Predict Bone Metastasis Research Articles

Parathyroid hormone-related protein expression, in combination with nodal status, predicts bone metastasis and prognosis of breast cancer patients

Parathyroid hormone-related protein (PTHrP) has been known to play an important role in the formation of meta-static lesions in the bone. However, there remains controversy over its practical role in predicting the occurrence of bone metastasis and the prognosis of breast cancer patients. In this study, we attempted to investigate the clinical value of PTHrP expression status in the primary lesions of breast cancer patients. We immunohistochemically investigated PTHrP expression in surgically resected specimens from 125 primary breast cancer patients whose clinicopathological background and long-term prognosis were available. Positive PTHrP staining was demonstrated in 79 (63.2%) tumors. PTHrP was expressed significantly more frequently in the tumors of premenopausal patients. Bone metastases were significantly more common in patients with T4 tumors, with a positive node, with distant metastasis and with PTHrP-positive tumors. Multivariate logistic analysis revealed positive PTHrP expression as an independent risk factor for predicting bone metastasis. PTHrP expression was significantly related to a shorter overall survival. Bone metastasis was found significantly more frequently (28.3%) in PTHrP- and node-positive cases than in double-negative cases, and the rate was more pronounced in postmenopausal cases (32.1%). Expression of PTHrP in primary lesions, in combination with positive nodal status, is indicative of an increased risk of bone metastasis in breast cancer patients.

Global Gene Expression Analysis of the Interaction between Cancer Cells and Osteoblasts to Predict Bone Metastasis in Breast Cancer

BackgroundBone metastasis is a main cause of morbidity in breast cancer. Since breast cancer is a heterogeneous disease, the interactions of cancer cells with the skeletal host cells might also be diverse. We hypothesized that gene expression signatures induced by heterotypic interaction of breast cancer cells and osteoblasts might be of clinical relevance.Methodology/Principal FindingsWe established an ex vivo co-culture model using benign breast epithelial cells or a panel of 5 malignant breast epithelial cells in combination with primary human osteoblasts and determined associated gene expression changes with HEEBO microarrays. Pretreatment gene expression profiles of 295 early stage breast cancers published from the Netherlands Cancer Institute with a median follow up of 12.6 years allowed evaluating in vitro effects in the in vivo situation.The effects of the interaction between osteoblasts and breast cancer cell lines of different origin were very heterogeneous. Hs578T cells started to proliferate in co-culture with osteoblasts, SKBR-3 induced a TGF-β response and MDA-MB231 cells showed two distinct sets of up-regulated genes: A set of interferon response genes associated with an up-regulation of STAT1 was in vivo remarkably coherent providing a basis for segregation of tumors into two groups. In a uni-variate analysis, early stage tumors with high expression levels (n = 136) of this gene set had a significantly lower overall survival rate (p = 0.005) (63% at 10 years) than tumors with low expression levels (n = 159) (overall survival: 77% at 10 years). The second gene set was associated with IL-6 and did not significantly change the overall survival rate (p = 0.165), but was significantly associated with a shorter time to bone metastasis (p = 0.049; 74% vs. 83% at 10 years).Conclusion/SignificanceAn IL-6 gene expression pattern induced by heterotypic interaction of breast cancer cells with osteoblasts in vitro is associated with a higher rate of bone metastasis in vivo.

P4-16-02: Problems with Identifying Bone Metastasis-Specific Genes without Considering Biological Differences between ER-Positive and ER-Negative Breast Cancers.

