Abstract P4-08-07: PIK3CA mutation, reduced AKT serine 473 phosphorylation, and increased ERα serine 167 phosphorylation are positive prognostic indicators in postmenopausal estrogen receptor-positive, HER2-negative early breast cancer
Authors: Ishida N , Hatanaka Y , Baba M , Hagio K , Okada H , Hatanaka KC , Matsuno Y , Yamashita H 
Published: February 2018

Background: Endocrine therapy is the most important treatment option for women with estrogen receptor (ER)-positive breast cancer. We recently reported that approximately two-thirds of patients who relapsed within 5 years had received anthracyclins and/or taxanes as adjuvant or neoadjuvant chemotherapy in addition to adjuvant endocrine therapy. New strategies, such as signal transduction inhibitors together with endocrine therapy are required to improve survival. PIK3CA mutations are detected in almost 40% of early ER-positive breast cancers, and are therefore the most frequent genetic alterations in this subtype. PIK3CA mutation status is reported to affect activation of AKT and ERα. Moreover, recent studies demonstrate that patients had a better prognosis when tumors expressed ER, androgen receptor (AR), and vitamin D receptor (VDR).

Methods: Expression of AR and VDR, phosphorylation of AKT serine (Ser) 473 (AKT phospho-Ser473) and ERα Ser167 (ERα phospho-Ser167) were examined by immunohistochemistry in ER-positive, HER2-negative early breast cancer tissues. Seventeen mutations in exons 1, 4, 7, 9, and 20 of the PIK3CA gene were detected in genomic DNA extracted from formalin-fixed paraffin-embedded tumor blocks. Correlations between these biological markers and clinicopathological factors and prognosis were analyzed separately in pre- and postmenopausal women.

Results: Levels of AKT phospho-Ser473 were significantly higher in premenopausal women (n = 62) than in postmenopausal women (n = 152) (P &lt; 0.0001 and P = 0.014, respectively). In contrast, expression levels of AR were significantly higher in postmenopausal women than in premenopausal women (P &lt; 0.0001). In premenopausal women, 26 tumors (43%) had a single mutation of PIK3CA gene, and 3 tumors (5%) had mutations at two sites. In postmenopausal women, 64 tumors (44%) had a single PIK3CA mutation, 6 tumors (4%) had mutations at two sites, and one tumor (1%) had mutations at three sites. In premenopausal women, wild type PIK3CA was associated with smaller tumor size, higher ER expression levels, and lower AR expression levels when compared with women in the same cohort with PIK3CA mutant tumors. In postmenopausal women, patients with PIK3CA wild-type tumors had higher Ki67 labeling index, higher AKT phospho-Ser473, and lower ERα phospho-Ser167 when compared to patients with PIK3CA mutant tumors. Postmenopausal women with PIK3CA wild-type tumors had significantly worse disease-free survival than patients with PIK3CA mutant tumors (P = 0.007). In contrast, PIK3CA mutation status was not correlated with survival in premenopausal women. Low levels of AKT phospho-Ser473 and high levels of ERα phospho-Ser167 were strongly associated with increased disease-free survival in postmenopausal women (P = 0.016 and P = 0.0016, respectively).

Conclusion: ERα activation, in addition to PIK3CA mutation, may be biomarkers for highly endocrine-responsive tumors. This would facilitate the selection of postmenopausal ER-positive breast cancer patients who are likely to benefit from endocrine therapy alone from those who are not.

Citation Format: Ishida N, Hatanaka Y, Baba M, Hagio K, Okada H, Hatanaka KC, Matsuno Y, Yamashita H. PIK3CA mutation, reduced AKT serine 473 phosphorylation, and increased ERα serine 167 phosphorylation are positive prognostic indicators in postmenopausal estrogen receptor-positive, HER2-negative early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-08-07.