Brazilian study links TP53 mutations to poor lung cancer prognosis

Lung cancer is the most common and deadly form of cancer worldwide. It is increasingly understood to be a complex genetic disease with different mutations that vary according to factors such as smoking and ethnicity. These mutations are already guiding more personalized treatments. A recent study conducted at Hospital de Amor in Barretos, in the interior of the state of São Paulo, Brazil, with support from FAPESP carried out a comprehensive analysis of the genetic profile of lung tumors and identified mutations in the TP53 gene that can directly influence prognosis and therapy selection. The results were published in the journal The Lancet Regional Health Americas.

The study evaluated the 20 main genes associated with lung cancer in tumor samples from 1,131 patients treated at Hospital de Amor in Barretos and Porto Velho, in the Amazonian state of Rondônia. One of the distinguishing features of the study was the sample size and diversity of patients, who came from all five of the country's macroregions, including a significant portion from the Western Amazon, which remains underrepresented in research. This allowed for the observation of regional variations and enabled an investigation into the influence of genetic ancestry in the country.

"These aren't patients selected for a clinical trial; they're patients treated in the day-to-day operations of our institution. This allows us to better understand what happens in real life," says Rui Manuel Reis, scientific director of the hospital's Institute of Teaching and Research and one of the coordinators of the study.

According to Reis, this type of analysis broadens the applicability of the results and helps guide medical decisions that are more aligned with the actual routine of public health services.

Relevant changes

Today, lung cancer is a prime example of precision oncology because there are drugs that target specific gene mutations. Patients with gene alterations such as those in EGFR, KRAS, and ALK already receive targeted therapies, which are more effective than traditional chemotherapy. Study data show that 88% of evaluated patients have relevant genetic alterations in their tumors, which reinforces the importance of molecular testing in disease management. The most common alterations were in the TP53 (58%), KRAS (25.6%), EGFR (20.6%), and ALK (6.6%) genes. 

The researchers identified that mutations in TP53, known as the "guardian of the genome," were more prevalent in individuals with a greater African ancestry. This finding is consistent with international research.

Reis emphasizes that the novelty of the study was its ability to demonstrate that the genetic context of a tumor impacts disease progression and response to treatment, not just mapping these genetic alterations in isolation. The data indicate that the presence of TP53 mutations was associated with a worse prognosis, particularly among patients with EGFR mutations – a group that generally benefits from targeted therapies. "Even when receiving the most modern treatment, patients with TP53 mutations fared worse," states Reis.

Traditionally, TP53 was neither used to guide medical decisions nor included in medical reports or patient records. However, this finding has already begun to change hospital practices. "We've now incorporated it into our routine because we've discovered that this information can help guide the best therapeutic choice. In other words, patients with mutations in both EGFR and TP53 respond less well to EGFR-targeted therapy and may be ideal candidates for new clinical trials," says Reis. As a result, TP53 stands out as a potential prognostic marker and guide for more individualized treatment choices.

The results also suggest that patients with a TP53 mutation may respond better to chemotherapy.

Targeted therapy remains essential and the best option currently available, but we're beginning to get clues on how to tailor treatment according to the molecular profile of a patient's tumor."

Rui Manuel Reis, corresponding author

Access still limited in the SUS

Despite advances in genomic medicine, access to genetic testing remains limited in Brazil. Currently, these tests are not covered by the SUS (Sistema Único de Saúde, Brazil's national public health network), hindering the adoption of precision medicine. Although the National Commission for the Incorporation of Technologies in the SUS (CONITEC) recently approved standalone funding for the EGFR gene, Reis emphasizes that the results of the study underscore the importance of analyzing other genes beyond this one. 

"Without a more comprehensive genetic test, the chosen treatment may be inappropriate. And we're talking about expensive therapies, which can range from BRL 20,000 to BRL 40,000 per month, so they need to be carefully prescribed," he says. According to Reis, the cost of broader genetic tests can range from BRL 2,000 to BRL 8,000. 

The researcher believes that the findings have the potential to guide public policy by indicating which mutations are most common in the Brazilian population. This information could help prioritize which tests and therapies should be used to avoid less effective treatments. 

Additionally, Reis highlights that the study opens up new avenues of research. About 12% of the evaluated patients did not have known genetic mutations, suggesting the existence of other genes involved in cancer development that have not yet been identified. "The next step is to expand the study to include the entire genome to identify other genes and understand what happens in these cases," he says.

Another avenue is to develop targeted therapies aimed directly at the TP53 gene. Recent studies are beginning to reveal ways to reactivate its function, which could expand treatment options in the future. "If we can reactivate this gene using new drugs, we can change the outlook for these patients," says Reis, for whom the main impact of the work lies in integrating research and clinical practice. "The research doesn't just stay on paper. It's already being used to improve care for future patients," he concludes.