Benefit of CDK4/6 inhibitors beyond PIK3CA mutations in metastatic breast cancer patients

CDK4/6 inhibitors (CDK4/6i) in combination with hormone therapy is the standard treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer (mBC). Resistance mechanisms are unknown and constitute an unmet medical need. In PALOMA-3 trial the PIK3CA mutations (PIK3CA mut) were not associated with resistance to palbociclib (p=0.34). The aim is to assess the role of PIK3CA mut in routine clinical practice as a mechanism of resistance to CDK4/6i in patients with luminal mBC. We conducted a retrospective and bi-centric study, between Hospital Clínico Universitario de Valencia and Hospital Universitario ‘12 de Octubre, to evaluate the impact of PIK3CA mut on CDK4/6i treatment in patients with HR+/HER2- mBC. The relationship between PIK3CA mutational status and progression-free survival (PFS) was analyzed by Cox's proportional hazards model and the log rank test. With the aim of homogenizing the sample, patients treated in the first line were also analyzed separately. All patients (n=92) were diagnosed with a luminal mBC. Forty patients (43.5%) presented PIK3CA mut and 52 (56.5%) were wild type (WT). The median PFS was 12.0 months (95% CI 9.3-14.6). No significant difference in PFS was found based on PIK3CA mutational status (10.9 months in PIK3CA mut, 95% CI 7.9-14.0; vs 12.7 months in PIK3CA WT, 95% CI 8.6-16.8) HR 1.05 p=0.84 (logrank test). The incidence of PIK3CA mutations were higher among patients treated at first line for ≤ 6 months (46.67%), however only 26.92% of long-term responders presented PIK3CA mutations. This effect was not identified at second line.Table 57PPatient baseline characteristicsn(%)PIK3CA mut (40)PIK3CA WT (52)Median age (years)51.948.92Menopausal status Premenopausal24 (60.0 %)27 (51.9 %) Postmenopausal16 (40.0 %)25 (48.0 %)Visceral met No24 (60.0%)29 (55.8%) Yes16 (40.0 %)23 (44.2 %)CDK4/6i Palbociclib29 (72.5 %)38 (73.0 %) Ribociclib9 (22.5 %)12 (23.1 %) Abemaciclib2 (5.0 %)2 (3.8 %)Line of therapy 1st Line14 (35.0 %)27 (51.9%) 2nd or more lines26 (65.0 %)25 (48.1%) Open table in a new tab The presence of PIK3CA mutations was not associated with resistance to CDK4/6 inhibitors in terms of PFS. Nevertheless, the frequency of PIK3CA mutations was lower in patients with extended benefit (more than 6 months) at first line of treatment. Future studies to explore the impact of triplet combination therapy (PIK3CA and CDK4/6i plus endocrine treatment) are needed.