CancerPancreatic cancer

Pancreatic cancer: one disease, many molecular subtypes

Affiliations: La ligue contre le cancer, France

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Summary: Pancreatic cancer is one of the most life-threatening cancers but its molecular subtyping and classification is still fairly recent. In this paper the authors summarize existing classifications of tumors by their genes. They further explain how a consensual classification could improve treatment personalization in the near future.

Pancreatic ductal adenocarcinoma (PDA) accounts for >95% of pancreatic cancers and is one of the most life-threatening cancer forms. It has been reported by researchers to have several subtypes, defined by the molecular characteristics of cancer cells. Importantly, each of the distinct subtypes presents different prognosis and response to treatment.

Compared to other cancer forms, the molecular subtyping of pancreatic cancer is only quite recent, meaning that no consensual classification has been established yet. In 2019, a group of medical doctors and scientists published one of the most recent reviews summarizing the different molecular subtypes that have been described for PDA.

Classifying tumors by their genes

The authors focus on transcriptomic or molecular subtypes that are established through the measurement of gene expression in tumor cells. From the different analyses carried out by more than ten research groups, two to four distinct transcriptomic subtypes of pancreatic cancer were identified. More specifically, two subtypes were found to be described by every one of the research groups:

1) The epithelial classical subtype

2) The basal mesenchymal subtype

Tumors of the epithelia classical (also known as classical progenitor) subtype are characterized by increased survival rate and a good response to chemotherapy or other therapies targeting specific genes in cancer cells. These tumors are mainly composed of mature, specialized cells (also known as differentiated cells) that resemble normal pancreatic cells, and are thus more sensitive to conventional chemotherapy.

On the other hand, patients presenting a tumor of the basal mesenchymal subtype have a poorer response to chemotherapy and a considerably worse survival rate compared with the epithelial classical type. Basal mesenchymal tumors are mainly made up of immature cancer cells (also known as undifferentiated cells) that express genes which regulate the division and survival of cells, as well as the resistance to therapy and ability to invade cells. Such molecular characteristics increase the malignant potential of basal mesenchymal tumors.

How is tumor classification used in the clinic?

Grouping patients based on the molecular characteristics of a tumor they present is essential for more targeted and effective therapeutic decisions. Tumors that appear similar at a morphological level, may in fact be dramatically different at the molecular level, presenting different characteristics that make them more or less vulnerable to a certain therapy.

Diverse studies have been carried out in order to define the best therapeutic regimes for each of the distinct molecular subtypes reported for pancreatic adenocarcinoma. So far, many of the studies have focused on the basal mesenchymal tumor subtype and have evaluated the response of tumor subtypes to standard chemotherapeutic drugs used in pancreatic cancer (FOLFIRINOX or gemcitabine). As emphasized by the authors in this article, the different studies have used various approaches to evaluate the response to treatment but they have not yet been replicated. More trials are thus required in order to truly determine what therapies are the most effective for each pancreatic adenocarcinoma molecular subtype. Nonetheless, the progress made to date by different research groups gives hope to the scientific and medical community to soon reach a consensus on the molecular classification of different pancreatic cancer cells, facilitating in fine treatment personalization against this deadly disease.

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