Abstract Background: Bone metastasis-specific genes in breast cancer have been reported without considering the significant differences in ER status between bone and non-bone metastases. The aims of this study were to validate genes that had been reported as bone metastasis-specific genes using our data set and to identify bone metastasis-specific genes on the basis of biological differences between ERpositive and ER-negative breast cancers. Patients and Methods: We used Affymetrix GeneChip arrays to analyze tumor samples obtained from 365 primary invasive breast cancer patients who underwent surgery from 1999 to 2008. We excluded patients with HER2−positive breast cancer (normalized HER2 mRNA expression [probe set 216836_s_at] > 12.54). We classified the samples into 3 cohorts according to first metastatic site: bone, non-bone, or no metastasis. Differential expression of genes between bone and non-bone cohorts that were differentially expressed was identified using the Cox proportional hazards model, and gene sets was assessed using gene-set analysis. Results: Of the 365 patients, 34 (9.3%) were included in the bone cohort and 32 (8.8%) in the non-bone cohort. Two hundred fourteen (58.6%) had ER-positive and 151 (41.4%) had ER-negative breast cancer. First, we performed gene-set analysis using 5 gene sets that had been reported to be associated with bone metastasis. One gene set, which had been detected using an ER-negative breast cancer cell line, was validated as predicting bone metastasis in ER-positive breast cancer. None of the 5 gene sets predicted bone metastasis in ER-negative breast cancer. We then determined the levels of individual genes associated with bone metastasis by ER status using all 16,712 probe sets filtered by average gene expression level. When we analyzed all patients without any stratification by ER status, as in previous studies, 592 probe sets were significantly overexpressed in the bone cohort compared with the non-bone cohort, with a false discovery rate of ≤0.05. However, when we analyzed ER-positive and ER-negative breast cancers separately, no genes were found with significant differences between bone and non-bone cohorts. Finally, we used 2,246 functionally annotated gene sets assembled from Gene Ontology to examine possible biological differences between bone and non-bone cohorts. In the bone cohort, 151 and 125 gene sets were significantly overexpressed in ER-positive and ER-negative breast cancers, respectively (P ≤ 0.05). Ppathways related to Cellular growth and proliferation, and intracellular and second-messenger signaling were overexpressed in ER-positive breast cancer, whereas pathways related to nuclear receptor and cytokine signaling were overexpressed in ER-negative breast cancer. Most bone-metastasis-related pathways were different in ER-positive and ER-negative breast cancers (91.4% and 89.6% of the gene sets, respectively). Discussion: No genes were found that can predict bone metastasis. ER-positive and ER-negative breast cancers have different biological potentials for bone metastasis. Therefore, we need to assess the prediction model of bone metastasis based on the biological features for each ER status separately. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-16-02.

P2-01-15: RT-PCR Gene Profiling for the Prediction of Bone Metastases in Primary Breast Cancer.

Abstract Background: Patients with breast cancer frequently develop bone metastases, which are responsible for high morbidity and mortality. It is known that numerous molecules are involved in the bone metastasization process and that only cancer cells with a specific molecular profile are capable of reaching and colonizing bone tissue. The early detection of patients with a high probability of relapsing to bone could be used to select candidates for tailored therapy with bone-specific drugs such as bisphosphonates or RANK-L inhibitors. The aim of the present study was to identify a pattern of tissue markers from primary breast cancer capable of predicting bone metastatization. Material and methods: The expression of different markers was retrospectively analyzed in frozen breast cancer tissue samples from 40 patients comprising 15 cases with no evidence of disease (NEDP), 15 with bone metastases (BMP), and 10 with visceral metastases (VMP). Twelve transcripts were analyzed by Quantitative Real time PCR: trefoil factor 1(TFF1), DKK1, bone sialoprotein (IBSP), heparanase (HPSE), osteopontin (SPP1), Agr2, SPARC, CTGF, COMP, follistatin (FST), osteoprotegerin and RANK. The predictive accuracy of each marker was calculated using receiver operating characteristic (ROC) curves. Results: Analysis of marker expression in the 3 different subgroups showed twofold higher median values of COMP and HPSE in BMP with respect to either NEDP or VMP (no significant difference). Furthermore, TFF1 median value was about sevenfold higher in BMP than in the other 2 subgroups (p=0.05). The area under the curve (AUC) was 0.73 for TFF1 and 0.62 for COMP and HPSE. Considering markers as dichotomous variables, TFF1 expression in BMP reached 67% compared to 21% and 20% in NEDP and VMP, respectively. In dichotomous variable analysis, the most important result was observed for TFF1; in particular, TFF1 positivity was observed in 67% of cases in the BMP subgroup compared to only 21% and 20% in NEDP and VMP, respectively. The combination analysis of TFF1 and other markers showed that positivity to at least one of the three markers, TFF1, DKK1, or IBSP, was observed in 80% of cases for the BMP group, and in only in 21% and 20% of cases in NEDP and VMP subgroups (p=0.041). Another interesting marker was RANK: although sensitivity was fairly low (12%), specificity reached 100% in both control groups. Conclusions: Our preliminary study identified a RT-PCR gene expression pattern in primary breast cancer that could predict patients destined to bone relapse. Such patients could consequently benefit from adjuvant treatment with bone-targeted therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-01-15.

