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Abundant preclinical evidences indicate that stress-induced autophagy in tumor cells is predominantly cytoprotective and that inhibition of autophagy can enhance tumor cell death by diverse anticancer therapies. A major negative regulator of autophagy is the mammalian target of rapamycin (mTOR), activated downstream of PI3KAKT pathway. mTOR inhibitors, including rapamycin, have been shown to induce autophagy in tumor cells, while the combination of PI3K-AKT/mTOR and autophagy inhibitors shown synergistic effect on increased apoptosis and reduced autophagy (Takeuchi H. 2005). This project aimed to characterize the role of autophagy in Breast Cancer models exposed to new potent Genentech PI3K/AKT inhibitors GDC0068 (Ipatasertib) and GDC0032 (Taselisib) currently in phase III clinical trials on TNBC and ER+ patients. However, the efficacy of PI3K/AKT inhibitors may be limited by resistance mechanisms that result in minimal cell death in tumor cells. In order to investigate the role of autophagy as possible mechanisms of resistance, Ipatasertib and Taselisib have been evaluated in breast cancer cell lines characterized by different receptors profile: TNBC, HER2/c-erb-2 and luminal A cell lines. Our results showed that both drugs are able to induce G1/S cell cycle block and increase of autophagy signaling measured by p62 level and LC3 II/LC3 I ratio and by the percentage of cells exhibiting LC3 positive puncta. In addition, apoptosis increase was also evaluated by measuring positive annexin V staining, by flow cytometry technique, and apoptosis markers, such as PARP and cleaved caspase 3, by immunoblot assay. Furthermore, the supplement of pharmacologic inhibitors of autophagy, such as hydroxichloroquine, were able to reduce cell viability evaluated by both short- and long-term assays in cell lines exposed to Ipatasertib and Taselisib. 3D breast cancer models are ongoing to confirm the synergic effect of PI3K/AKT inhibitors and hydroxychloroquine, in order to provide a new therapeutic combinatorial approach potentially translatable to patients. Citation Format: Cocco S, Leone A, Buonfanti G, Sisalli MJ, Budillon A, De Laurentiis M. Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032 [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 P4-07-09.

Triple-negative breast cancers (TNBCs) represent a heterogeneous disease characterized by several molecular subtypes with different prognoses and responses to therapy. For a correct clinical management of TNBC patients the knowledge of the gene regulation mechanisms related to tumor progression and drug response has become fundamental. LncRNAs regulate gene expression through various processes, including chromatin modification, transcription and post-transcription and they are emerging as important cancer biomarkers being involved in tumor pathogenesis, metastatic progression and drug resistance. In this study we aimed to analyze the expression of the lncRNA HOTAIR, mainly involved in breast cancer disease, in a large case series of TNBC patients. We used ISH methods by a RNA probe to better define its staining in tumor tissues and its relation with clinical-pathological parameters and outcomes of patients. Our results show that high HOTAIR expression in tumor tissues is strongly correlated with lymph nodes metastasis (LNM) (p=0.039), as reported also for other tumor types, and has a direct strong association with Androgen Receptor (AR) expression (p= 0.019). These data confirm the prognostic role of HOTAIR in TNBC, and, its involvement in the regulation of AR pathway, suggests the possibility to establish new therapeutic strategies for AR+TNBC patients.

e12532 Background: Addition of CDKi to ET in ER-positive mBC has proven effective in improving both progression-freesurvival (PFS) and Objective Response Rate (ORR). However, no randomized clinical trial (RCT) has so far shown a significant increase of Overall Survival (OS). We carried out a metanalysis of all RTCs to better characterize the efficacy of CDK4/6i in some relevant subgroups, with particular reference to OS. Methods: Literature search of main databases was carried out up to 08 Dec 2018. Hazard ratios (HRs) for PFS and OS and risk ratios (RRs) for ORR were extracted/calculated for each trial and then pooled by using both fixed and random effect model. Confidence intervals (CIs) at 95% were calculated for each statistics. Kaplan-Meier meta-curves were generated by pooling data of all trials, among ET sensitive and ET resistant pts. Results: Eight RCTs were included accounting for a total of 4580 pts, 2802 receiving a CDKi (palbociclib, ribociclib or abemaciclib) in association with ET (NSAI, tamoxifene or fulvestrant) and 1778 receiving ET alone or plus placebo. Pooled analysis of HRs showed a significant improvement in PFS, regardless ET sensitivity, disease site, number of metastatic sites and treatment free interval. Analysis of OS included 3 RCTs with a total of 1243 pts and showed a statistically significant improvement of OS (HR 0.769 [95% CI 0.638, 0.926], p-value 0.006). Pooled estimate for RR showed higher ORR in CDK 4/6 arm both in ET sensitive (RR 1.35 [95% CI 1.19, 1.52]) and ET resistant group (RR 2.19 [95% CI 1.66, 2.89]). Similarly, pts with measurable disease showed a RR of 1.34 (95% CI 1.20, 1.50) in ET sensitive group and 2.26 (95% CI 1.72, 2.96) in ET resistant group. Pooled survival curves showed an absolute benefit in PFS, both in ET sensitive (median PFS: NR vs 15 months) and ET resistant (median PFS: 19.2 vs 8.9 months). Conclusions: Our findings suggest that addition of CDKi to ET improve clinical outcome in terms of PFS, ORR and OS, irrespective of pts/tumor characteristics.

BACKGROUND To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. PATIENTS AND METHODS A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. RESULTS Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P