | Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations |
| title_fullStr | Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations |
| title_full_unstemmed | Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations |
| title_short | Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations |
| title_sort | precision medicine in pancreatic ductal adenocarcinoma the impact of targeted therapies on survival of patients harboring actionable mutations |
| topic | PDAC precision medicine gene alterations molecular profiling molecular targeted therapies |
| url | https://www.mdpi.com/2227-9059/11/9/2569 |
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