Nestin and collagen triple helix repeat containing 1 in breast cancer progression

We have shown that nestin expression is higher in breast carcinoma with a basal phenotype [1] and collagen triple helix repeat containing 1 (CTHRC1) and periostin may predict bone metastasis of breast cancer [2]. Our aim therefore was to examine the simultaneous role of nestin and CTHRC1 in breast cancer progression.

The Role of CXCR4 in the Prediction of Bone Metastases from Breast Cancer: A Pilot Study

Objective: The chemokine receptor CXCR4 is involved in tumor growth and homing of cancer cells to distant sites. The aim of our retrospective case-control study was to evaluate whether CXCR4 expression is more effective than conventional markers (estrogen receptor and HER-2) in predicting bone relapse in breast cancer. Methods: CXCR4 expression was evaluated by immunohistochemical staining in paraffin-embedded tissue sections of primary breast cancers from 20 patients with bone metastases (BM), 10 with visceral metastases (VM) and 10 with no evidence of disease (NED) at a median follow-up of 10.5 years (range 10.1–11.8). Results: Cytoplasmic CXCR4 expression was high in BM patients (45%, 95% CI 23–67), much lower in NED patients (10%, 95% CI 0–29) and negative in the VM group. CXCR4 coexpression in the nucleus and cytoplasm was observed in about half of the BM patients (45%) but never in NED or VM patients (p = 0.013). Conversely, estrogen receptor-positive and HER-2-negative status identified 80 and 95% of bone relapse patients, respectively, but did not discriminate between cases and controls. Conclusions: Our results suggest a pivotal role of CXCR4 expression as a predictor of BM in primary breast cancer. A larger study is ongoing to confirm these results.

Identification of miRs-143 and -145 that Is Associated with Bone Metastasis of Prostate Cancer and Involved in the Regulation of EMT

The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bone. MicroRNAs (miRNAs) play a crucial role in many tumor metastases. The importance of miRNAs in bone metastasis of PCa has not been elucidated to date. We investigated whether the expression of certain miRNAs was associated with bone metastasis of PCa. We examined the miRNA expression profiles of 6 primary and 7 bone metastatic PCa samples by miRNA microarray analysis. The expression of 5 miRNAs significantly decreased in bone metastasis compared with primary PCa, including miRs-508-5p, -145, -143, -33a and -100. We further examined other samples of 16 primary PCa and 13 bone metastases using real-time PCR analysis. The expressions of miRs-143 and -145 were verified to down-regulate significantly in metastasis samples. By investigating relationship of the levels of miRs-143 and -145 with clinicopathological features of PCa patients, we found down-regulations of miRs-143 and -145 were negatively correlated to bone metastasis, the Gleason score and level of free PSA in primary PCa. Over-expression miR-143 and -145 by retrovirus transfection reduced the ability of migration and invasion in vitro, and tumor development and bone invasion in vivo of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. Their upregulation also increased E-cadherin expression and reduced fibronectin expression of PC-3 cells which revealed a less invasive morphologic phenotype. These findings indicate that miRs-143 and -145 are associated with bone metastasis of PCa and suggest that they may play important roles in the bone metastasis and be involved in the regulation of EMT Both of them may also be clinically used as novel biomarkers in discriminating different stages of human PCa and predicting bone metastasis.

