Background:Phosphatidylinositol 3-kinase (PI3K) pathway activation has been suggested to negatively influence response to anti-HER2 therapy in breast cancer patients. The present study focused on mutations of the PIK3CA gene, encoding one of the two PI3K subunits.Methods:PIK3CA mutations were assessed by direct sequencing in 80 HER2-positive patients treated with 1 year of trastuzumab. All patients preoperatively received four cycles of anthracycline-based chemotherapy, followed by four cycles of docetaxel and 1 year of trastuzumab, starting either before surgery with the first cycle of docetaxel and continuing after surgery (neoadjuvant trastuzumab arm, n=43), or only after surgery (adjuvant trastuzumab arm, n=37).Results:PIK3CA mutations were found in 17 tumours (21.3%). Better disease-free survival (DFS) was observed in patients with PIK3CA wild-type compared with mutated tumours (P=0.0063). By combining PIK3CA status and treatment arms, four separate prognostic groups with significantly different DFS (P=0.0013) were identified.Conclusion:These results confirm that the outcome of HER2-positive patients treated with trastuzumab is significantly worse in patients with PIK3CA-mutated compared with wild-type tumours.

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Background: In ER+ HER2- metastatic breast cancer (MBC) patients, the clinical choice between 1st line hormone therapy (HT, the recommended option) or chemotherapy (CT) is based on the absence of “visceral crisis” or adverse prognostic factors, with no proven/objective criteria. In that context, STIC CTC (NCT01710605) was set up as a strategy trial to test whether circulating tumor cells (CTC) count could help customize the choice between 1st line HT or CT. Methods: For this multicenter phase 3 non-inferiority trial, the main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to HT or CT and informed consent. The a priori treatment choice (HT or CT) and CTC count (CellSearch®) were obtained in all patients prior to randomization. Patients were randomized 1:1 between clinically-driven choice (CTC count not disclosed, HT or CT administered as decided a priori), or a CTC-driven choice (HT if <5 CTC/7.5ml, CT if ≥5 CTC/7.5ml). The primary objective was treatment efficacy (PFS hazard ratio), non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is ≤1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: 761 MBC patients were randomized between 02/2012 and 08/2016. Baseline characteristics: 7.8% of patients had a PS=2, 24.1% had a de novo metastatic disease; 63.3% received prior adjuvant HT and 49.9% prior adjuvant CT; 31.3% had ≥3 metastatic sites. A priori treatments (HT or CT) and CTC count (< or ≥5 CTC/7.5ml) were well balanced between the two arms. After randomization, in the clinically-driven arm, N=267 (72.4%) patients received HT and N=102 (27.6%) CT (as decided a priori). In the CTC-driven arm: (1) the a priori choice of HT was confirmed by a low CTC count in N=181 (67.5%) of patients, while N=87 (32.5%) were switched to CT due to a high CTC count; (2) the a priori choice of CT was confirmed by high CTC count in only N=48 (48%) patients, while N=52 (52%) were switched to HT. The primary endpoint was met, PFS being not inferior in the CTC-driven arm (HR=0.98, 90%CI=[0.84–1.13]). Analyses focusing on discordant subgroups showed that for patients with a priori choice of HT but with high CTC count (leading to a switch to CT in the CTC-arm), PFS was significantly longer in the CTC-driven arm than in the standard arm (HR=0.67, 95%CI=[0.49–0.92]; p=0.01), with a non-significant trend toward longer OS (HR=0.68, 95%CI=[0.44–1.07]; p=0.09). Inversely, for patients with a priori choice of CT but with low CTC count (i.e. de-escalation to HT in the CTC arm), PFS was not statistically different between the two arms. Conclusion: This trial demonstrates the clinical utility of CTC count as an objective decision tool when considering 1st line therapy in ER+ HER2- MBC. In most patients, CTC count did confirm the a priori clinical choice; however, trial results show that in discrepant cases, CTC count may be trusted for either escalating (i.e. considering CT in patients if high CTC count) or de-escalating (i.e. considering HT in patients if low CTC count) 1st line therapy. Funding: French National Cancer Institute; Menarini Silicon Biosystems. Citation Format: Bidard F-C, Jacot W, Dureau S, Brain E, Bachelot T, Bourgeois H, Goncalves A, Ladoire S, Naman H, Dalenc F, Gligorov J, Espie M, Levy C, Ferrero J-M, Loirat D, Cottu P, Dieras V, Simondi C, Berger F, Alix-Panabieres C, Pierga J-Y. Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-07.