Abstract Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m −2 , to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039 ). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90–100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016 ). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449 .
Adjuvant bisphosphonates are associated with improved breast cancer survival in postmenopausal patients. Addition of zoledronic acid (ZA) to neoadjuvant chemotherapy did not improve pathological complete response in the phase III NEOZOTAC trial. Here we report the results of the secondary endpoints, disease-free survival, (DFS) and overall survival (OS). Patients with HER2-negative, stage II/III breast cancer were randomized to receive the standard 6 cycles of neoadjuvant TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy with or without 4 mg intravenous (IV) ZA administered within 24 h of chemotherapy. This was repeated every 21 days for 6 cycles. Cox regression models were used to evaluate the effect of ZA and covariates on DFS and OS. Regression models were used to examine the association between insulin, glucose, insulin growth factor-1 (IGF-1) levels, and IGF-1 receptor (IGF-1R) expression with survival outcomes. Two hundred forty-six women were eligible for inclusion. After a median follow-up of 6.4 years, OS for all patients was significantly worse for those who received ZA (HR 0.468, 95% CI 0.226–0.967, P = 0.040). DFS was not significantly different between the treatment arms (HR 0.656, 95% CI 0.371–1.160, P = 0.147). In a subgroup analysis of postmenopausal women, no significant difference in DFS or OS was found for those who received ZA compared with the control group (HR 0.464, 95% CI 0.176–1.222, P = 0.120; HR 0.539, 95% CI 0.228–1.273, P = 0.159, respectively). The subgroup analysis of premenopausal patients was not significantly different for DFS and OS ((HR 0.798, 95% CI 0.369–1.725, P = 0.565; HR 0.456, 95% CI 0.156–1.336, P = 0.152, respectively). Baseline IGF-1R expression was not significantly associated with DFS or OS. In a predefined additional study, lower serum levels of insulin were associated with improved DFS (HR 1.025, 95% CI 1.005–1.045, P = 0.014). Our results suggest that ZA in combination with neoadjuvant chemotherapy was associated with a worse OS in breast cancer (both pre- and postmenopausal patients). However, in a subgroup analysis of postmenopausal patients, ZA treatment was not associated with DFS or OS. Also, DFS was not significantly different between both groups. IGF-1R expression in tumor tissue before and after neoadjuvant treatment did not predict survival. ClinicalTrials.gov, NCT01099436 , April 2010.
<b><i>Introduction:</i></b> In this paper, we report a case of visual impairment during treatment with sunitinib in a patient with metastatic renal cell carcinoma. <b><i>Methods:</i></b> Retrospective chart review was used. <b><i>Case Presentation:</i></b> We describe a 74-year-old male with metastatic renal cell carcinoma who was treated with sunitinib and experienced severe loss of visual acuity due to serous retinal detachment and intraretinal fluid. Upon discontinuation of sunitinib, the retinal fluid resolved, and visual acuity was restored. <b><i>Conclusion:</i></b> Serous retinal detachment has been described as a side effect of sunitinib use. Discontinuing sunitinib promptly resolved the subretinal fluid collections and restored vision.
11074 Background: Variation in the genes coding for the estrogen receptor (ESR-1), CYP2c19 and UGTB15 is associated with worse outcome in tamoxifen treated early breast cancer patients. It is unclear whether this variation is a predictive marker for tamoxifen efficay or if it is a prognostic marker for breast cancer outcome. The aim of this study was to examine if SNP’s in these genes are also associated with survival in early breast cancer patients treated with adjuvant exemestane as to explore a prognostic potential of these markers. Methods: Patients of whom tissue was available were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples. The following 4 SNPs were genotyped using Taqman assays: rs9340799 and rs2234693 in the ESR-1 gene, rs1902023 in the UGTB15 gene and rs4244285in the CYP2c19 gene. Primary endpoint was relapse-free survival (RFS) and secondary endpoint was overall survival (OS). A Kaplan-Meier analysis was performed and Cox proportional hazards models assessed survival differences. Analyses were adjusted for age at diagnosis, tumor size, nodal status, histological grade, surgery, adjuvant radiotherapy and chemotherapy. Results: 807 patients were included in the analyses and genotypes were obtained in 84%-96% of the samples. No association was found with the primary endpoint of relapse free survival with any of the four SNPS. However, the rs2234693 variant in ESR1 was associated with worse overall survival with an odds ratio of 1,4 (P = 0.016) consistent with a prognostic rather than a predictive drug response effect. Conclusions: Variation in the ESR-1 gene is related to overall survival in early breast cancer patients. Variation in the ESR-1 gene may be used as a prognostic marker of early breast cancer survival regardless of which endocrine treatment is used.
The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N = 807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480-0.989, P = 0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411-0.923, P = 0.019) and multivariate analyses (HR 0.571, 95% CI 0.380-0.856, P = 0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR + breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research.
Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.
Activation of the insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis, tumor progression, and therapy resistance in solid tumors. We examined whether variability in serum levels of IGF-1, IGF-2, and IGF-binding protein 3 (IGF-BP3) can predict event-free survival (EFS) and overall survival (OS) in Ewing sarcoma patients treated with chemotherapy.Serum levels of IGF-1, IGF-2, and IGF-BP3 of 22 patients with localized or metastasized Ewing sarcoma treated with six cycles of vincristine/ifosfamide/doxorubicin/etoposide (VIDE) chemotherapy were recorded. Baseline levels were compared with presixth cycle levels using paired t-tests and were tested for associations with EFS and OS. Continuous variables were dichotomized according to the Contal and O'Quigley procedure. Survival analyses were performed using Cox regression analysis.High baseline IGF-1 and IGF-BP3 serum levels were associated with EFS (hazard ratio [HR] 0.075, 95% confidence interval [CI] 0.009-0.602 and HR 0.090, 95% CI 0.011-0.712, respectively) in univariate and multivariate analyses (HR 0.063, 95% CI 0.007-0.590 and HR 0.057, 95% CI 0.005-0.585, respectively). OS was improved, but this was not statistically significant. IGF-BP3 and IGF-2 serum levels increased during treatment with VIDE chemotherapy (P=0.055 and P=0.023, respectively).High circulating serum levels of IGF-1 and IGF-BP3 and the molar ratio of IGF-1:IGF-BP3 serum levels were associated with improved EFS and a trend for improved OS in Ewing sarcoma patients treated with VIDE chemotherapy. These findings suggest the need for further investigation of the IGF-1 pathway as a biomarker of disease progression in patients with Ewing sarcoma.
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.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).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.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.
The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid.Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis.During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032).Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC.ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.
