Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

IntroductionClinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated.MethodsWe used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer.ResultsAdipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases.ConclusionsCollectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1088-6) contains supplementary material, which is available to authorized users.

A combination of immune-checkpoint inhibitors and radiation therapy (RT) represents a promising therapeutic strategy in part mediated by the abscopal effect, but clinical experience related to this combination remains scarce. Clinical data and patterns of treatment were retrospectively collected from all consecutive patients with metastatic melanoma and receiving programmed-death 1 (PD-1) immune-checkpoint inhibitors. Survival data, best overall response, and acute and delayed toxicities (graded according to Common Terminology Criteria for Adverse Events, v 4.3) were compared between patients receiving concurrent RT (IR) or no irradiation (NIR). Fifty-nine patients received anti-PD-1 immunotherapy [pembrolizumab (n=28) or nivolumab (n=31)] between August 2014 and December 2015 at our institution. Among these, 29% (n=17) received palliative RT for a total of 21 sites, with a mean dose of 30 Gy delivered in 10 fractions. Acute and late toxicity profiles were similar in the two groups. After a 10-month median follow-up, the objective response rate (complete or partial response) was significantly higher in the IR group versus the NIR group (64.7 vs. 33.3%, P=0.02) and one complete responder after RT was compatible with an abscopal effect. The 6-month disease-free survival and overall survival rates for the NIR group versus the IR group were 49.7 versus 64.7% (P=0.32) and 58.8 versus 76.4% (P=0.42), respectively. We report here that the combination of RT and anti-PD-1 immunotherapy is well tolerated and leads to a significant higher tumor response rate within and outside the irradiated field, which is emphasized by the first reported case of an abscopal effect in solid tumors.

Local consolidative radiotherapy in the treatment of metastatic malignancies has shown promising results in several types of tumors. The objective of this study was to assess consolidative radiotherapy to the bladder and to residual metastases in metastatic urothelial bladder cancer with no progression following first-line systemic therapy. Materials/methods: Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan–Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. Results: A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1–9) vs. 3 (1–5) (p = 0.04) at metastatic presentation, and 1 (0–5) vs. 2 (0–5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). Conclusion: Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively.

BackgroundAdvanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs.MethodsPatients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1.5 mg/m2, q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan–Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1).ResultsEleven patients treated with trabectedin for advanced SFT were identified. Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %). The best RECIST response was a partial response (PR) in one patient (9.1 %) and stable disease (SD) in eight patients (72.7 %). Disease-control rate (DCR = PR + SD) was 81.8 %. After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS was 22.3 months (95 % CI = 9.1 months; not reached). The median GMI was 1.49 (range: 0.11–4.12).ConclusionTrabectedin is a very promising treatment for advanced SFTs. Further investigations are needed.