Molecular patient profiling to calibrate therapy to produce maximum efficacy is already a reality in many common tumors, such as colorectal or lung cancer. The same prospect now opens up for rare neoplasms such as neuroendocrine tumors of the gastro-entero-pancreatic tract (Gep-Nen), thanks to the results of a new study just published in the pages of the ‘British Journal of Cancer’ by Massimo Milione, director of the SC of Anatomy Pathology 1 of the Irccs Foundation Tumor Institute of Milan (Int), conducted thanks to the historic collaboration with the Molecular Biology Laboratory of the University of Padua directed by Matteo Fassan. This was discussed today at the Milanese Foundation on the occasion of the VI Workshop of Pathological Anatomy 1 entitled ‘The clinical predictivity of Surgical Pathology’.
Neuroendocrine cells – we read in a note – have mixed characteristics between nerve cells and endocrine cells, which are responsible for the production of hormones. Overall, they constitute the so-called diffuse neuroendocrine system (Sned) and are present in various organs, where they carry out particular tasks necessary for their functioning: for example, they regulate the flow of air in the lungs, the speed of transit of food in the gastrointestinal tract or the production of gastric juices in the stomach. We therefore speak of neuroendocrine tumors when the neoplasm originates from the cells of the neuroendocrine system, and can therefore concern the gastrointestinal system or the lungs.
Neuroendocrine tumors of the Gep-Nen tract are of particular importance, i.e. located in the stomach, duodenum, small and large intestine, rectum and appendix, as well as the pancreas. More than ten years ago, the idea emerged that for a particular type of Gep-Nen, neuroendocrine carcinomas, the 2010 World Health Organization (WHO) classification was too broad. Hence the original intuitions and subsequent research of Professor Milione. “In 2012, in a large conference held in Milan, I pointed out this anomaly of the pathological anatomy, finding confirmation from the comparison with the major oncologists of the time who were participating in the event – explains Milione – From there the initiative of bring together the leading Italian anatomopathologists to collect and analyze data relating to this type of tumors collected from all over Italy: the first data were presented already in 2015 during the world congress of Pathological Anatomy Uscap in Boston and confirmed the correctness of our intuition, because the category of neuroendocrine carcinomas is actually a heterogeneous group of neoplasms”.
These results were implemented by the WHO and integrated into the 2022 classification, making a leap in quality in therapies, treating the neoplasm based on histological characteristics. In the case of neuroendocrine tumors, a distinction is made between grade 3 tumors (Net-G3), with well-differentiated lesions, and neuroendocrine carcinomas (Nec), with poorly differentiated lesions. “Net-G3 can be treated with drugs that are very well tolerated by the patient, very often with an infusion of therapy every 21 days – explains Milione – the disease is thus made chronic, with a very long survival, so much so that death in the majority of cases occurs for other types of diseases. In the case of Nec, however, the only therapy available has been, at least so far, chemotherapy based on platinum salts, with a survival of the order of a few months”. However, the situation could soon change, thanks to the progress made in the molecular characterization of these tumors.
“Recently – continues Milione – the usefulness of Ki-67 has been demonstrated, a biomarker that functions as a sort of ‘tachometer’ of cellular replication and therefore also as an index of the aggressiveness of the neoplasm” which, as is known, replicates faster than a healthy cell. Precisely the measurement of Ki-67, associated with molecular analysis, allows us to “unpack” the category of tumors with poorly differentiated lesions into Nec with Ki-67 lower than 55% (Nec< 55) and greater than or equal to 55% (Nec ≥55). “Our latest study characterized the differences between the three categories Net-G3, Nec< 55 and Nec ≥55 from a genomic and transcriptomic point of view – that is, on the basis of the genetic heritage and the proteins encoded by the genome – a result that has profound consequences in terms of prognosis and therapy - specifies the professor - For Net-G3 and for Nec ≥55 the situation changes little, while there are interesting innovations for the 'grey area' represented by Nec<55, which present similarities with tumors, such as colon adenocarcinomas or lung carcinomas, which already benefit from standardized chemotherapies and 'targeted' therapies: the concrete prospect is therefore to transfer these therapies to NECs <55%, which until now ended up in the cauldron of Necs which had as the only option is platinum salt chemotherapy."
New and important indications have also emerged regarding the site of onset of the tumor. “Tumors present a different level of aggressiveness depending on the site – concludes Milione – with the same characteristics, for example, Necs of the pancreas have a more favorable prognosis than those of the colon. However, there is still one last step missing. We have, so to speak, pierced the veil of uniformity of treatment, but unfortunately we have not yet arrived at a targeted therapy, because demonstrative studies are still lacking, even if this is the goal towards which we are headed”.
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