# Clinical and Morphological Features of ER-Positive HER2-Negative Breast Tumors with PIK3CA Mutations in Russian Patients

## TL;DR

This study examines the frequency and characteristics of PIK3CA mutations in Russian patients with a specific type of breast cancer and finds that testing should go beyond common mutation sites.

## Contribution

The study emphasizes the need for comprehensive PIK3CA testing beyond hotspots in Russian HR+/HER2− breast cancer patients.

## Key findings

- PIK3CA mutations were found in 37% of HR+/HER2− breast cancer cases.
- Common commercial kits may miss up to 12% of PIK3CA mutations.
- PIK3CA mutations were not linked to treatment resistance in a subgroup of patients.

## Abstract

Mutations in PIK3CA occur in approximately one-third of hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC) and represent a target for specific inhibitors. The current study established the frequency and spectrum of PIK3CA alterations in HR+/HER2− BC from Russian patients. We conclude that the overall prevalence and characteristics of PIK3CA-positive cases are consistent with previously published data and do not depend on the patient’s ethnic background. We also show that PIK3CA testing should not be limited to hot-spot variants, as commercially available kits may miss up to 12% of PIK3CA-mutated cases.

Background: Several targeted drugs have been recently approved for the treatment of PIK3CA-mutated hormone receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC). This study aimed at a comprehensive evaluation of the spectrum of PIK3CA alterations in Russian BC patients. Methods: The tumor material from 1872 patients with ER+/HER2− BC was tested by a combination of PCR-based methods. Results: Mutations were detected in 693/1872 (37%) cases, including 46 BC with two PIK3CA lesions. The three most common substitutions (E542K, E545K, and H1047R) were identified in 542/693 (78%) PIK3CA-mutated cases, while as many as 5.5–12% of identified mutations were not potentially detectable by common commercial kits. The study included patients of Slavic and non-Slavic ethnicities residing in regions with different climate conditions, however, these factors did not influence the distribution of PIK3CA mutations. The presence of PIK3CA variants was associated with older patient age at diagnosis (p = 0.0002), smaller tumor size (p = 0.005), lower grade (p = 0.005), Ki67 <20% (p = 0.0001) and progesterone receptor-positive status (p = 0.002) at the initial disease diagnosis, and fewer distant metastases at the time of the detection of BC spread (p = 0.0001). In a subgroup of 413 BC patients who received adjuvant tamoxifen or aromatase inhibitors, PIK3CA mutations were not associated with resistance to either type of treatment. Conclusions: The results of this study highlight the need to extend the PIK3CA testing beyond the hotspot regions of this gene. Although PIK3CA alterations contribute to the pathogenesis of HR+/HER2− BC and represent a target for several novel drugs, they are not intrinsically associated with unfavorable clinical characteristics of this subtype of cancer disease.