Survival of rare and difficult-to-treat tumors improves with therapies targeted against the Idh protein. For this reason it is necessary, already at the time of diagnosis, to do the molecular test. This is the appeal to raise awareness among clinicians and institutions launched by the Foundation for Personalized Medicine (Fmp), today in Rome during a media tutorial on the most advanced frontier of precision oncology, focused on the oncogenic role of Idh mutations and created with the non-conditioning contribution of the Servier Group in Italy. The mutation of the Idh1 gene, recently discovered – explains a note – can be found in 80% of low-grade gliomas, a type of brain cancer, in 20% of cholangiocarcinomas and in 10% of cases of acute myeloid leukemia.
“In the histological model the therapeutic indication was based on the location of the tumor, in the mutational model it derives from genomic profiling – explains Paolo Marchetti, Fmp president – The key point of the new process is represented by genomic profiling, i.e. the identification of the molecular alterations that play a fundamental role in the development of the disease and, from here, the choice of the drug and the therapeutic indication derives, regardless of the location of the tumor, the age and sex of the patient”.
In detail, “gliomas are a form of brain tumor and every year in Italy about 3 thousand new cases are recorded – says Andrea Pace, head of Neuroncology at the Irccs Regina Elena Tumor Institute in Rome – 20% are made up of grade 2 gliomas, that is, low grade, which are more frequent in young people between the ages of 20 and 40. The symptoms at onset usually consist of epileptic seizures, which are often resistant to treatments, because the diseased cells tend to infiltrate the healthy nervous tissue brain tumors have slow growth, but over the years they can become high-grade and, therefore, more aggressive. For 20 years the therapies following surgery”, chemotherapy and radiotherapy, “have remained identical – he highlights – Today neuro-oncology can benefit. of precision medicine. Idh1 mutations are present in 80% of grade 2 gliomas, those of Idh2 in approximately 5%. In the Indigo study published in the ‘New England Journal of Medicine’, on approximately 330 patients with gliomas grade 2 non-aggressive patients who underwent surgery but not chemotherapy and radiotherapy, vorasidenib, an Idh inhibitor, more than doubled progression-free survival compared to observation alone: 27.7 months compared to 11.1. It is essential, as established by the WHO classification, that molecular analysis is performed in each patient at the time of diagnosis.”
Idh1 mutations are also present in approximately 20% of cases of cholangiocarcinoma (in the intrahepatic form). “It is a type of primary liver tumor which causes approximately 5,400 new diagnoses in Italy every year – explains Andrea Casadei Gardini, oncologist at the Medical Oncology Unit of Irccs San Raffaele Hospital in Milan and associate professor of Oncology at the Vita-Salute University San Raffaele di Milano – 70% of patients are diagnosed with an already advanced disease”. 5-year survival is still low, at 17% in men and 15% in women. “45% of patients with cholangiocarcinoma – continues the specialist – present a potentially ‘actionable’ genetic alteration, i.e. the target of targeted therapies. The most frequent in intrahepatic forms are Idh1 mutations, present in approximately 20% of cases, and Fgfr2 translocations, detectable in 10%.” Clinical trials have demonstrated the efficacy of targeted therapies, in particular with ivosidenib, the first targeted Idh1 inhibitor approved in Europe for patients with locally advanced or metastatic cholangiocarcinoma with an Idh1 mutation, previously treated with at least one line of systemic therapy. “In the ClarIdhy study published in ‘Jama Oncology’ – adds Casadei Gardini – the new molecule highlighted a reduction in the risk of disease progression by 63%. The benefits were also confirmed in a ‘real world’ study, which reproduces the practice daily clinic”.
Molecular profiling is also a fundamental part in the diagnosis of acute myeloid leukemia (AML), a blood cancer that affects approximately 2,100 people in Italy every year. “The 5-year survival is around 30% – underlines Maria Teresa Voso, full professor of Hematology at the Tor Vergata University and head of the advanced oncohaematological diagnostics laboratory at the Tor Vergata Polyclinic in Rome – The average age at diagnosis is 69 years old. Elderly or frail patients are unable to tolerate standard intensive chemotherapy” and possible “allogeneic stem cell transplant”. Up to 50% have at least one mutation potentially actionable for a targeted therapy”. Mutations affecting the Idh genes are among the most common: 10% have Idh1 and 10-15% Idh2. The European Commission has approved ivosidenib in combination with a hypomethylating agent, azacitidine, for the treatment of adult patients with newly diagnosed AML with the Idh1 mutation, who are ineligible to receive standard induction chemotherapy” In the Agile study, published in the ‘New England Journal of Medicine’ – Voso specifies – targeted therapy with ivosidenib in combination with azacitidine in the first line tripled the median overall survival compared to placebo and azacitidine, 2 years versus 7.9 months”.
“Today there is a growing availability of extended genomic profiling tests, with panels that can examine even 500 genes with a single test – concludes Marchetti – It is therefore essential to establish Molecular Tumor Boards, in which skills from different areas are involved, such as oncohaematology, pathological anatomy, medical genetics, molecular biology, clinical pharmacology, hospital pharmacy and other professional figures”.
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