Value of C-telopeptide-cross-linked Type I collagen, osteocalcin, bone-specific alkaline phosphatase and procollagen Type I N-terminal propeptide in the diagnosis and prognosis of bone metastasis in patients with malignant tumors

SummaryBackgroundStudies show markers of bone turnover can help the clinician in the diagnosis and follow-up of bone metastases. The present study aimed to investigate the value of biochemical markers of bone turnover in the diagnosis and prognosis of bone metastases of malignant tumors.Material/MethodsThe serum levels of C-Telopeptide-Cross-Linked Type I Collagen (CTx), Procollagen Type I N-Terminal Propeptide (PINP), Bone-Specific Alkaline Phosphatase (B-ALP) and Osteocalcin (OST) in patients with bone metastases and control subjects were measured using radioimmunoassay and immunochemiluminescent assay.ResultsThe levels of CTx, PINP, B-ALP and OST in the metastasis group were significantly higher than those in both control groups and correlated with the number of bone metastatic sites. The levels of these markers were higher in prostate cancer patients with bone metastasis. The CTX of >426 ng/ml had the highest sensitivity and NPV, and PINP of >51.21 ng/ml had the highest specificity and PPV in healthy subjects. In addition, CTX of >547 ng/ml had the highest sensitivity and OST of >20.34 ng/ml the highest specificity in the non-metastasis group. Furthermore, both B-ALP of >15.55 ng/ml had relatively high negative predictive value and positive predictive value.ConclusionsBiochemical markers of bone turnover, including CTx, PINP, B-ALP and OST, play important roles in the diagnosis and prognosis of metastatic bone cancer. CTX had a high sensitivity, and PINP had a high specificity in predicting bone metastasis. B-ALP is an ideal biochemical marker of bone turnover for metastatic bone cancer.

Accuracy of RANK/OPG and CXCR4 compared to hormone receptors in predicting bone metastases in patients with breast cancer.

e11507 Background: The RANK/RANK-L/OPG system is an important part of the bone metastasization process. CXCL12 is overexpressed in bone and like its receptor, CXCR4, is a determinant of organ tropism. The objective of the present study was to evaluate whether the expression of these markers in primary breast cancer can predict the onset of bone metastases. Methods: Marker expression was evaluated by immunohistochemical staining in paraffin-embedded sections of primary breast cancers from 40 individuals: 10 patients (median age 64 years, range 48-78) were disease-free (DFP) at a median of 9.8 (range 6.9-11.5) years, while 30 (median age 67 years, range 42-87) had relapsed. Within the latter subgroup, 10 (median age 66 years, range 42-87) had visceral metastases (VMP), and 20 (median age 69 years, range 42-87) had bone metastases (BMP). Results: In the overall series, 68% of tumors were ER-positive and 45% were PgR-positive. Moreover, 17.5% of tumors were positive for RANK, 22.5% for OPG and 25% for CXCR4. No significant associations were observed among the different markers. Analyzing the different patient subgroups, it was seen that RANK and OPG were equally expressed in 20% of DFP and in 25% of BMP. CXCR4 was expressed in only 10% of DFP but in 45% of BMP. Moreover, 20% of VMP expressed OPG but none showed RANK or CXCR4 expression. None of the patients expressed RANKL. The highest sensitivity in predicting bone metastasis was observed for ER positivity (80%), which, however, showed low specificity (30%), followed by triple positive RANK, CXCR4 and OPG (75%). Moreover, the highest specificity was observed for CXCR4 (90%) followed by RANK or OPG (80%). Conclusions: Our results indicate that, despite high sensitivity, ER-positive status is burdened by low specificity. Conversely, RANK, OPG, and CXCR4 expression would appear to be a more accurate predictor of bone relapse. The validation of these results is ongoing in a larger series of patients with breast cancer. No significant financial relationships to disclose.

An exploratory determination of new bone markers in natural history of prostate cancer (PC) patients.

e15121 Background: PC is one of the most expanded oncologic diseases worldwide. Currently, PSA is the only biological marker able to follow PC natural history. We investigated serum and urinary bone markers (BM) that may earlier define PC evolution either in hormone naive or not and free-bone metastatic pts or not. Methods: 40 PC pts distributed in 4 groups were studied as follow: A, Non castration-refractory patients (NCRP) without distant mets; B, NCRP with distant mets; C, Castration-refractory patients (CRP) without distant mets; D, CRP with distant mets. Serum BM investigated were osteogenesis-related (Osteocalcin, procollagen amino-terminal propeptide 1 {P1NP}, bone alkaline phosphatase) and osteolysis-related (collagen carboxyterminal peptide {CTX}, carboxyterminaltelopeptide type 1 collagen {1CTP}, tartrate resistant acid phosphatase {TRAP}, osteoprotegerin, receptor/activator of nuclear factor KB ligand {RANKL}). Other markers were albumin, creatinine, parathyroid hormone, total calcium and 25- OH vitamin D3. Urinary BM studied were crosslaps and creatinine. Results: Most significant markers (univariate) were used for logistic/discriminant analysis. The most contributing markers differentiating the following strata were: (1) A vs B vs C vs D : 1CTP, creatinine, P1NP, TRAP and albumine; (2) BD vs AC: P1NP, 1CTP and RANKL (ROC: AUC=0.85); (3) AB vs CD: albumine, 1CTP, P1NP and TRAP (ROC: AUC=0.88); (4) A vs C : serum and urinary creatinine, TRAP, CTX and urinary crosslaps levels (ROC: AUC=0.98). Conclusions: New BM were investigated and P1NP seems to be a relevant marker to follow natural history of PC. P1NP could be useful to predict bone metastasis evolution and a longitudinal study is under investigation. Given the small sample used in this analysis, results should be received with caution. No significant financial relationships to disclose.

Abstract 2241: Role of tissue markers in the prediction of bone metastases from breast cancer

Abstract Introduction: Bone metastasis is a frequent event in patients with breast cancer. OPG (osteoprotegerin) protects bone from excessive resorption by binding to RANK-L (receptor activator of nuclear factor-kB-ligand) and by preventing it from binding to RANK. These molecules are closely involved in the process of metastasization to bone. CXCL12/SDF-1α, the ligand of CXCR4, is overexpressed in bone, and the local chemokine milieu is now emerging as a key determinant in organ selectivity by tumor cells. We carried out a retrospective analysis to evaluate the potential role of these biological markers in predicting bone metastasization in breast cancer patients. Materials and methods: OPG and CXCR4 expression was determined by avidin-biotin immunohistochemistry using a polyclonal (H-249, Santa Cruz) and monoclonal (Ab58176, Abcam) antibody, respectively. Immunohistochemical staining was carried out on sections from paraffin-embedded blocks of 40 primary breast cancers. Ten patients (median age of 64 years, range 48-78) were disease-free (DF) at a median of 9.8 (range 6.9-11.5) years, while 30 (median age 67 years, range 42-87) had relapsed. In the latter group, 10 (median age 66 years, range 42-87) had visceral metastases (VM) and 20 (median age 69 years, range 42-87) had bone metastases (BM). Results: Considering only strong cytoplasmic expression as positive, 22.5% of tumors were positive for OPG and 25% for CXCR4. In particular, OPG was expressed in 20% of tumors in DF patients and in 25% in BM patients. Conversely, CXCR4 was expressed in 10% of tumors in DF patients and in 45% in BM patients. OPG was expressed in only 20% of tumors in VM patients. There was no correlation between OPG and CXCR4 expression, and positivity to at least one of the two markers was observed in 30% of tumors in DF patients, 20% in VM patients and 55% in BM patients. In this last subgroup, there were no statistically significant associations between marker expression and tumor characteristics. Furthermore, no relation was observed between marker expression and disease-free or overall survival in BM patients. Conclusions: Our preliminary results suggest that cytoplasmic CXCR4 expression in primary breast cancers could play a role in predicting bone metastases. Enrolment of breast cancer patients in a larger study is ongoing to confirm these data and to evaluate the predictive role of RANK and RANK-L in bone metastasization. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2241.

