Abstract PD5-7: PTEN and PIK3CA but not p4EBP1 are associated with low rates of pathological complete response (pCR) to trastuzumab based chemotherapy in primary HER2-overexpressing breast cancer
Authors: Loibl Sibylle , Darb-Esfahani Silvia , Klimowicz Alexander , von Minckwitz Gunter , Lederer Bianca , Huober Jens , Hartmann Arndt , Eidtmann Holger , Pfitzner Berit Maria , Fasching Peter A , Tiemann Katharina , Jackisch Christian , Mehta Keyur , Untch Michael , Denkert Carsten 
Published: May 2015

Abstract
Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) aberrations are common in breast cancer (BC). PIK3CA mutation is associated with lower pCR rates especially in patients treated with double anti-HER2 therapy (Loibl et al. JCO accepted). Another mechanism of resistance for trastuzumab-based treatment could be loss of PTEN, resulting also in downstream activation of the pathway. We investigated the correlation between PIK3CA, PTEN, p4EBP1 (phosphorylated E4 binding protein 1) and pCR in pts receiving neoadjuvant therapy.
Methods: In addition to PIK3CA we retrospectively evaluated PTEN and p4EBP1 by immunohistochemistry in HER2+ patients who received EC followed by docetaxel within the G4 study (Untch et al. 2011). The G4 study demonstrated a higher pCR rate by adding trastuzumab to chemotherapy. HER2 and hormone receptors (HR) were centrally assessed. PTEN was assessed using the automated quantitative immunofluorescence analysis (Aqua) using an antibody (Cell Signalling Technology). p4EBP1 assessed by immunohistochemistry with an immunreactive score ranging from 0-12. PTEN was categorized by an optimized cut-off determined by the cut-off finder software (http://molpath.charite.de/cutoff/) and p4EBP1 was measured as a continuous variable and correlated with PIK3CA genotype and pCR (ypT0, ypN0). Central HER2+ve cases with a tumor cell content of ≥20% were selected (n=181).
Results: Median age was 48years (22-77); HR+ve 51%; Grade 3, 47.4%; pCR rate 32%. p4EBP1 analysis was available from 137 and PTEN from 108 patients. PIK3CA genotype was available in 83 of these patients. 58 pts had PIK3CA and PTEN assessable, 14/58 had a PIK3CA mutation (mut) (25%).
Overall, pCR rate in PTEN low tumors was 27.6% vs 57.1% in PTEN high (p=0.010). Within the PIK3CA mut cohort 13/14 (92.9%) tumors were PTEN low. Within the PIK3CA wild-type (wt) cohort 30/44 (68.2%) were PTEN low (p=0.066). The tumours were grouped into 4 subsets using PIK3CA (mut vs wt) and PTEN (low vs. high). pCR rate was 57.1% (8/14) in PTEN high/PIK3CA wt cohort and decreased to 15.4% in the PTEN low/PIK3CA mut cohort. The group with either PTEN low and PIK3CA wt or PTEN high and PIK3CA mut had a pCR rate of 32.2% (p=0.015). In multivariable analysis after adjustment for baseline parameters PTEN was an independent predictor for pCR in the complete cohort (OR 12.3 [95% 1.82-82.9] p=0.010) and in PIK3CA wt cohort (OR 10.3 [95% CI 1.31-81.62] p=0.027). Within the HR+ve group PTEN low tumors had a pCR rate of 22.2% vs 61.5% in the PTEN high group (p=0.007). In multivariable analysis PTEN was independently predictive for pCR in the HR+ve group (OR 49.5 [95% 3.4-707] p=0.004). p4EBP1 correlated weakly with PIK3CA (p=0.049) but not with PTEN. There was no association of p4EBP1 with pCR.
Conclusion: Low PTEN was significantly associated with lower pCR and added independent predictive information not only in the overall HER2+ve cohort but also in the PIK3CA wt and HR+ve cohort. It will be confirmed in a larger sample size if PTEN assessment adds information to PIK3CA genotype to select patients with low pCR rates after trastuzumab therapy.
Citation Format: Sibylle Loibl, Silvia Darb-Esfahani, Alexander Klimowicz, Gunter von Minckwitz, Bianca Lederer, Jens Huober, Arndt Hartmann, Holger Eidtmann, Berit Maria Pfitzner, Peter A Fasching, Katharina Tiemann, Christian Jackisch, Keyur Mehta, Michael Untch, Carsten Denkert. PTEN and PIK3CA but not p4EBP1 are associated with low rates of pathological complete response (pCR) to trastuzumab based chemotherapy in primary HER2-overexpressing breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-7.