Editor's note
At the 2024 European Society for Medical Oncology (ESMO) Annual Meeting, the researchers presented the latest research on pancreatic cancer driver gene mutations and prediction of patient prognostic response. Studies have shown that there are significant differences in the diversity of driver mutations between healthy pancreatic tissues and tumor tissues, and these differences may play a key role in the formation and progression of pancreatic cancer, and also provide an important basis for personalized treatment of pancreatic cancer. Dr. Francisco Martínez-Jiménez from the Vall d'Hebron Hospital in Barcelona, Spain, interprets the key findings and discusses their significance in clinical applications.
Driver gene mutations reveal the diversity of mechanisms of pancreatic cancer
At the 2024 ESMO Annual Meeting, a team of researchers from United Kingdom, Netherlands, and Spain revealed significant differences between healthy pancreatic and tumor tissues through an in-depth analysis of healthy pancreatic tissue and tumor tissue [1]. The study comprehensively analyzed 181 pancreatic samples from 118 healthy donors and 62 tumor tissue samples from 4 patients with pancreatic ductal adenocarcinoma (PDAC), and systematically revealed the mutational characteristics of somatic cells in the samples using laser capture microdissection, whole-exome sequencing, and NanoSeq.
The results of the study showed that the mutational burden in healthy pancreatic tissue was significantly lower than in tumor tissue. Among healthy donors, only 0.81% to 3.6% of cells carry driver mutations, mainly involving APC and PRSS1, among others. In contrast, in patients with untreated PDAC, up to 45% to 64% of cells carry driver gene mutations, and the mutated genes are mainly concentrated in KRAS and TP53 (see Figure 1). In addition, in 16 samples from 9 donors, the researchers also found incidental precancerous lesions with mutations in the KRAS driver gene.
In this study, the somatic mutation profiles of different tissue samples of pancreatic cancer were analyzed, which was helpful to reveal the early molecular events of cancer occurrence and its evolution. In the future, in-depth research on the interaction mechanism between these driver mutations and other environmental factors will help identify high-risk groups for pancreatic cancer, thereby facilitating the development of early diagnosis and prevention strategies for cancer. In addition, this study has important implications for the development of precision medicine, which can promote further progress in personalized treatment of pancreatic cancer and provide patients with more effective treatment options. By integrating molecular biology and clinical data, it is expected that more accurate risk assessment and treatment selection will be possible in the future.
Figure 1. NanoSeq technology reveals a driver gene profile in healthy pancreatic tissue
A functional model for predicting treatment response in patients with pancreatic cancer
In another study, researchers significantly improved the predictive power of response to specific treatments in patients with pancreatic cancer by integrating molecular and clinical variables into patient-derived organoid (PDO) functional screening [2]. The research team collected a total of 155 PDO samples from 70 pancreatic cancer patients and 85 colorectal cancer patients to simulate the drug response in clinical treatment to evaluate the response of each PDO to different treatment regimens. This approach allows researchers to more accurately predict how patients will respond in a real treatment setting, providing a more reliable basis for personalized treatment.
Based on these data, the researchers developed a prospective patient response prediction model that combined biochemical endpoint detection results with multimodal analysis to comprehensively evaluate the treatment response to PDO. The results showed that the model was effective in predicting global treatment response and progression-free survival (PFS) in patients with complete clinical outcome data. Further analysis showed that the accuracy of prediction was significantly improved when molecular and clinical variables such as the number of treatment lines and disease type were included in the prediction model, and the prediction value of PDO functional screening results was enhanced after controlling for clinical and molecular variables (HR: 4.36; P=0.0027; 95%CI：1.66~11.41）。 This finding highlights the potential role of patient-specific testing in precision treatment.
This study not only reveals the potential of PDO functional screening in the prediction of treatment response, but also provides new ideas and tools for the development of personalized therapy in the future. By accurately predicting a patient's specific response, clinicians are able to more accurately select the most appropriate treatment options, thereby significantly improving the patient's survival prognosis. This progress will promote the application of precision medicine in the treatment of pancreatic cancer, facilitate more effective clinical decision-making, and lay an important foundation for the development of personalized treatment strategies.
Clinical significance and future prospects
"The two studies highlight the diversity of driver gene mutations, clinical variables, and the important impact of molecular factors on tumor development and patient prognosis," noted Dr. Francisco Martínez-Jiménez from the Vall d'Hebron Hospital in Barcelona, Spain. In contrast, mutations in other genes may occur in healthy pancreatic tissue, but these mutations are usually selected only on a small scale (i.e., "forward selection"), meaning that cells carrying the mutations may have a growth advantage in local tissues, but not enough to cause them to eventually evolve into cancer cells. This phenomenon suggests that KRAS and TP53 have unique "transformational potential", while other genetic mutations that undergo positive selection in healthy pancreas may lack the ability to cause cancer. ”
The researchers noted that although driver gene mutations are important conditions for cancer development, these mutations alone are often not enough to cause cancer. This finding suggests that other environmental factors play a crucial role in the selection and transformation of pancreatic cancer, such as chronic inflammation, microenvironmental changes, or long-term exposure to external carcinogenic factors. Therefore, the occurrence of cancer is not the result of a single factor, but the result of the interaction of multiple complex internal and external factors. This study not only deepens our understanding of the early pathogenesis mechanism of pancreatic cancer, but also provides a new perspective and foundation for the development of personalized treatment strategies, which will help identify potential intervention targets and high-risk groups, thereby promoting the application of precision medicine in the treatment of pancreatic cancer.
The above studies not only deepen our understanding of pancreatic cancer driver genes, but also reveal their important value in the prediction of treatment response and survival prognosis of patients. By combining molecular biology with clinical data, we are able to more accurately predict the individualized treatment outcome of patients, providing a new scientific basis for personalized treatment strategies for pancreatic cancer. In the future, with the deepening of more research, we will further elucidate the mechanism of action of pancreatic cancer driver genes and promote the application of precision medicine in the treatment of pancreatic cancer. Researchers are not only expected to make breakthroughs in early diagnosis, therapeutic target discovery, and prognosis evaluation, but also significantly improve the survival and prognosis of patients and promote the development of precision medicine for pancreatic cancer.
Bibliography:
1.Nicola PA, et al. The somatic mutation landscape of the normal and malignant pancreas. ESMO Congress 2024, Abstract 1O.
2.Gryspeert A-R, et al. Multivariate analysis of functional organoid assays predicts patient responses in the clinic for colorectal and pancreatic cancer. ESMO Congress 2024, Abstract 10P.
Source: Tumor Lookout Digestive News