The Value of TNM Tumour Staging and Serum Alkaline Phosphatase Levels in Predicting the Presence of Bone Metastases in Patients with Renal Cell Carcinoma

Objectives: To determine if the TNM tumour staging and serum alkaline phosphatase levels (SAP) can be used to identify which patients with renal cell carcinoma (RCC) are at greatest risk of osseous metastases. Patients and methods: A retrospective review of patients with histologically proven RCC was conducted. All patients had initial CT or MRI staging scans of the chest and abdomen. Patients also underwent bone scintigraphy and all abnormal areas were further evaluated with either serial or collaborative imaging to determine their nature. Results: 91 patients including 66 men and 25 women, with a mean age of 61, were included in the study. The incidence of bone metastases was 17.6%. The incidence of bone metastases in T1–4 disease was 4%, 31.3%, 31.8% and 66.7%, respectively. Patients with >T1N0M0 disease, as defined by initial staging scans, accounted for 53% of the cohort and included all instances of proven osseous disease. Thus ‘>T1N0M0’ was 100% sensitive and 57.3% specific as a predictor of bone metastases. Conversely, a raised SAP (>129 U/L) was only 25% sensitive but had a specificity of 94.3%. Conclusions: Patients with >T1N0M0 staging should undergo bone scintigraphy. SAP is a far less sensitive predictor and its concurrent use is unwarranted.

Relevance of Traditional CEA and CA15-3 and Bone Turnover Markers in Predicting Bone Relapse in Breast Cancer Patients.

Abstract Background: Over 50% of breast cancer patients who relapse systemically develop bone metastases. The RANK/RANKL/OPG axis governs osteoclastogenesis and bone reabsorption. In particular, osteoprotegerin (OPG) is a decoy receptor of RANK-L (receptor activator of nuclear factor kappa B ligand) and seems to prevent bone destruction by blocking the binding of RANKL with its receptor. We studied the efficacy of circulating OPG compared to the traditional markers CEA and CA15-3 for the early detection of bone lesions.Methods: The study was carried out on peripheral blood from 72 patients with breast cancer, of whom 33 were disease-free and 39 had bone metastases. The OPG transcript was determined using quantitative PCR analysis, and the traditional markers were quantified by immunoenzymatic assays.Results: The OPG median value was higher in disease-free patients (median = 1.7, 0.4-8.9) than in bone-relapse patients (median = 0.6, 0.1-5.2) (p<0.001). CEA and CA15-3 median values were 1.3 (0.0-8.3) ng/ml and 10.6 (0-45.7) U/ml, respectively, in disease-free patients and 4.8 (0.0-90.6) ng/ml and 69.8 (7-1538) U/ml, respectively, in patients with bone metastases (p< 0.0001 for both markers). Considering 0.9 as cut off of OPG relative expression, our analyses revealed a specificity of 88% with respect to 97% for CEA and 94% for CA15-3. OPG sensitivity was 73% compared to only 49% for CEA and 67% for CA15-3. When OPG was considered in combination with the traditional markers, sensitivity increased from 49% to 83% for CEA and from 67% to 88% for CA15.3.Conclusions: Our results on a preliminary series of breast cancer patients indicate that the bone turnover marker OPG greatly increases CEA and CA15-3 sensitivity in predicting bone metastases. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3027.

Role of PSA as a predictor of bone metastases among the different racial groups with prostate cancer in KwaZulu Natal, South Africa

