Prognosis of breast cancer patients is often related with changes in inflammatory status, which involves a multitude of interactions between different cell types and chemical mediators. Omega-3 polyunsaturated fatty acids (PUFAs), mainly represented by eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are able to inhibit different pathways including leukocyte chemotaxis, adhesion molecule expression and interactions, and production of inflammatory cytokines, through the action of specialized proresolving lipid mediators (such as resolvins - Rvs, protectins, and maresins), acting in reducing/resolving the inflammatory process and stimulating the phases of resolution of inflammation. In this light, the resolution of inflammation is nowadays considered as an active process to be pursued in cancer.
We primarly aim to describe the signature of the Resolvins status (circulating levels) in a cohort of patients with breast cancer candidate to breast surgery. In addition, in a subgroup of participants supplemented with oral DHA enriched formula, which we expect to be able to release and modulate Resolvins levels, we aim to evaluate how Resolvins circulating levels may change after this metabolic intervention.
Patients with new diagnosis of primary breast cancer and patients with benign breast disease (control group) will be considered before undergoing planned breast surgery, and plasma levels of RvD1, RvD2, RvD3, RvE1, RvE2 and RvE3 will be assessed by liquid chromatography¿tandem mass spectrometry analytical method at baseline and after 10 days of oral DHA supplementation, comparing the results between patients and controls.
By this study, we expect to obtain more information on possible metabolic and nutritional changes and on the inflammatory status and its prognostic value in the short and long term in a population of patients with breast cancer. This will allow to identify potential novel metabolic intervention to modulate Resolvins status in breast cancer
By this study we expect to obtain more information on possible pre-operative metabolic and nutritional changes and on the inflammatory status and its prognostic value in the short and long term in a population of patients with breast cancer.
Several studies have addressed the therapeutic effects of omega-3 PUFAs in cancer showing that omega-3 PUFAs can improve efficacy and tolerability of chemotherapy [1,2]. There are clinical trials where DHA alone or combinations of omega-3 PUFAs are being tested for cancer prevention, support, or therapy [2,3]. DHA as a treatment strategy is often combined with chemotherapeutic drugs since DHA most likely enhances the cytotoxic effects of these drugs [2].
In the last recent years, the availability of novel technologies applied to metabolomics [4] has developed plasma lipid profiling and the comprehension of the underlying pathophysiologic mechanisms of lipid derangement, together with their role in the development of human chronic conditions. Of particular note is the study of omega-3 and omega-6 PUFAs, notably EPA, DHA, and arachidonic acid, and their transformation into bioactive lipid mediators. In this light, new families of PUFA-derived lipid mediators, including, in particular, resolvins derived from EPA and DHA, are being increasingly investigated because of their active role in the "return to homeostasis" process and resolution of inflammation [5]. Recent evidences indicated that omega-3 EPA and DHA are decreased in most cancer tissues compared to normal ones, and that increments in omega-3 PUFAs consumption and an omega-6/omega-3 ratio of 2-4:1, are associated with a reduced risk of different cancers including breast cancer. This condition is associated with lipid metabolism imbalance and novel data that we will obtain on resolvins status may suggest novel recommendations of consumption and/or supplementation of omega-3 fatty acids. Moreover, resolvins status may inform physicians on their potential role in a prognostic perspective.
Thus, the current approach for profiling specific omega-3 and omega-6-derived bioactive fatty acid metabolomes can provide information of potentially diagnostic and therapeutic value. Currently, assessment of omega-3 fatty acids incorporated in red blood cell membranes is a useful method, along with the omega-3 index that correlates with this membrane compartment and functional outcomes such as in aging humans. Rigorous pro-resolving lipid mediators profiling is needed because human resolution phenotypes have only recently emerged in healthy individuals and those undergoing surgery.
Additionally, the present project may potentially impact on cancer research field unraveling new molecular mechanisms and providing the rationale for strategies based on the modulation of cancer-related inflammation.
An effective treatment is also based on early diagnosis. In this light, this project explores the possibility to use proresolving lipid mediators (resolvins status) as biomarkers of breast cancer, thus allowing to predict clinical outcomes as well as to improve nutritional and metabolic status aimed at ameliorating response to anti-cancer treatment and reducing morbidity and mortality.
Resolution of inflammation is an active process, mainly driven by the synthesis of PUFA-derived proresolving lipid mediators. It is becoming increasingly clear that omega-3 PUFAs are both anti-inflammatory and proresolving nutrients. In fact, EPA and DHA not only act as anti-inflammatory agents, according to the classical view (i.e., by competing for the synthesis of proinflammatory, omega-6-derived mediators) but also actively promote the resolution of inflammation through
the synthesis of the proresolving lipid mediators. Administration of fatty acids affects proresolving lipid mediators levels in plasma, the immune function, and it may be associated with better outcome and reduce health costs in cancer patients.
The possibility to assess circulating proresolving lipid mediators levels before and after omega-3 PUFAs supplementation will possibly allow to assess the efficacy of the treatment and to better clarify the mechanisms through which omega-3 PUFAs and PUFA-derived mediators may confer clinical benefit in breast cancer patients.
In this light, our project is intended to investigate novel aspect of Personalized Medicine, aimed at identifying the traits of uniqueness of specific categories of patients (specifically breast cancer patients) that determine some peculiar abilities in response to medical treatments.
Essential Refs:
1. Bougnoux et al. Br J.Cancer 2009;101:1978¿1985
2. Nabavi et al. Cancer Metast Rev 2015;34:359¿380
3. Berquin et al. Cancer Lett 2008;269:363¿377.
4. Molfino, et al. Oxid Med Cell Longev 2019;2019:1280987
5. Molfino, et al. Oxid Med Cell Longev 2017;2017:5987082