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Combined Label-Free Quantitative Proteomics and microRNA Expression Analysis of Breast Cancer Unravel Molecular Differences with Clinical Implications
No full textBetter knowledge of the biology of breast cancer has allowed the use of new targeted therapies, leading to improved outcome. High-throughput technologies allow deepening into the molecular architecture of breast cancer, integrating different levels of information, which is important if it helps in making clinical decisions. microRNA (miRNA) and protein expression profiles were obtained from 71 estrogen receptor-positive (ER(+)) and 25 triple-negative breast cancer (TNBC) samples. RNA and proteins obtained from formalin-fixed, paraffin-embedded tumors were analyzed by RT-qPCR and LC/MS-MS, respectively. We applied probabilistic graphical models representing complex biologic systems as networks, confirming that ER(+) and TNBC subtypes are distinct biologic entities. The integration of miRNA and protein expression data unravels molecular processes that can be related to differences in the genesis and clinical evolution of these types of breast cancer. Our results confirm that TNBC has a unique metabolic profile that may be exploited for therapeutic intervention
Prospective Validation of a 21-Gene Expression Assay in Breast Cancer
No full textPrior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker
Twelve serum proteins progressively increase with disease stage in squamous cell cervical cancer patients
No full textObjective This study aimed to reliably identify serum protein profile alterations that may be useful for elucidation of the disease mechanism and/or finding new targets for treatment and intervention.
Materials and Methods A total of 1057 women at 4 different squamous cell cervical cancer stages (noninvasive, invasive International Federation of Gynecology and Obstetrics stages I, II, and III) were included in this cross-sectional study. Forty-seven serum proteins were profiled using multiplex Luminex immunoassays.
Results Serum concentration of serum amyloid A (SAA), C-reactive protein (CRP), soluble tumor necrosis factor receptor I and II (sTNFRI and sTNFRII), soluble interleukin 2 receptor α (sIL2Rα), CXCL1, CXCL9, hepatocyte growth factor, squamous cell carcinoma antigen (SCCA), insulin-like growth factor binding protein 2, CA125, and carcinoembryonic antigen (CEA) were elevated significantly as disease progressed in cervical cancer patients. Serum levels are significantly different at early stage (I) for SAA, CRP, sIL2Rα, sTNFRII, SCCA, and CEA (P values ranged from 0.02 for CEA to 0.0001 for CRP and SCCA) and at late stages (II and III) for all 12 proteins (P values ranged from 8.78E-5 for CA125 to 3.49E-47 for SAA), as compared to the noninvasive stage. The areas under the curves of these proteins for disease state separation also improved with the advancement of the disease. The correlations between serum concentrations of these proteins also show different patterns at different clinical stages. These proteins are involved in multiple mechanisms including inflammation and immunity, angiogenesis, growth promotion, and metastasis.
Conclusions A number of serum proteins are significantly different between patients at different stages of cervical cancer
Association between mammographic features and response to neoadjuvant chemotherapy in locally advanced breast carcinoma
No full textPurpose: Mammography is the cornerstone of breast cancer (BC) evaluation. This report investigates whether breast density (BD) and mammographic features of the tumor can provide information on both BC susceptibility to chemotherapy and other clinicopathologic features of locally advanced BC (LA BC).
Materials and methods: We evaluated mammography films and clinicopathological information of patients with LA BC who received neoadjuvant chemotherapy (NAC) followed by tumor resection at the Instituto Nacional de Enfermedades Neoplásicas (INEN) from 2000 to 2011.
Results: We selected 494 LA BC cases. Most cases were at clinical tumor stage 4 (48.5%), node stage 1 (58.8%) and had high histologic grade (53.3%). BI-RADS 1, 2, 3, and 4 BD were found in 16.9%, 22%, 35.7% and 25.1% of patients, respectively. High BD has been associated with younger age (p < 0.001), obesity (p = 0.017) and no skin infiltration (T3 vs T4) (p = 0.018). An association between dusty microcalcifications and HER2 group, as well as between casting microcalcifications and TN BC group (p = 0.05) was found. NAC included anthracyclines and taxanes in 422 (85.5%) cases. Miller–Payne pathologic responses 4 and 5 (pCR) in the primary lesion and absence of axillary lymph nodes involvement were found in 15.3% of cases and were associated with younger age (p < 0.001) and HG-3 lesions (p < 0.001), but not with mammographic images.
