Abstract B027: PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients

Abstract

The PIK3CA gene, encoding the p110α catalytic subunit of PI 3-kinase (PI3K), is mutated in more than 30% of breast cancers. Most mutations concentrate to the hotspots E542K and E545K and H1047R and are associated with hyperactivation of the phosphatidylinositol 3′-kinase/Akt pathway in vitro. The estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) (ER+/HER2-) breast cancers stand for more than 40% of the PIK3CA mutations where these constitute a new therapeutic target for endocrine-treatment resistant advanced breast cancers. Although PIK3CA is an oncogene, its mutations are associated with good prognosis. Here, we explored the prognostic and predictive role of PIK3CA hotspot mutations for low-risk postmenopausal breast cancer patients randomized to receive tamoxifen vs. no systemic treatment, followed for over 25 years and with extensive clinical records. Mutation analysis was performed using formalin-fixed paraffin-embedded tumors with digital droplet PCR (ddPCR). PIK3CA mutations were present in 35,6% of patients, predominantly within the ER+/HER2- subtype (49,8%) compared with the HER2+ and TNBC subtypes. The most frequent mutation found in all patients was H1047R (18%) followed by E545K (14%) and E542K (6%). Significant associations were found between all hotspot mutations and low grade, positive progesterone receptor (PR) expression, HER2 negative status, low Ki-67 (proliferation marker), and high expression score of a PIK3CA-mutation-associated gene module. Moreover, PIK3CA mutations were often found in patients with ultralow risk to develop distant recurrences according to the 70-gene signature. All PIK3CA mutations were coupled with longer distant recurrence-free interval (DRFI) in all patients in univariate and multivariable analysis after adjusting for tumor size, receptor status (ER, PR, HER2), tumor grade, Ki-67 and tamoxifen: HR multivariable (95% CI)=0.53 (0.28-0.98). In agreement with our previous results, PIK3CA mutations indicated good prognosis for patients with highly proliferative tumors (Ki-67>15%): H.R multivariable (95% CI)=0.15 (0.03-0.69) and high risk by the 70-gene signature: HR multivariable (95% CI)=0.14 (0.03-0.61) but not for low proliferative tumors (Ki-67<15%). In fact, PIK3CA mutations indicated adverse prognosis within those patients with ultralow risk where the registered survival was 100% in presence of the PIK3CA wild type genotype. PIK3CA mutations did not have predictive value for tamoxifen. In conclusion, PIK3CA mutations predominate within the ER+/HER2- subtype, are coupled with good clinical markers and longer DRFI in all patients and especially among aggressive tumors but not in ultralow risk patients. Further investigation will be needed to decipher the role of PIK3CA in patients with ultralow risk or indolent tumors who may present long-term relapses and specially benefit from PI3K inhibition. Citation Format: Carolin Jönsson, Zeinab Alkashaf, Josefine Sandström, Annelie Johansson, Tommy Fornander, Linda S. Lindström, Gizeh Perez Tenorio. PIK3CA hotspot mutations as biomarkers for prognosis and treatment prediction in low-risk postmenopausal breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B027.