Upregulation of Translationally Controlled Tumor Protein (TCTP) is associated with poorly differentiated aggressive tumors, including breast cancer, but the underlying mechanism(s) are still debated. Here, we show that in breast cancer cell lines TCTP is primarily localized in the nucleus, mostly in the phosphorylated form.The effects of Dihydroartemisinin (DHA), an anti-malaria agent that binds TCTP, were tested on breast cancer cells. DHA decreases cell proliferation and induces apoptotic cell death by targeting the phosphorylated form of TCTP. Remarkably, DHA enhances the anti-tumor effects of Doxorubicin in triple negative breast cancer cells resulting in an increased level of apoptosis. DHA also synergizes with Trastuzumab, used to treat HER2/neu positive breast cancers, to induce apoptosis of tumor cells.Finally, we present new clinical data that nuclear phospho-TCTP overexpression in primary breast cancer tissue is associated with high histological grade, increase expression of Ki-67 and with ER-negative breast cancer subtypes. Notably, phospho-TCTP expression levels increase in trastuzumab-resistant breast tumors, suggesting a possible role of phospho-TCTP as a new prognostic marker.In conclusion, the anti-tumor effect of DHA in vitro with conventional chemotherapeutics suggests a novel therapeutic strategy and identifies phospho-TCTP as a new promising target for advanced breast cancer.

Northern Italy has been one of the European regions reporting the highest number of COVID-19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID-19-positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID-19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer-related outcome. In this article, we attempt to estimate the individual riskbenefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID-19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. The Oncologist 2020;25:1-8 Implications for Practice: Managing patients with breast cancer during the COVID-19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID-19-related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients' and health workers' psychological distress.

and serves on data safety monitoring committees for Novartis and Merck.

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Purpose: The interplay between estrogen-receptor (ER) and erb-B tyrosine-kinase receptors (RTKs) impacts growth and progression of ER+/HER2+ breast cancer (BC) and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this crosstalk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab) and CDK4/6-inhibition (palbociclib) (PFHPert). Methods: Cytotoxic drug effects, interactions and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2+, two HER2low, and two ER-/HER2+ BC cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ BC treated with neoadjuvant PFHPert in NA-PHER2 Trial (NCT02530424). Results: In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2low cells. In patients, Ki67 downregulation at week2 and surgery were significantly associated to upregulation of senescence-related genes (p=7.7E-4 and p=1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (p = 0.019). Conclusions: Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by co-targeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2low tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2+ BC and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.

Adjuvant chemotherapy recommendations for ER+/HER2− early-stage breast cancers (eBC) involve integrating prognostic and predictive information which rely on physician judgment; this can lead to discordant recommendations. In this study we aim to evaluate whether Oncotype DX improves confidence and agreement among oncologists in adjuvant chemotherapy recommendations. We randomly select 30 patients with ER+/HER2− eBC and recurrence score (RS) available from an institutional database. We ask 16 breast oncologists with varying years of clinical practice in Italy and the US to provide recommendation for the addition of chemotherapy to endocrine therapy and their degree of confidence in the recommendation twice; first, based on clinicopathologic features only (pre-RS), and then with RS result (post-RS). Pre-RS, the average rate of chemotherapy recommendation is 50.8% and is higher among junior (62% vs 44%; p < 0.001), but similar by country. Oncologists are uncertain in 39% of cases and recommendations are discordant in 27% of cases (interobserver agreement K 0.47). Post-RS, 30% of physicians change recommendation, uncertainty in recommendation decreases to 5.6%, and discordance decreases to 7% (interobserver agreement K 0.85). Interpretation of clinicopathologic features alone to recommend adjuvant chemotherapy results in 1 out of 4 discordant recommendations and relatively high physician uncertainty. Oncotype DX results decrease discordancy to 1 out of 15, and reduce physician uncertainty. Genomic assay results reduce subjectivity in adjuvant chemotherapy recommendations for ER +/HER2− eBC.

e12017 Background: Liver metastasis is one of the most frequent cause of death in breast cancer patients. Among loco-regional approaches available for solid tumor liver metastasis, TACE allows a prolonged intra-lesion exposure to chemotherapeutic agents. Initial studies have highlighted a benefit in terms of response rate (RR) and overall survival (OS) in breast cancer patients treated with TACE versus systemic chemotherapy. Methods: We have retrospectively evaluated 14 patients affected by breast cancer with liver metastasis. Patients had been selected for liver TACE according to the presence of liver metastasis as only site of disease, or in the event of further sites of metastasis that were stable or in response from the previous treatment. All the patients received one or more TACE with DC-Bead (Biocompatibles UK) 100-300 micron, loaded with a chemotherapeutic agent (doxorubicin, paclitaxel).The systemic therapy received by patients before TACE could be confirmed or changed according to disease response. Objective of the study was to evaluate the response rate to TACE and its correlation with the response to the very last treatment performed before it. As surrogate of efficacy, time to progression (TTP) and OS were analyzed. Results: Among the 14 treated patients (5 heavily pretreated, with more than three lines of chemotherapy) only one obtained a complete remission (RC). Four patients presented a partial remission (PR). Three of them were progressing from previous treatment and one had a PR. Stable disease (SD) after TACE was obtained in four cases: two of them had a progressive disease (PD) before TACE and two had a responsive disease. Five patients did not respond to TACE (one with PR from the previous line of therapy). Median TTP observed in responsive patients (CR + PR) was 4.5 times higher than non-responders (PD) (13.2 vs. 2.9 months). Patients with SD had a median TTP of 4.3 months. Median OS of responsive patients was 25.6 months vs. 17.5 and 19.2 months of patients with SD or PD respectively. Conclusions: In our experience, chemoembolization can represent a valid therapeutic option in breast cancer patients with liver metastasis, independently from the response to the previous systemic therapy, and may prolong survival.