EGFR related mutational status and association to clinical outcome of third-line cetuximab-irinotecan in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>As supplement to <it>KRAS </it>mutational analysis<it>, BRAF and PIK3CA </it>mutations as well as expression of PTEN may account for additional non-responders to anti-EGFR-MoAbs treatment. The aim of the present study was to investigate the utility as biomarkers of these mutations in a uniform cohort of patients with metastatic colorectal cancer treated with third-line cetuximab/irinotecan.</p> <p>Methods</p> <p>One-hundred-and-seven patients were prospectively included in the study. Mutational analyses of <it>KRAS, BRAF </it>and <it>PIK3CA </it>were performed on DNA from confirmed malignant tissue using commercially available kits. Loss of PTEN and EGFR was assessed by immunohistochemistry.</p> <p>Results</p> <p>DNA was available in 94 patients. The frequency of KRAS, <it>BRAF </it>and <it>PIK3CA </it>mutations were 44%, 3% and 14%, respectively. All were non-responders. EGF receptor status by IHC and loss of PTEN failed to show any clinical importance. <it>KRAS </it>and <it>BRAF </it>were mutually exclusive. Supplementing <it>KRAS </it>analysis with <it>BRAF </it>and <it>PIK3CA </it>indentified additional 11% of non-responders. Patient with any mutation had a high risk of early progression, whereas triple-negative status implied a response rate (RR) of 41% (p < 0.001), a disease control (DC) rate of 73% (p < 001), and a significantly higher PFS of 7.7(5.1-8.6 95%CI) versus 2.3 months (2.1-3.695%CI) (p < 0.000).</p> <p>Conclusion</p> <p>Triple-negative status implied a clear benefit from treatment, and we suggest that patient selection for third-line combination therapy with cetuximab/irinotecan could be based on triple mutational testing.</p

Precision medicine in cancer: Challenges and recommendations from an EU-funded cervical cancer biobanking study

Background:Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality worldwide. CC pathogenesis is triggered when human papillomavirus (HPV) inserts into the genome, resulting in tumour suppressor gene inactivation and oncogene activation. Collecting tumour and blood samples is critical for identifying these genetic alterations.Methods:BIO-RAIDs is the first prospective molecular profiling clinical study to include a substantial biobanking effort that used uniform high-quality standards and control of samples. In this European Union (EU)-funded study, we identified the challenges that were impeding the effective implementation of such a systematic and comprehensive biobanking effort.Results:The challenges included a lack of uniform international legal and ethical standards, complexities in clinical and molecular data management, and difficulties in determining the best technical platforms and data analysis techniques. Some difficulties were encountered by all investigators, while others affected only certain institutions, regions, or countries.Conclusions:The results of the BIO-RAIDs programme highlight the need to facilitate and standardise regulatory procedures, and we feel that there is also a need for international working groups that make recommendations to regulatory bodies, governmental funding agencies, and academic institutions to achieve a proficient biobanking programme throughout EU countries. This represents the first step in precision medicine

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Fertility-sparing surgery in gynecologic cancer: A systematic review

Fertility-sparing surgery (FSS) is increasingly being offered to women with a gynecological malignancy who wish to preserve fertility. In this systematic review, we evaluate the best evidence currently available on oncological and reproductive outcome after FSS for early stage cervical cancer, epithelial ovarian cancer, and endometrial cancer. An extensive literature search was conducted using the electronic databases Medline (OVID), Embase, and Cochrane Library to identify eligible studies published up to December 2020. In total, 153 studies were included with 7544, 3944, and 1229 patients who underwent FSS for cervical, ovarian, and endometrial cancer, respectively. We assessed the different FSS techniques that are available to preserve fertility, i.e., omitting removal of the uterine body and preserving at least one ovary. Overall, recurrence rates after FSS are reassuring and therefore, these conservative procedures seem oncologically safe in the current selection of patients with low-stage and low-grade disease. However, generalized conclusions should be made with caution due to the methodology of available studies, i.e., mostly retrospective cohort studies with a heterogeneous patient population, inducing selection bias. Moreover, about half of patients do not pursue pregnancy despite FSS and the reasons for these decisions have not yet been well studied. International collaboration will facilitate the collection of solid evidence on FSS and the related decision-making process to optimize patient selection and counseling

Human Leukocyte Antigen-DR Expression is Significantly Related to an Increased Disease-Free and Disease-Specific Survival in Patients With Cervical Adenocarcinoma

OBJECTIVES: Human leukocyte antigen (HLA) class II antigens are expressed on antigen-presenting cells, that is, macrophages, dendritic cells, and B lymphocytes. Under the influence of IFN-γ, HLA class II molecules can also be expressed on T lymphocytes, epithelial and endothelial cells. In addition, HLA class II antigens can be expressed in a variety of malignancies; however, the link with prognosis and ultimately patient survival is controversial. METHODS: The pattern of HLA-DRA expression in cervical carcinoma was studied using immunohistochemistry. In total, 124 cervical carcinomas were examined, of which 60 (48.4%) were squamous cell carcinomas and 64 (51.6%) were adenocarcinomas. RESULTS: In squamous cell carcinoma, HLA-DRA was expressed in 41 (68.3%) of 60 tumors, whereas in adenocarcinoma, HLA-DRA was expressed in 60 (93.8%) of 64 tumors (P < 0.001). In adenocarcinoma, HLA-DRA expression was associated with an increased disease-free survival (211.0 ± 13.0 vs 53.3 ± 30.5 months; P = 0.004) and disease-specific survival (226.45 ± 11.5 vs 75.8 ± 27.6 months; P = 0.002). CONCLUSIONS: Upregulation of HLA-DRA is significantly related to an increased disease-free and disease-specific survival in cervical adenocarcinoma. These data warrant further analysis of the functional role of HLA-DRA in these tumors

Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

Tumors avoid destruction by cytotoxic T cells (CTL) and natural killer (NK) cells by downregulation of classical human leukocyte antigens (HLA) and overexpression of non-classical HLA. This is the first study to investigate HLA expression in relation to histology (squamous cell carcinoma (SCC) vs. adenocarcinoma (AC)), clinicopathological parameters and survival in a large cervical cancer patient cohort. Classical (HLA-A and HLA-B/C)- and non-classical HLA molecules (HLA-E and HLA-G) were studied on primary tumors and paired lymph node (LN) metastases from cervical cancer patients (n = 136) by immunohistochemistry. The Chi2 test was used for the comparison of clinicopathological characteristics between SCC and AC patients. The Related-Samples Wilcoxon Signed Rank test was used to compare HLA expression between the primary tumor and metastasis in LN. Patient survival rates were analyzed by Kaplan-Meier curves and Log Rank test. The Mann-Whitney U Test was used to compare the distribution of HLA class I expression between SCC and AC. Decreased expression of HLA-A (SCC P  < 0.001), HLA-B/C (SCC P  < 0.01; AC P  < 0.01) and total classical HLA (SCC P  < 0.001; AC P = 0.02) was apparent in metastatic tumor cells compared to the primary tumor. In primary SCC, there was a clear trend towards complete loss of HLA-A (P = 0.05). SCC metastases showed more complete loss of HLA-A, while AC metastases showed more complete loss of HLA-B/C (P = 0.04). In addition, tumor size and parametrium involvement were also related to aberrant HLA class I expression. No significant associations between HLA expression and disease-specific (DSS) or disease-free survival (DFS) were found in this advanced disease cohort. However, in the SCC group, samples showing loss of HLA-A or loss of total classical HLA but positive for HLA-G were linked to poor patient survival (DSS P = 0.001 and P = 0.01; DFS P = 0.003 and P = 0.01, for HLA-A and total classical HLA, respectively). These results strengthen the idea of tumor immune escape variants leading to metastasis. Moreover, SCC tumors showing downregulation of HLA-A or total classical HLA in combination with HLA-G expression had poor prognosis. Our findings warrant further analysis of HLA expression as a biomarker for patient selection for CTL- and NK- cell based immunotherapeutic interventio

High and Interrelated Rates of PD-L1+CD14+ Antigen-Presenting Cells and Regulatory T Cells Mark the Microenvironment of Metastatic Lymph Nodes from Patients with Cervical Cancer

A better understanding of the microenvironment in relation to lymph node metastasis is essential for the development of effective immunotherapeutic strategies against cervical cancer. In the present study, we investigated the microenvironment of tumor-draining lymph nodes of patients with cervical cancer by comprehensive flow cytometry-based phenotyping and enumeration of immune-cell subsets in tumor-negative (LN(-), n = 20) versus tumor-positive lymph nodes (LN(+), n = 8), and by the study of cytokine release profiles (n = 4 for both LN(-) and LN(+)). We found significantly lower CD4(+) and higher CD8(+) T-cell frequencies in LN(+) samples, accompanied by increased surface levels of activation markers (HLA-DR; ICOS; PD-1; CTLA-4) and the memory marker CD45RO. Furthermore, in LN(+), we found increased rates of a potentially regulatory antigen-presenting cell (APC) subset (CD11c(hi)CD14(+)PD-L1(+)) and of myeloid-derived suppressor cell subsets; the LN(+) APC subset correlated with significantly elevated frequencies of FoxP3(+) regulatory T cells (Treg). After in vitro stimulation with different Toll-like receptor (TLR) ligands (PGN; Poly-IC; R848), we observed higher production levels of IL6, IL10, and TNFα but lower levels of IFNγ in LN(+) samples. We conclude that, despite increased T-cell differentiation and activation, a switch to a profound immune-suppressive microenvironment in LN(+) of patients with cervical cancer will enable immune escape. Our data indicate that the CD14(+)PD-L1(+) APC/Treg axis is a particularly attractive and relevant therapeutic target to specifically tackle microenvironmental immune suppression and thus enhances the efficacy of immunotherapy in patients with metastasized cervical cancer. Cancer Immunol Res; 3(1); 48-58. ©2014 AAC

Additional file 2: Figure S1. of Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

Survival plots of HLA expression in the primary tumor and paired metastatic tumor samples. 5-years disease specific survival (DSS) rates for patients with cervical SCC (A) and AC (B) in relation to HLA-A, HLA-B/C, total classical HLA, HLA-E and HLA-G expression in primary tumor cells and paired metastases. P-value was calculated by Log rank test. (TIF 20952 kb

Additional file 1: Table S1. of Classical and non-classical HLA class I aberrations in primary cervical squamous- and adenocarcinomas and paired lymph node metastases

HLA Expression pattern comparison between primary tumor and metastatic tumor samples. (DOC 56 kb