IGF1 and Insulin Receptor Single Nucleotide Variants Associated with Response in HER2-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without a Fasting Mimicking Diet (BOOG 2013-04 DIRECT Trial).

AIM: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. METHODS: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. RESULTS: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). CONCLUSIONS: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD.

Short-Term Fasting Synergizes with Solid Cancer Therapy by Boosting Antitumor Immunity.

Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy.