Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency. METHODS: Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature. RESULTS: Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models. CONCLUSIONS: Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients.

Inhibition of Mitochondrial Redox Signaling with MitoQ Prevents Metastasis of Human Pancreatic Cancer in Mice.

At diagnosis, about 35% of pancreatic cancers are at the locally invasive yet premetastatic stage. Surgical resection is not a treatment option, leaving patients with a largely incurable disease that often evolves to the polymetastatic stage despite chemotherapeutic interventions. In this preclinical study, we hypothesized that pancreatic cancer metastasis can be prevented by inhibiting mitochondrial redox signaling with MitoQ, a mitochondria-targeted antioxidant. Using four different cancer cell lines, we report that, at clinically relevant concentrations (100-500 nM), MitoQ selectively repressed mesenchymal pancreatic cancer cell respiration, which involved the inhibition of the expression of PGC-1α, NRF1 and a reduced expression of electron-transfer-chain complexes I to III. MitoQ consequently decreased the mitochondrial membrane potential and mitochondrial superoxide production by these cells. Phenotypically, MitoQ further inhibited pancreatic cancer cell migration, invasion, clonogenicity and the expression of stem cell markers. It reduced by ~50% the metastatic homing of human MIA PaCa-2 cells in the lungs of mice. We further show that combination treatments with chemotherapy are conceivable. Collectively, this study indicates that the inhibition of mitochondrial redox signaling is a possible therapeutic option to inhibit the metastatic progression of pancreatic cancer.

Predictive Biomarkers of Response to Neoadjuvant Chemotherapy in Breast Cancer: Current and Future Perspectives for Precision Medicine.

Pathological complete response (pCR) after neoadjuvant chemotherapy in patients with early breast cancer is correlated with better survival. Meanwhile, an expanding arsenal of post-neoadjuvant treatment strategies have proven beneficial in the absence of pCR, leading to an increased use of neoadjuvant systemic therapy in patients with early breast cancer and the search for predictive biomarkers of response. The better prediction of response to neoadjuvant chemotherapy could enable the escalation or de-escalation of neoadjuvant treatment strategies, with the ultimate goal of improving the clinical management of early breast cancer. Clinico-pathological prognostic factors are currently used to estimate the potential benefit of neoadjuvant systemic treatment but are not accurate enough to allow for personalized response prediction. Other factors have recently been proposed but are not yet implementable in daily clinical practice or remain of limited utility due to the intertumoral heterogeneity of breast cancer. In this review, we describe the current knowledge about predictive factors for response to neoadjuvant chemotherapy in breast cancer patients and highlight the future perspectives that could lead to the better prediction of response, focusing on the current biomarkers used for clinical decision making and the different gene signatures that have recently been proposed for patient stratification and the prediction of response to therapies. We also discuss the intratumoral phenotypic heterogeneity in breast cancers as well as the emerging techniques and relevant pre-clinical models that could integrate this biological factor currently limiting the reliable prediction of response to neoadjuvant systemic therapy.

MitoQ Prevents Human Breast Cancer Recurrence and Lung Metastasis in Mice.

In oncology, the occurrence of distant metastases often marks the transition from curative to palliative care. Such outcome is highly predictable for breast cancer patients, even if tumors are detected early, and there is no specific treatment to prevent metastasis. Previous observations indicated that cancer cell mitochondria are bioenergetic sensors of the tumor microenvironment that produce superoxide to promote evasion. Here, we tested whether mitochondria-targeted antioxidant MitoQ is capable to prevent metastasis in the MDA-MB-231 model of triple-negative human breast cancer in mice and in the MMTV-PyMT model of spontaneously metastatic mouse breast cancer. At clinically relevant doses, we report that MitoQ not only prevented metastatic take and dissemination, but also local recurrence after surgery. We further provide in vitro evidence that MitoQ does not interfere with conventional chemotherapies used to treat breast cancer patients. Since MitoQ already successfully passed Phase I safety clinical trials, our preclinical data collectively provide a strong incentive to test this drug for the prevention of cancer dissemination and relapse in clinical trials with breast cancer patients.

Tumor apelin and obesity are associated with reduced neoadjuvant chemotherapy response in a cohort of breast cancer patients.

