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Page 14 of 24                       Peyvandi et al. J Cancer Metastasis Treat 2019;5:44  I  http://dx.doi.org/10.20517/2394-4722.2019.16












































               Figure 4. Strategies to improve chemotherapy-induced immunological dormancy. Based on work by others and us, we propose four
               clinically feasible approaches to induce or maintain breast cancer dormancy, primarily in TNBC. Firstly, we propose neo-adjuvant
               chemotherapy (nCTX) to promote chemotherapy-induced immune response. Chemotherapy may be pursued as adjuvant therapy
               (aCTX) if necessary. Secondly, during and following surgery we propose the administration of NSAIDs (in particular Ketorolac) to prevent
               surgery-associated inflammation that may potentially promote relapses. Thirdly, the cytotoxic immune response could be stimulated by
               providing type I IFN, or inducers of an interferon response such as TLR4 ligands, in particularly in low IFN-producing patients. Fourthly,
               addition of checkpoint inhibitors, such as anti-PD1/PDL-1 antibodies, may be applied to maintain the immune response active

               by critical cell survival and proliferation pathways (e.g., PI3K-AKT or MAPK pathways), stem cell pathways
               (e.g., WNT, NOTCH) or cell adhesion molecules (e.g., b1 integrin) would be virtually excluded for such an
               approach given their expected long-term systemic toxicities. We are proposing here selected strategies based
               on limiting the host (unwanted) inflammatory response and stimulating the (wanted) anti-tumoral-immune
               response that may be rapidly tested in clinical-translation studies in breast cancer [Figure 4].


               NSAIDs
               There is growing clinical and experimental evidence that inflammation can trigger cancer relapse, in
               particular in breast cancer, and that NSAIDs treatment can prolong dormancy and delay or reduce
               relapses [246,248,249,252,254,255,257] . The overall positive safety profile of aspirin and other NSAIDs would make them
               realistic candidate drugs for such long-term therapies [258] . Even more interesting, as a short perioperative
               treatment with ketorolac has been shown to significantly decrease the risk of breast cancer relapses
               particularly in obese patients [255] , a short term NSAID treatment at time of surgery may have long-lasting
               effects through suppression of surgery-associated inflammation.


               Neoadjuvant chemotherapy
               A second approach to consider, is to exploit the ability of chemotherapy to elicit an effective immune
                                                                                    +
               response in breast cancer, particularly in lymphocyte-infiltrated TNBC or HER2 tumors [211,212,222,224,226,227,259] .
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