247P Efficacy of therapy directed against PI3K and cyclin inhibitors based on the location of PI3K mutations

Abstract

Activation of the phosphatidylinositol-3-kinase (PI3K) pathway is responsible of activating the phosphorylation cascade that regulates cell survival and metabolism. Mutations in this pathway may occur in 28-46% of HR+/HER2- advanced breast cancers. It is known that the presence of this mutation confers a worse prognosis. We set out to analyze if PI3K mutations in different exons confer resistance to treatments directed against this target and to cyclin inhibitors (inh-CDK4/6). We have analyzed 96 patients with advanced breast cancer HR+/HER2- subsidiaries of treatment with PI3K-targeted therapy in the hospital of Jaén from February/20 to January/23. To detect PIK3CA mutations we used the cobas ® diagnostic kit that detects: exons 1 (R88Q), 4, 7 (C420R), 9 (E542K, E545K/A/D/G, Q546E/R) and 20 (H1047R/Y/L). We obtained 26% mutations in PI3K (5% exon 1, 40% exon 9, 55% exon 20). All in women with a mean age at diagnosis of 48 years and 56 at diagnosis of metastases, located at bone 65%, lung 35%, liver 23% and CNS 4% All patients have been treated with inh-CDK4/6. The median progression-free survival (mSLP) is 17 months (1-60). In patients with exon 1 mutation, mSLP is 25 months, in exon 9, 13 (2-43) and in exon 20, 19 (1-60) 60% of the patients have progressed to inh-CDK4/6 and as next treatment we used alpelisib. In 58% corresponds to 2 line in metastatic disease. The mSLP is 5 months (1-22) with a median follow-up of 14 months (1-34) and 69% of events. In patients with mutation in exon 1 the mSLP is 2 months, in exon 9, 5 (1-13) and in exon 20, 9 (2-22). Treatment was associated with an antiestrogen (77%) with a mSLP 7 months (1-22) or an aromatase inhibitor with a mSLP 3 months (2-10). 53% suffered grade 3 adverse effects (G3 AE): hyperglycemia (80% exon 9, 16% exon 20), diarrhea (20% exon 9) and skin rash (16% exon 20). 14% discontinued treatment due to toxicity. The PFS with alpelisib is lower than reported in the SOLAR1 study and is similar to Bylieve study, whose population is most similar to our sample. Exon 20 carriers are those who obtain a higher PFS, as well as those who receive it with an antiestrogen. Exon 9 carriers have a higher rate of G3 AE With respect to inh-CDK4/6, the PFS corresponds to the literature, with exon 20 carriers obtaining a higher PFS.