Tumour heterogeneity and a long-standing paucity of effective therapies other than chemotherapy have contributed to triple-negative breast cancer (TNBC) being the subtype with the least favourable outcomes. In the past few years, advances in omics technologies have shed light on the relevance of the TNBC microenvironment heterogeneity, unveiling a close dynamic relationship with cancer cell features. An improved understanding of tumour-immune system co-evolution supports the need to adopt a more comprehensive view of TNBC as an ecosystem that encompasses the intrinsic and extrinsic features of cancer cells. This new appreciation of the biology of TNBC has already led to the development of novel targeted agents, including PARP inhibitors, antibody-drug conjugates and immune-checkpoint inhibitors, which are revolutionizing the therapeutic landscape and providing new opportunities both for patients with early-stage TNBC and for those with advanced-stage disease. The current therapeutic scenario is only the tip of the iceberg, as hundreds of new compounds and combinations are in development. The translation of these experimental therapies into clinical benefit is a welcome and ongoing challenge. In this Review, we describe the current and upcoming therapeutic landscape of TNBC and discuss how an integrated view of the TNBC ecosystem can define different levels of risk and provide improved opportunities for tailoring treatment.

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.

Background: Fulvestrant 500 mg (F500) is the most active endocrine single agent in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC). Few data are available regarding the effectiveness of the drug in a real-world setting. Patients and methods: This prospective, multicenter cohort study aimed to describe the patterns of treatment and performance of F500 in a large population of unselected women with MBC, focusing on potential prognostic or predictive factors for disease outcome and response. The primary endpoints were progression-free survival (PFS) and clinical benefit rate. Results: From January 2011 to December 2015, 490 consecutive patients treated with F500 were enrolled. Overall, three different cohorts were identified and analyzed: the first received F500 after progression from previous chemotherapy (CT) or endocrine therapy; the second received the drug for de novo metastatic disease; and the third was treated as maintenance following disease stabilization or a response from a previous CT line. Median overall survival (OS) in the whole population was 26.8 months, ranging from 32.4 in first line to 22.0 and 13.7 months in second line and subsequent lines, respectively. Both the presence of liver metastasis and the treatment line were significantly associated with a worse PFS, while only the presence of liver metastasis maintained its predictive role for OS in multivariate analysis. Conclusions: The effectiveness of F500 was detected in patients treated both upon disease progression and as maintenance. The relevant endocrine sensitivity of 80% of patients included in the study could probably explain the good results observed in terms of outcome.

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Background The CDK4/6 inhibitor palbociclib combined with endocrine therapy has proven to prolong progression-free survival (PFS) in previously untreated and pretreated women with HR+/HER2- MBC. Few data are available regarding the performance of such a regimen outside the clinical trials, and there is the need to understand its performances in real world. Methods We report a multicenter real-life experience aimed to verify the patterns of treatment and outcome of palbociclib plus endocrine therapy in an unselected population of MBC patients (pts). The primary endpoint was clinical benefit rate (CBR: complete response [CR], partial response [PR], or stable disease for longer than 6 months [SD]); secondary aims were median progression-free survival (mPFS) and safety of the combination. Statistical analysis was performed to identify variables potentially predictive of outcomes. Patients received P at 125 mg daily, 3 wk on/1 wk off in a 28d cycle, combined with letrozole administered orally 2.5 mg on a continuous daily dosing schedule (cohort A) or Fulvestrant 500 mg (F500) i.m. q4wks with loading dose (cohort B); treatment was given until disease progression, toxicity or patient's refusal. Results The study enrolled 150 postmenopausal pts (65 in cohort A, 85 in cohort B) treated from December 2016 to April 2018 at 4 Italian Institutions. Median age in the whole population was 62 years (range 47-79; mean age 59 years in cohort A, 64 in cohort B); 13 pts (20%) in cohort A and 23 pts (27%) in cohort B had de novo metastatic disease; 46% of pts in cohort A and 55% had visceral involvement, while 17% and 20% respectively had bone-only disease. The median number of prior lines was 2 in cohort A (range 1-3) and 3 (range 2-5) in cohort B, including ET (median 3) and chemotherapy (median 2); in cohort B 37 pts (43%) had previously received F 500, while 12% (cohort A) and 15% (cohort B) had been pretreated with everolimus. In cohort A a PR as best response was observed in 32% (20 pts), with 14 pts (23%) achieving SD lasting ≥ 6 months for a CBR of 52%. In cohort B CBR was 60%, with 25% PR, 48% SD lasting ≥ 6 months in 35 pts (41%). The most common adverse events in both cohorts were neutropenia (grade 1-2 in 67%, grade 3-4 in 35%), grade 1 anemia (52%) and thrombocytopenia (34%), requiring dose reduction in 27% of cases. At a median follow-up of 12 months (range 1-16), mPFS was 6.3 months in cohort A and 5.5 months in cohort B. In both groups a better mPFS was observed in pts treated as ≤ 3rd versus > 3rd line: 9.6 versus 5.2 in cohort A (p=0.003), 8.8 versus 4.1 months in cohort B, respectively (p= 0.002). No significant outcome differences were observed according to prior endocrine therapy with F500 or everolimus, or dominant metastatic site. Conclusions Our real life data, in line with the results of reported clinical trials, indicate that palbociclib plus letrozolo or F500 is active and safe in HR+/HER2- MBC, also suggesting a better performance of the combinations in earlier treatment lines. Citation Format: Palumbo R, Torrisi R, Quaquarini E, Sottotetti F, Gambaro A, Collovà E, Ferzi A, Fava S, Agostinetto E, Tagliaferri B, Licata L, Teragni C, Bernardo A. Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive (HR+)/HER2 receptor-negative (HER2-) metastatic breast cancer (MBC): A real life multicenter Italian study [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 P6-18-28.