Obesity is a known factor increasing the risk of developing breast cancer and reducing disease free survival. In addition to these well-documented effects, recent studies have shown that obesity is also affecting response to chemotherapy. Among the multiple dysregulations associated with obesity, increased level of the apelin adipokine has been recently shown to be directly involved in the association between obesity and increased breast cancer progression. In this study, we analyzed in a retrospective cohort of 62 breast cancer patients the impact of obesity and tumoral apelin expression on response to neoadjuvant chemotherapy. In the multivariate logistic regression, obesity and high tumoral apelin expression were associated with a reduced response to NAC in our cohort. However, obesity and high tumoral apelin expression were not correlated, suggesting that those two parameters could be independently associated with reduced NAC response. These findings should be confirmed in independent cohorts.

Epithelioid angiosarcoma arising after an endovascular aneurysm repair: case report and review of the literature.

Objectives: We report the case of a 68-year-old male who was hospitalized for suspicion of endoleak and thrombosis of an aortic endoprosthesis, arising after multiple endovascular interventions during the last few months. During the intervention, amass was discovered, and biopsies were made. The anatomopathology results were in favor of an epithelioid angiosarcoma with atypical expression of CD31 and ERG- and no amplification of c-MYC. The main objective of this review is to highlight the difficulty of differential diagnosis, but also to evaluate overall survival according to treatments.Methods: We performed a large review of the literature using PubMed for reports concerning angiosarcoma arising from Dacron grafts from 1981 to 2019. Articles presenting potentially relevant studies were read and analyzed.Results: In our review, most of the patients were male (10 cases over 11 described), with amedian age of 63 years old (50-84 years old, 11 cases described). The overall interval time for the diagnosis after the endoprosthesis placement was 7.8 years (from 3.5 years to 17 years, 10 cases with the description) and the overall survival was 5 months (from 0 to 10 months, the only patient alive is not included, and only 8 cases had the description).Conclusion: In most of the reviewed cases, there was no information concerning immunohistochemistry. Biopsies remain the standard for the diagnosis with immunochemistry and molecular test to avoid amisdiagnosis. Epithelioid angiosarcomas derived from Dacron grafts are a rare entity, which are difficult to diagnose because of the paucity of cases. Prognosis is poor, even if surgical option is possible.

When a metastatic breast cancer is mimicking a pancreatic cancer: case report and review of the literature.

We report the case of a 51 year-old female who complained of jaundice and weight loss. At the time of presentation, she had been in remission from a stage 2a ductal breast carcinoma for 58 months. The clinical presentation was suggestive of a primary pancreas cancer with liver metastases and retroperitoneal lymph nodes. We performed liver and pancreas biopsies that demonstrate a relapse of her old breast carcinoma with positive hormone receptors and HER2 positive. Conservative treatment by chemotherapy was given with Paclitaxel - Trastuzumab and Pertuzumab. Pancreatic metastases are uncommon. Furthermore, pancreatic metastases from breast cancer are very rare. We performed a review of the literature and found 48 cases of pancreatic metastases from breast cancer. We would like to highlight by this case that when a pancreatic lesion appears, in patients with a past history of cancer, physicians must not forget the possibility of metastases from primary tumor even if the initial stage, of the tumor, is low. However the diagnosis is not always easy. If liver and pancreatic lesions occur simultaneously, the clinical presentation can mimic metastatic primary pancreatic cancer. Therefore performing biopsy is highly recommended for making the correct diagnosis and also for the staging of the disease and the choice of the best treatment according to immunohistochemical analysis.

Primary infectious costochondritis due to Prevotella nigrescens in an immunocompetent patient: clinical and imaging findings.

Infection of costal cartilage is a rare observation. We report the case of a 43-year-old male patient without relevant history who presented with a progressive painful swelling of the left chest wall since 4 months. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated an abscess within the left ninth costal cartilage with surrounding reactive changes. A CT-guided biopsy was performed and the culture of the sample revealed the presence of Prevotella nigrescens. Musculoskeletal infections by Prevotella are rarely described in the literature, Prevotella oralis and Prevotella bivia being the most frequently observed pathogens. These infections usually originate from a hematogenous spread after thoracic surgery or dental procedure. In our patient, conservative treatment was chosen. A clinical improvement was noted after 1-month antibiotherapy, confirmed by short-term and 6-month imaging follow-up showing the complete disappearance of all previously observed abnormalities.