Predictive value of angiogenic proteins in patients with metastatic melanoma treated with bevacizumab monotherapy

The incidence of malignant melanoma is rising worldwide and survival for metastatic disease is still poor. Recently, new treatment options have become available. Still, predictive biomarkers are needed to optimise treatment for this patient group. In this study, we investigated the predictive value of 60 angiogenic factors in patients with metastatic melanoma treated with the anti‐vascular endothelial growth factor A antibody bevacizumab. Thirty‐five patients were included in a clinical phase II trial and baseline serum samples were analysed by multiplex protein array. High‐serum concentration of Activin A was significantly associated with objective response (OR) to treatment (p = 0.014). Candidate proteins that indicated a borderline association with treatment response were further investigated by immunohistochemistry. Strong expression of Activin A, interleukin‐1β, and urokinase‐type plasminogen activator receptor in metastases was significantly associated with OR (p = 0.011, p = 0.003, and p = 0.007, respectively), as well as with markers of activated angiogenesis, such as higher number of proliferating vessels and the presence of glomeruloid microvascular proliferations. Our findings indicate that these proteins may be potential predictive markers for treatment with bevacizumab monotherapy.publishedVersio

A novel age-related gene expression signature associates with proliferation and disease progression in breast cancer

Background and objective Breast cancer (BC) diagnosed at ages <40 years presents with more aggressive tumour phenotypes and poorer clinical outcome compared to older BC patients. Here, we explored transcriptional BC alterations to gain a better understanding of age-related tumour biology, also subtype-stratified. Methods We studied publicly available global BC mRNA expression (n = 3999) and proteomics data (n = 113), exploring differentially expressed genes, enriched gene sets, and gene networks in the young compared to older patients. Results We identified transcriptional patterns reflecting increased proliferation and oncogenic signalling in BC of the young, also in subtype-stratified analyses. Six up-regulated hub genes built a novel age-related score, significantly associated with aggressive clinicopathologic features. A high 6 Gene Proliferation Score (6GPS) demonstrated independent prognostic value when adjusted for traditional clinicopathologic variables and the molecular subtypes. The 6GPS significantly associated also with disease-specific survival within the luminal, lymph node-negative and Oncotype Dx intermediate subset. Conclusions We here demonstrate evidence of higher tumour cell proliferation in young BC patients, also when adjusting for molecular subtypes, and identified a novel age-based six-gene signature pointing to aggressive tumour features, tumour proliferation, and reduced survival—also in patient subsets with expected good prognosis.publishedVersio

CD47 and CD68 expression in breast cancer is associated with tumor-infiltrating lymphocytes, blood vessel invasion, detection mode, and prognosis

CD47 expressed on tumor cells binds to signal regulatory protein alpha on macrophages, initiating inhibition of phagocytosis. We investigated the relationships between tumor expression of CD47 and CD68 macrophage content, subsets of tumor-infiltrating lymphocytes (TILs), and vascular invasion in breast cancer. A population-based series of 282 cases (200 screen detected and 82 interval patients) from the Norwegian Breast Cancer Screening Program was examined. Immunohistochemical staining for CD47 and CD68 was evaluated on tissue microarray (TMA) slides. For CD47 evaluation, a staining index was used. CD68 tumor-associated macrophages were counted and dichotomized. TIL subsets (CD45, CD3, CD4, CD8, and FOXP3) were counted and dichotomized using immunohistochemistry on TMA slides. Vascular invasion (both lymphatic and blood vessel) was determined on whole tissue slides. High CD47 tumor cell expression or high counts of CD68 macrophages were significantly associated with elevated levels of all TIL subsets (p < 0.02), CD163 macrophages (p < 0.001), blood vessel invasion (CD31 positive) (p < 0.01), and high tumor cell Ki67 (p < 0.004). High CD47 expression was associated with ER negativity (p < 0.001), HER2 positive status (p = 0.03), and interval-detected tumors (p = 0.03). Combined high expression of CD47–CD68 was associated with a shorter recurrence-free survival (RFS) by multivariate analysis (hazard ratio [HR]: 2.37, p = 0.018), adjusting for tumor diameter, histologic grade, lymph node status, and molecular subtype. Patients with luminal A tumors showed a shorter RFS for CD47–CD68 high cases by multivariate assessment (HR: 5.73, p = 0.004). This study demonstrates an association of concurrent high CD47 tumor cell expression and high CD68 macrophage counts with various TIL subsets, blood vessel invasion (CD31 positive), other aggressive tumor features, and interval-presenting breast cancer. Our findings suggest a link between CD47, tumor immune response, and blood vessel invasion (CD31 positive). Combined high expression of CD47–CD68 was an independent prognostic factor associated with poor prognosis in all cases, as well as in the luminal A category.publishedVersio

Detection and significance of small and low proliferation breast cancer

Objectives To determine the frequency and discuss possible implications of early breast cancer with particularly good prognosis and defined by tumor diameter and cell proliferation. Setting Detection of small and slowly growing tumors presents a challenge in breast cancer management, due to the risk of over-treatment. Here, we attempted to define a group of such tumors by combining small diameter (≤10 mm, T1ab tumors) with low tumor cell proliferation (≤10% Ki67 expression rate). These tumors were termed small low proliferation cancers (SLPC). Methods Two population-based cohorts were studied: a small research series (n = 534), and a nation-wide registry-based series of prospectively collected routine data (n = 8433). In the latter, we stratified by detection mode; screen-detected, interval, and breast cancers detected outside of screening. Patients were treated according to national guidelines at time of their diagnosis. For both cohorts, we compared tumor histopathology and risk of breast cancer death using a log-rank test for cases with SLPC versus non-SLPC. Results In the research series (median follow-up 151 months), the frequency of SLPC was 10% (54/534), with one breast cancer death compared with 78 among the remaining 480 cases of non-SLPC (p = 0.008). In the registry series (median follow-up 42 months), the frequency of SLPC was 10% (854/8433), with five deaths compared to 187 among the remaining 7579 cases (p = 0.0004). Conclusions SLPC was associated with very low risk of breast cancer death. Prospective randomized trials are needed to clarify whether less aggressive treatment could be a safe option for women with such early breast cancers.acceptedVersio

Fibulin-2 expression associates with vascular invasion and patient survival in breast cancer

Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004–2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1–3) and dichotomized as high expression (grade 2–3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0–2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.publishedVersio