The pathogenetic role of PIK3CA gene mutations in breast cancer patients

Karcinom dojke je maligna bolest s najvećom incidencijom i prevalencijom na svjetskoj razini. Predstavlja glavni uzrok smrti od malignih bolesti kod žena u svijetu, a njegova incidencija i dalje raste. Jedan od čimbenika za nastanak karcinoma su PIK3CA mutacije koje dovode do pretjerane aktivacije PI3K/AKT/mTOR signalnog puta koji može nizvodno aktivirati mnoštvo drugih signalnih puteva koji dovode do nastanka karcinoma dojke. PIK3CA mutacije su povezane s razvojem rezistencije na endokrinu terapiju i kemoterapiju te s agresivnijom kliničkom slikom i lošijom prognozom. Pretjerana aktivacija CDK 4/6 kompleksa također dovodi do nastanka karcinoma dojke, a njegova aktivacija može biti potaknuta PIK3CA mutacijama. Provedena je retrospektivna kohortna studija s 203 pacijentice koje su terapiju CDK 4/6 inhibitorima započele u KBC-u Zagreb od 01.08.2018. do 01.10.2020. Kod 76 pacijentica je provedena molekularna analiza za PIK3CA mutacije. Cilj istraživanja bio je usporediti agresivnost kliničke slike i odgovora na terapiju CDK 4/6 inhibitorima između pacijentica s potvrđenom mutacijom i pacijentica bez mutacije. Kod 32 pacijentice je identificirana PIK3CA mutacija, a najčešća mutacija je bila H1047X mutacija u eksonu 20. Utvrđeni su povećani relativni rizici kod pacijentica s PIK3CA mutacijom za isključivo visceralnu bolest (3,208) i za infiltraciju koštane srži (4,125). Relativni rizik za inicijalno metastatsku bolest je također bio povećan (1,455). Sva tri čimbenika odraz su agresivnije kliničke slike. Medijan vremena do neuspjeha terapije kod pacijentica s mutacijom (21 mjesec) je bio 5 mjeseci kraći nego kod pacijentica bez mutacije (26 mjeseci), a rizik za progresiju bolesti je iznosio 1,372. Preživljenje je također bilo kraće kod pacijentica s mutacijom, 30,32 mjeseca naspram 32,35 mjeseci. Dobiveni podaci podupiru hipotezu da pacijentice s PIK3CA mutacijom imaju težu kliničku sliku s kraćim odgovorom na terapiju CDK 4/6 inhibitorima i kraćim sveukupnim preživljenjem.Breast cancer is the malignant disease with the highest incidence and prevalence in the world. It is the main cause of death from malignant diseases among women in the world and its incidence is still on the rise. PIK3CA mutations are an important factor in tumour formation. They lead to an overactivation of the PI3K/AKT/mTOR signalling pathway which can activate many other pathways downstream that can cause breast cancer. PIK3CA mutations have been associated with resistance to endocrine therapy and chemotherapy and with a more aggressive disease and worse prognosis. Overactivation of the CDK 4/6 complex can also lead to breast cancer, and its activation can be caused by PIK3CA mutations. A retrospective cohort study was performed with 203 patients that started therapy with CDK 4/6 inhibitors at KBC Zagreb between August 2020. and October 2020. A molecular analysis for PIK3CA mutations was performed in 76 patients. The goal of the study was to compare the outcome and clinical presentation of patients with the mutation to the ones without it. A PIK3CA mutation was identified in 32 patients, and the most common subtype was the H1047X mutation in exon 20. Patients with the mutation had an increased relative risks for visceral-only disease (3.208) and bone marrow infiltration (4.125). The relative risk of de novo metastatic disease was also increased (1.455). All three factors depict a more aggressive disease. The time to treatment failure median was 5 months shorter in patients with a mutation (21 months) than in those without it (26 months) and the risk for disease progression was 1.372. Overall survival was also shorter, 30.32 months compared to 32.35 months. The results of the study support the hypotheses that patients with PIK3CA mutations have a more aggressive disease with a shorter response to therapy with CDK 4/6 inhibitors and shorter overall survival