• Tue. Oct 26th, 2021

The oncologist: “Discovery causes lung cancer resistance to immunotherapy”


May 7, 2021

In Italy there are about 41 thousand new diagnoses of lung cancer every year. In recent years, however, immunotherapy has revolutionized the treatment of tumors, achieving surprising clinical results, even in lung neoplasms. The good news is that a fair percentage of all lung cancer subjects who previously had a poor prognosis respond to immunotherapy with PD-1 / PD-L1 inhibitors and become long-term survivors. Unfortunately, however, a not insignificant part of patients do not benefit from this treatment. A recent study (https://www.sciencedirect.com/science/article/pii/S0923753420421702) by the team led by Marcello Maugeri-Saccà, medical oncologist and researcher at the Division of Medical Oncology 2 of the Irccs Regina Elena National Cancer Institute of Rome, published in ‘Annals of Oncology’ (official journal of the European Society for Medical Oncology), reveals that a subgroup of patients with pulmonary adenocarcinomas presenting contemporary mutations in the genes KEAP1, PBRM1, SMARCA4 and STK11 are particularly disadvantaged and resistant to immunotherapy. “For some years – says Maugeri-Saccà in an interview published on Aleati per la Salute, the new portal dedicated to medical-scientific information created by Novartis – for the treatment of these tumors we have available a new and important therapeutic weapon, or immunotherapy. These are the so-called monoclonal antibodies which aim to stimulate our immune system against the disease “. Despite the excellent results in terms of clinical efficacy, unfortunately not all patients benefit from this treatment. “Our study – continues the oncologist – has identified a subgroup of patients who do not benefit from immunotherapy, to be traced back to the presence in the tumor of a specific mutational repertoire. This results in a faster disease progression and in a lower survival compared to patients who do not have specific mutations. We are talking about 10-15% of all subjects with lung adenocarcinoma, the most frequent lung neoplasm “.” These are coexisting mutations – explains Maugeri-Saccà – which involve at least two of the following genes: KEAP1, PBRM1, SMARCA4 and STK11. This mutational pattern identifies immunologically ‘cold’ tumors, despite a high mutational burden, as described in the study. Although relatively little known, these genes are frequently mutated in lung adenocarcinoma. Thanks to advances in molecular biology and precision medicine in oncology, we can currently identify q These mutations in two ways: directly on the tumor tissue sample taken from the patient, for example on a biopsy sample or surgery, or they can be identified in the circulating tumor DNA present in the patient’s blood, or with a simple blood sample “. The a priori identification of the so-called non-responding patients, according to the expert, can allow on the one hand to avoid subjecting them unnecessarily to a therapy that is ineffective for them and with sometimes dangerous side effects, and on the other hand to study the mechanisms of resistance in attempt to develop new pharmacological approaches. “Knowing the mutational structure of tumors before starting oncological treatments – underlines Maugeri-Saccà – is fundamental: it allows us to know if the tumor is sensitive to one drug rather than another, it provides us with information on the biology of the tumor and on expected clinical trend. The results of our study suggest that knowing the patients whose tumors present these mutations before starting immunotherapy treatment could represent a ‘wake-up call’ on the course of the disease, which is characterized by a more tumultuous and a low rate of responses to immunotherapy. On the other hand, patients who do not show these mutations in the tumor seem to benefit more than others from immunotherapy treatment, and who therefore obtain prolonged disease control thanks to this class of Although this is a discovery considered “revolutionary”, at the moment the a priori identification of non-r respondents is not clinical practice. “These genomic analyzes – confirms Maugeri-Saccà – require technical instruments and human capital that not all Italian centers have at their disposal. It involves using multigene panels, if not sequencing the entire exome (the coding DNA),” by next-generation sequencing, in order to simultaneously test a large number of mutations “. In this context, “it should be emphasized that this type of discovery is the result of a mix of factors – concludes the oncologist – Two above all: the collaboration with other bodies, in this case the University of Rome ‘La Sapienza’ , and the multidisciplinarity of the research group (medical oncologists, researchers, bioinformaticians, pathologists). In this regard, the oncological IRCCs are certainly making a fundamental contribution, in the context of a collaborative program (Alliance against cancer, Acc) that has , among the various objectives, that of making sequencing techniques available and reproducible, on a relatively large scale, to be applied to clinical practice “. Read the news also on: https://www.alleatiperlasalute.it/tumori-polmone-scoperta- cause-resistance-immunotherapy