Journal of Men's HealthVol. 6, No. 3 WCMH AbstractsRole of PSA as a predictor of bone metastases among the different racial groups with prostate cancer in KwaZulu Natal, South Africa22E.H. Abdel Goad and Poovan GovenderE.H. Abdel GoadSearch for more papers by this author and Poovan GovenderSearch for more papers by this authorPublished Online:21 Nov 2013https://doi.org/10.1016/j.jomh.2009.08.024AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Role of PSA as a predictor of bone metastases among the different racial groups with prostate cancer in KwaZulu Natal, South Africa." Journal of Men's Health, 6(3), p. 234FiguresReferencesRelatedDetails Volume 6Issue 3Sep 2009 InformationWPMH GmbHTo cite this article:E.H. Abdel Goad and Poovan Govender.Role of PSA as a predictor of bone metastases among the different racial groups with prostate cancer in KwaZulu Natal, South Africa.Journal of Men's Health.Sep 2009.234-234.http://doi.org/10.1016/j.jomh.2009.08.024Published in Volume: 6 Issue 3: November 21, 2013PDF download

Predicting Bone Metastasis in Prostate Cancer Patients: Value of Prostate Specific Antigen

Objective Serum prostate specific antigen (PSA) concentration has been widely applied as a biomarker to diagnose and monitor prostate cancer. Technetium-99m methylene diphosphate (Tc-99m MDP) whole body bone scintigraphy is currently a well-accepted diagnostic procedure for bone metastasis in malignancy. The aim of this study was to establish a useful serum PSA cut-off value to predict the presence of bone metastasis in men with prostate cancer. Materials and Methods Consecutive male patients diagnosed with prostate cancer were retrospectively analyzed. All of the subjects had received both Tc-99m MDP whole body bone scintigraphy and had their serum PSA concentration measured within 1 month. The proper cut-off value was established based on statistical analysis in order to predict the possibility of bone metastasis among prostate cancer patients. Results In total, 101 consecutive male patients (age, 71.92 ± 0.76 years) with prostate cancer were enrolled, and 57 patients (56%) were confirmed by scintigraphic findings to have bone metastases. A serum PSA concentration of 13 ng/mL gave the best sensitivity (96.43%) and specificity (84.09%). The area under the receiver operating characteristics curve revealed excellent discriminatory power (0.93 ± 0.02; p = 0.001). The positive predictive value, negative predictive value and likelihood ratios for positive and negative test were 88.52%, 94.87%, 6.06 and 0.04, respectively. The resulting diagnostic accuracy and odds ratio were 73.87% and 142.76. Conclusion A cut-off value of 13 ng/mL appears to be an appropriate benchmark for stratifying metastatic bone disease in prostate cancer patients such that if a patient with newly diagnosed prostate cancer and without any skeletal symptoms has a serum PSA concentration of less than 13 ng/mL, we suggest that they would not need to undergo bone scintigraphy.

Bone metastasis is strongly associated with estrogen receptor–positive/progesterone receptor–negative breast carcinomas

Bone is one of the most common sites of distant metastasis for breast carcinomas. In this study, our objective is to identify molecular markers and molecular subtypes that may predict patients at higher risk of developing bone metastasis. Immunohistochemical analysis with antibodies against estrogen receptor alpha, progesterone receptor, androgen receptor, Her2/neu, epidermal growth factor receptor, CK5/6, CK14, CK17, CK8, and CK18 was performed on representative sections of 21 breast carcinomas with bone metastasis and 94 cases without bone metastasis. The expression rates of receptors, subtype distributions (basal versus nonbasal) of 3 molecular classifications (cytokeratin, triple negative, and cytokeratin/triple negative), and 5 subtypes of cytokeratin/triple negative classification were compared between these 2 groups. We found that (1) the breast cancers with bone metastasis were associated with a significant percentage of estrogen receptor-positive/progesterone receptor-negative tumors compared with tumors without bone metastasis (38% versus 6%, P < .0001). (2) There was significant difference on estrogen receptor expression between high grade and non-high grade in tumors with or without bone metastasis (P = .0084 and 1.0000, respectively). (3) The breast cancers with bone metastasis were more likely to be estrogen receptor positive (85%) and androgen receptor positive (95%) compared with those without bone metastasis (59% and 74%, respectively, both P < .05). (4) There was no significant difference between tumors with or without bone metastasis in subtype distribution (basal versus nonbasal) among all 3 molecular classifications. (5) Luminal B carcinomas of cytokeratin/triple negative classification tended to be associated with bone metastasis but not to a statistically significant extent. In conclusion, bone metastasis is strongly associated with estrogen receptor-positive/progesterone receptor-negative tumors. Significant difference in estrogen receptor expression between high-grade and non-high-grade tumors with bone metastasis suggests that different panels of molecular markers should be used to predict bone metastasis in these 2 groups of tumors.

