The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis

Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen–2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95 % CI 0.560–0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95 % CI 0.878–2.297; HR low IS 1.657, 95 % CI 1.131–2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95 % CI 1.375–4.495; HR low IS 2.422, 95 % CI 1.439–4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95 % CI 0.950–2.395; HR low IS 1.848, 95 % CI 1.277–2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population

Can Zoledronic Acid be Beneficial for Promoting Tumor Response in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy?

The antitumor effect of bisphosphonates (BPs) is under increasing scrutiny. Preclinical and clinical evidence has shown that BPs might sensitize breast tumors to chemotherapy. Here, we present a review of current preclinical and clinical evidence for antitumor effects of BPs, and evaluate how BPs might play a role in neoadjuvant treatment of women with breast cancer

A retrospective analysis of surgical site infections after chlorhexidine-alcohol versus iodine-alcohol for pre-operative antisepsis

Background: Surgical site infection (SSI) is the most common hospital-acquired infection in the Netherlands. There is little evidence in regard to differences in the efficacy of pre-operative topical antisepsis with iodine-alcohol as compared with chlorhexidine-alcohol for preventing SSI. Methods: We conducted a retrospective analysis at a single center, involving all patients who underwent breast, colon, or vascular surgery in 2010 and 2011, in which pre-operative disinfection of the skin was done with iodine-alcohol in 2010 and with chlorhexidine-alcohol in 2011. Demographic characteristics, surgical parameters, and rates of SSI were compared in the two groups of patients. Subgroup analyses were done for wound classification, wound type, and type of surgery performed. Associations of patient characteristics with SSI were also investigated. Data were analyzed with χ2 tests, Student t-tests, and logistic regression analysis. Results: No statistically significant difference was found in the rates of SSI in the two study groups, at 6.1% for the patients who underwent antisepsis with iodine-alcohol and 3.8% for those who underwent disinfection with chlorhexidine-alcohol (p=0.20). After multivariable analysis, an odds ratio (OR) of 0.68 (95% confidence interval [CI] 0.30-1.47) in favor of chlorhexidine-alcohol was found. Male gender, acute surgery, absence of antibiotic prophylaxis, and longer hospital length of stay (LOS) were all associated with SSI after pre-operative topical antisepsis. Conclusion: In this single-center study conducted over a course of one year with each of the preparations investigated, no difference in the rate of SSI was found after an instantaneous protocol change from iodine-alcohol to chlorhexidine-alcohol for pre-operative topical antisepsis. © Mary Ann Liebert, Inc

Prognostic significance of hyperammonemia in neuroendocrine neoplasm patients with liver metastases

Neuroendocrine neoplasms (NENs) are rare usually slow-growing tumors, often presenting with extensive liver metastases. Hyperammonemia due to insufficient hepatic clearance has been described in NEN cases, however no systematic evaluation of risk factors and outcomes of NEN-associated hyperammonemia exists so far. This case report and retrospective review of NEN patients developing hyperammonemia from the years 2000-2020 at the Erasmus Medical Center in Rotterdam, the Netherlands, aimed to describe these patients and determine prognostic factors to improve evaluation and treatment. Forty-four NEN patients with documented hyperammonemia were identified. All patients had liver metastases with 30% (n=13) showing signs of portal hypertension. Patients who developed encephalopathy had higher median ammonia levels, but there was no association between the severity of hyperammonemia and liver tumor burden or presence of liver insufficiency. Eighty-four percent (n=37) of patients died during follow-up. The median (IQR) time from diagnosis of hyperammonemia to death was 1.7 months (0.1-22.7). Hyperbilirubinemia, hypoalbuminemia, elevated INR, presence of liver insufficiency, encephalopathy and ascites were associated with worse outcome. Their role as independent risk factors for mortality was confirmed using the Child-Pugh score as a summary factor (p<0.001). No difference was seen concerning overall survival between our hyperammonemia patients and a propensity score matched control stage IV NEN cohort. In conclusion, hyperammonemia comprises a relevant and potentially underdiagnosed complication of NEN liver metastases and is associated with worse outcome. Assessment of signs of encephalopathy, risk factors and the Child-Pugh score could be helpful in selecting patients in whom ammonia levels should be measured

Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01)

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, 201

Improved Circulating Tumor Cell Detection by a Combined EpCAM and MCAM CellSearch Enrichment Approach in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy

Circulating tumor cells (CTC) are detected by the CellSearch System in 20% to 25% of patients with primary breast cancer (pBC). To improve CTC detection, we investigated melanoma cell adhesion molecule (MCAM) as enrichment marker next to epithelial cell adhesion molecule (EpCAM) and tested the clinical relevance of MCAM-positive CTCs in patients with HER2-negative stage II/III pBC starting neoadjuvant chemotherapy (NAC) in the NEOZOTAC trial. Using the CellSearch System, EpCAM-positive and MCAM-positive CTCs were separately enriched from 7.5 mL blood, at baseline and after the first NAC cycle. Circulating endothelial cells (CEC) were measured using flow cytometry. Primary objective was to improve the CTC detection rate to ≥ 40% combining EpCAM/MCAM. Correlations of CTC and CEC counts and pathologic complete response (pCR) were also explored. At baseline, we detected EpCAM-positive and MCAM-positive CTCs in 12 of 68 (18%) and 8 of 68 (12%) patients, respectively. After one cycle, this was 7 of 44 (16%) and 7 of 44 (16%) patients, respectively. The detection rate improved from 18% at baseline and 16% after one cycle with EpCAM to 25% (P = 0.08) and 30% (P = 0.02), respectively, with EpCAM/MCAM. No patients with MCAM-positive CTCs versus 23% of patients without MCAM-positive CTCs at baseline achieved pCR (P = 0.13). EpCAM-positive CTCs and CEC counts were not correlated to pCR. Combined EpCAM/MCAM CellSearch enrichment thus increased the CTC detection rate in stage II/III pBC. We found no associations of CTC and CEC counts with pCR to NAC. The clinical relevance of MCAM-positive CTCs deserves further stud