Conclusion: Mammographic features are associated with specific clinicopathological features of pre-NAC BC lesions but do not predict pCR. The implications and biological reasons for these findings require further study
Relationship between tumor-associated immune infiltrate and p16 staining over clinicopathological features in acral lentiginous melanoma
No full textPurpose: This study aims to evaluate the association between composition of tumor-infiltrating lymphocytes (TIL) and expression of p16 in acral lentiginous melanoma (ALM), and their impact on prognosis
Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer
No full textObjectives: Data on chemotherapy regimens in elderly patients with metastatic breast cancer (MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC aged ≥ 65 years. Materials and methods: A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048). Patients received ixabepilone (40 mg/m(2) as a 3-hour intravenous infusion every 3 weeks) plus oral capecitabine (1000 mg/m(2) administered twice each day), or capecitabine alone (1250 mg/m(2) twice each day). Results: In total, 251 randomized patients were aged ≥ 65 years (ixabepilone plus capecitabine, n=116; capecitabine monotherapy, n=135). Efficacy results were consistent in patients aged <65 and ≥ 65 years with respect to the observed improvement in progression-free survival and objective response rate with ixabepilone plus capecitabine compared with capecitabine alone. No significant differences in overall survival between arms were observed for either subgroup. In the ixabepilone plus capecitabine arm, grade 3/4 hematologic adverse events (AEs) were similar in both subgroups except leukopenia and febrile neutropenia, which had a higher incidence in patients aged ≥ 65 years. The majority of grade 3/4 nonhematologic AEs were similar in the two subgroups, including fatigue, peripheral sensory neuropathy, and hand-foot syndrome. Conclusion: The combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC, with a similar safety profile to patients aged < 65 years
Implication of miRNA in the diagnosis and treatment of breast cancer
No full textBreast cancer (BC) comprises a group of different diseases characterized by changes in tissue structure and gene expression. Recent advances in molecular biology have shed new light on the participation of genes and their products in the biology of BC. MicroRNAs (miRNAs) are small noncoding endogenous RNA molecules that appear to modulate the expression of more than a third of human genes, and their implications in cancer have grasped the attention of the scientific community. Recently, several studies have described the association between miRNA expression profiles and pathological and clinical BC features. Moreover, these molecules represent a new type of molecular marker that can identify prognosis and guide the management of BC patients. With the increasing understanding of miRNA networks and their impact in the biology of BC, as well as the development of viable strategies to modulate specific miRNAs, we could improve the treatment of this disease
Phase I and pharmacokinetic study of lonafarnib, SCH 66336, using a 2-week on, 2-week off schedule in patients with advanced solid tumors
No full textPurpose: This phase I study was performed to determine the safety profile, maximum tolerated dose (MTD) and biological activity of lonafarnib (SCH 66336). Single-dose and multi-dose pharmacokinetics were conducted.
Methods: Twenty-one patients with advanced solid tumors were enrolled. Each patient received single-dose administration on day 1, cycle 1 then switched to a twice daily (BID) dosing regimen on days 2-14 of a 28-day cycle; subsequent cycles continued BID dosing on days 1-14. Dose-limiting toxicity (DLT) was assessed during the cycle one; toxicity evaluation was closely monitored throughout the treatment. Radiographic scans were completed to assess tumor response. Blood and urine pharmacokinetics were evaluated on days 1 and 14 in cycle 1. SCH 66336- induced farnesylation inhibition was assessed via conversion of prelamin A to lamin in buccal mucosa.
Results: DLT and most common adverse events were diarrhea, fatigue, nausea and anorexia. No grade 3 or 4 hematological toxicities were observed. Nineteen of 21 patients were evaluable for response; short-term stable disease was observed in 5 patients. SCH 66336 systemic exposure increased with dose; however, drug accumulation was higher than projected. Renal excretion of parent drug was negligible. Farnesyl transferase inhibition was detected at the 200 and 300 mg BID doses.
Conclusion: The MTD and recommended phase II dose is 200 mg BID on days 1-14 of a 28-day dosing regimen. The plasma concentration profile suggests the pharmacokinetics of SCH 66336 is dose and time dependent. Farnesyl transferase target inhibition was observed at doses of lonafarnib recommended for further study