Simple Summary: Insulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD)... Show moreSimple Summary: Insulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD) targets insulin signaling pathway downregulation to hamper tumor growth. Genes encoding for the insulin receptors on the cell's surface contain genetic variation between patients, which can affect insulin receptor function and cellular response. Therefore, a group of 113 patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy with or without a fasting mimicking diet were investigated. We found that two IGF1 receptor variants were associated with worse pathological response compared to the reference alleles, out of the 17 interrogated common variants. Additionally, two IGF1 receptor variants could interact negatively within the FMD group regarding radiological response. These results emphasize that genetic variation harbors predictive clinical relevance to optimize and personalize cancer therapy. 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. Show less
Simple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced.... Show moreSimple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced. The use of high dose systemic corticosteroids around docetaxel infusion appeared to decrease the incidence of HSR and fluid retention and has been applied in daily practice ever since. However, there is little evidence that supports this high dose of dexamethasone. Furthermore, the application of high-dosed corticosteroids can lead to undesirable adverse effects. In this phase 1 study, we aim to evaluate the impact of reducing the dose of dexamethasone as an adjunct to docetaxel on the incidence of HSR and fluid retention in patients with prostate or breast cancer. Background: There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. Patients and methods: Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). Results: Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg-8 mg-4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. Conclusions: It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome. Show less
Hagenaars, S.C.; Groot, S. de; Cohen, D.; Dekker, T.J.A.; Charehbili, A.; Kranenbarg, E.M.K.; ... ; Dutch Breast Can 2021
The tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a... Show moreThe tumor-stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma-low tumors. Since the role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2-negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin-stained sections of pre-treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller-Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi-square, Cochran-Armitage test for trend and regression analyses. A stroma-low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)-negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma-low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34-4.51, P = .004), which attenuated to 1.90 (95% CI 0.85-4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER-negativity (95% CI 1.19-29.48, P = .030) and 1.48 for ER-positivity (95% CI 0.73-3.01, P = .281). In conclusion, a low amount of stroma on pre-treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment. Show less
Charehbili, A.; Groot, S. de; Straaten, T. van der; Swen, J.J.; Pijl, H.; Gelderblom, H.; ... ; Kroep, J.R. 2015
