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Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study.In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/mBetween April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15·1 years (IQR 8·4-16·3), median disease-free survival was not significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51-not reached] vs not reached [17·54-not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98-1·29]; log-rank p=0·11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17·45-not reached] vs 16·52 [14·24-17·54]; 0·77 [95% CI 0·67-0·89]; p=0·0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred.Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule.Bristol-Myers Squibb, Pharmacia, Dompè Biotec Italy, Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer.

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.

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.