ACE and CXCL10 as predictive biomarkers in the LEA study

Background: LEA Study (GEICAM/2006-11/GBG51), is a randomized clinical trial comparing bevacizumab in combination with endocrine therapy (ET + B) with endocrine therapy (ET) in postmenopausal women with advanced or metastatic HR-positive/HER2-negative breast cancer (BC) with indication of hormonotherapy as first-line treatment. Patients with secondary hypertension had better progression-free survival (PFS) and overall survival (OS). We have evaluated the role of two hypertension-related biomarkers, Angiotensin-Converting Enzyme (ACE) and Small-Inducible Cytokine B10 (CXCL10) as prognostic and/or predictive biomarkers of benefit to bevacizumab in the first line metastatic disease. Methods: From 380 patients, 266 were included in 33 Spanish sites. Median age was 64 years, 63.5% had measurable disease, 97.4% were metastatic at randomization, 51.5% had visceral disease and 52.6% received previous chemotherapy. PFS was 14.3 months (range 0.8-61.1), OS was 34 months (range 0.8-71.6) and 93 patients had Objective Response (OR). We analyzed 124 plasma samples collected before treatment (52 from ET and 72 from ET + B arms). Circulating levels of ACE and CXCL10 were determined by ELISA. ACE levels of 115ng/ml and 135ng/ml were pre-defined as cutoff values. CXCL10 was explored as a quantitative variable. Results: PFS was 15.1 months (range 1.4-61.1), OS was 31.1 months (range 2.8-61.1) and 40.3% had OR. OR was significantly different between treatment arms (p < 0.001) but not PFS or OS. Median ACE concentration was 130.9ng/ml (range 35.3-315.4). Low ACE (<135ng/ml) had better PFS in the whole population (p = 0.048) and in the ET + B arm (p = 0.041). ACE cutoff of 115 ng/ml was not able to identify any subgroup with better prognosis. Median CXCL10 concentration was 230.3pg/ml (range 15.1-4129.6). A higher expression of CXCL10 was significantly associated with worse OS in the whole population (p < 0.0001) and each treatment arm (p = 0.002 and p = 0.001 in ET and ET + B, respectively). No association with OR were identified neither for ACE nor for CXCL10. Conclusions: ACE levels could be considered a prognostic and a bevacizumab predictive biomarker of PFS. CXCL10 could be prognostic of OS. Confirmatory studies are warranted

Breast cancer risk factors and survival by tumor subtype: pooled analyses from the breast cancer association consortium

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P-adj > 0.30). The strongest associations were between all-cause mortality and BMI >= 30 versus 18.5-25 kg/m(2) [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age >= 30 years versus 0-= 10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.Surgical oncolog

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Microwave-ultrasound hybrid technology assisted extraction of pigments with antioxidant potential from red corn

Current trends in the use of new pigments of natural origin have led to the investigation of novel technologies for obtaining them. The objectives of this study were to evaluate the extraction process by microwave (MAE) and ultrasound (UAE) assisted techniques and a treatment using simultaneously both techniques (hybrid way) (HM-UE) of pigments from corn with different shades of red (highly pigmented corn = RA, moderately pigmented corn = RM and poorly pigmented corn = RB), and to determine the color, content of hydrolyzable polyphenols, condensed tannins, and antioxidant potential by DPPH, ABTS and FRAP tests. Finally, the pigments obtained by HM-UE underwent thermogravimetric analysis (TGA) and were characterized by Fourier transform infrared spectrometry (FTIR) and HPLC-MS. Results indicated that hybrid-assisted extraction (HM-UE) yields higher extraction yields (p < 0.05) compared to the individual techniques, and the hydrolyzable polyphenol content in HM-UE was 15.5 % higher than that of MAE and 77.3 % higher than that of UAE. In addition, the condensed tannin content was 43.6 % and 62.8 % higher than that of UAE and MAE, respectively. On the other hand, the concentration of condensed tannins and hydrolyzable polyphenols of the pigments obtained from RA with HM-UE showed concentrations of 1.49 and 0.33 mg/g of sample. The compounds identified in these pigments were derivatives belonging to the flavonoid family, such as Apigenin arabinoside-glucoside, 7,4′-Dihydroxyflavone, and Apigenin 6,8-di-C-glucoside, to which their high antioxidant potential is attributed. These results allowed to visualize that the hybrid microwave-ultrasound technique is a viable option for obtaining pigments with antioxidant potential from red corn

Lipocalin-2 and calprotectin potential prognosis biomarkers in peripheral arterial disease

Objective: Peripheral arterial disease (PAD) is the most prevalent cardiovascular (CV) condition globally. Despite the high CV risk of PAD patients, no reliable predictors of adverse clinical evolution are yet available. In this regard, previous transcriptomic analyses revealed increased expression of calprotectin (S100A8/A9) and lipocalin-2 (LCN2) in circulating extracellular vesicles (EVs) of patients with PAD. The aim of this study was to determine the prognostic value of LCN2 and calprotectin for CV risk assessment in PAD. Methods: LCN2 and the S100A9 subunit of calprotectin were examined in human femoral plaques by immunohistochemistry and qPCR. LCN2 and calprotectin were determined by ELISA in PAD (CHN cohort, n = 331, Fontaine IIeIV, serum), and PAD diagnosed by population based screening (VIVA trial, n = 413, the majority Fontaine 0eI, plasma). Patients were followed up for a mean of four years, recording the primary outcomes; CV death or amputation in the CHN cohort and CV death or major lower limb events (MALE) in the VIVA population. Secondary outcomes were all cause death or amputation, and all cause death or MALE, respectively. Results: LCN2 and S100A9 were detected in human plaques in regions rich in inflammatory cells. LCN2 and calprotectin levels were 70% and 64% lower in plasma than in serum. In the CHN cohort, high serum levels of LCN2 and calprotectin increased the risk of primary and secondary outcomes 5.6 fold (p < .001) and 1.8 fold (p = .034), respectively, after covariable adjustment. Similarly, elevated plasma levels of LCN2 and calprotectin increased by three fold the risk of primary and secondary outcomes (p <.001) in the VIVA cohort. Moreover, addition of the combined variable to basal models, considering clinically relevant risk factors, improved reclassification for the primary outcome in both cohorts (p <= .024). Conclusion: Combined assessment of the inflammatory biomarkers LCN2 and calprotectin might be useful for risk stratification in advanced and early PAD