Prediction of bone metastases by combination of tartrate‐resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients with prostate cancer

The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated. TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis. Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers. Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.

Histopathologic factors significantly associated with initial organ-specific metastasis by invasive ductal carcinoma of the breast: a prospective study

The purpose of this study was to identify histologic factors significantly associated with initial organ-specific metastasis by 1044 invasive ductal carcinomas (IDCs) of the breast with and without adjuvant therapy, separately, according to nodal status and pathologic TNM stage status. The following histologic factors were prospectively analyzed by multivariate analyses for distant organ metastasis and bone metastasis in patients with IDC who did not receive adjuvant therapy, and for distant organ metastasis, bone metastasis, liver metastasis, and lung metastasis in patients with IDC who received adjuvant therapy: (1) invasive tumor size, (2) histologic grade, (3) tumor necrosis, (4) fibrotic focus (FF), (5) lymphatic invasion, (6) blood vessel invasion, (7) adipose tissue invasion, (8) skin invasion, (9) muscle invasion, (10) age, (11) estrogen (ER)/progesterone (PR) status, and (12) nodal status. The results showed that FF diameter greater than 8 mm and FF fibrosis grade 1 were the factors that most accurately predicted distant organ metastasis and bone metastasis in patients with IDC who did not receive adjuvant therapy. In patients with IDC who received adjuvant therapy, FF diameter greater than 8 mm was the factor that most accurately predicted bone metastasis, and the presence of tumor necrosis and ER-/PR- were very important predictive factors for metastasis to the lung. Ten or more nodal metastases (N3) were the factor that most accurately predicted liver metastasis. Based on these findings, FF characteristics can be concluded to be the most important histologic factors for predicting metastasis to the bone, the presence of tumor necrosis and ER-/PR- for predicting metastasis to the lung, and N3 for predicting metastasis to the liver.

Farnesoid X receptor in primary breast carcinoma: A new marker to predict bone metastasis?

Farnesoid X receptor in primary breast carcinoma: A new marker to predict bone metastasis?

Serum Bone Turnover Markers (PINP and ICTP) for the Early Detection of Bone Metastases in Patients With Prostate Cancer: A Longitudinal Approach

An increase in bone turnover markers in patients with prostate cancer may predict bone metastases but it can also reflect the effects of androgen deprivation treatment. To assess the diagnostic efficacy of early detection of skeletal metastases we retrospectively performed serial measurements of a bone formation marker (PINP) and a bone resorption marker (ICTP) in serum of patients with prostate cancer. Residual serum samples from 64 patients with prostate cancer treated between 1999 and 2004 were selected from our prostate specific antigen serum archive, and divided into 3 groups of patients with no metastases (N0M0), with lymph node metastases only (N1M0) and with skeletal metastases (M1). In the M1 group the T(1) sample was collected near the first positive bone scintigraph. The N1M0 and M1 groups showed increased PINP levels (ANOVA T(0) p = 0.035, T(1) p <0.001). The PINP levels in the M1 group increased further (paired t test p = 0.028), while no increase was found in the other groups. There was no significant difference between the number of patients receiving androgen deprivation therapy in the N1M0 and the M1 groups. Increased PINP levels in the M1 group were detectable 8 months before the first positive bone scintigraph. The increase in ICTP in the M1 group differed significantly from the other groups (the Student t test in 45 patients p = 0.029). The increases in PINP and ICTP differentiated between patients with or without skeletal metastases (AUC 0.71, p = 0.002 and AUC 0.64, p = 0.045, respectively). Followup measurement of serum PINP and ICTP is useful in the early assessment of skeletal metastases in patients with prostate cancer regardless of the confounding role of androgen deprivation treatment. The bone formation marker is the most indicative.