A preoperative nomogram to predict the risk of synchronous distant metastases at diagnosis of primary breast cancer.
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ABSTRACT:
SUBMITTER: Boutros C
PROVIDER: S-EPMC4366891 | biostudies-other | 2015 Mar
REPOSITORIES: biostudies-other
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Project description:BACKGROUND:Breast cancer is a very heterogeneous disease and some patients are cured by the surgical removal of the primary tumour whilst other patients suffer from metastasis and spreading of the disease, despite adjuvant therapy. A number of prognostic and treatment predictive factors have been identified such as tumour size, oestrogen (ER) and progesterone (PgR) receptor status, human epidermal growth factor receptor type 2 (HER2) status, histological grade, Ki67 and age. Lymph node involvement is also assessed during surgery to determine if the tumour has spread which requires dissection of the axilla and adjuvant treatment. The prognostic and treatment predictive factors assessing the nature of the tumour are all routinely based on the status of the primary tumour. RESULTS:We have analysed a unique tumour set of fourteen primary breast cancer tumours with matched synchronous axillary lymph node metastases and a set of nine primary tumours with, later developed, matched distant metastases from different sites in the body. We used a pairwise tumour analysis (from the same individual) since the difference between the same tumour-type in different patients was greater. Glycopeptide capture was used in this study to selectively isolate and quantify N-linked glycopeptides from tumours mixtures and the captured glycopeptides were subjected to label-free quantitative tandem mass spectrometry analysis. Differentially expressed proteins between primary tumours and matched lymph node metastasis and distant metastasis were identified. Two of the top hits, ATPIF1 and tubulin ?-chain were validated by immunohistochemistry to be differentially regulated. CONCLUSIONS:We show that the expression of a large number of glycosylated proteins change between primary tumours and matched lymph node metastases and distant metastases, confirming that cancer cells undergo a molecular transformation during the spread to a secondary site. The proteins are part of important pathways such as cell adhesion, migration pathways and immune response giving insight into molecular changes needed for the tumour to spread. The large difference between primary tumours and lymph node and distant metastases also suggest that treatment should be based on the phenotype of the lymph node and distant metastases.
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Project description:Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
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Project description:The risk of distant recurrence in breast cancer patients is difficult to assess with current clinical and histopathological parameters, and no validated serum biomarkers currently exist. Using a recently developed recombinant antibody microarray platform containing 135 antibodies against 65 mainly immunoregulatory proteins, we screened 240 sera from 64 patients with primary breast cancer. This unique longitudinal sample material was collected from each patient between 0 and 36 mo after the primary operation. The velocity for each serum protein was determined by comparing the samples collected at the primary operation and then 3-6 mo later. A 21-protein signature was identified, using leave-one-out cross-validation together with a backward elimination strategy in a training cohort. This signature was tested and evaluated subsequently in an independent test cohort (prevalidation). The risk of developing distant recurrence after primary operation could be assessed for each patient, using her molecular portraits. The results from this prevalidation study showed that patients could be classified into high- versus low-risk groups for developing metastatic breast cancer with a receiver operating characteristic area under the curve of 0.85. This risk assessment was not dependent on the type of adjuvant therapy received by the patients. Even more importantly, we demonstrated that this protein signature provided an added value compared with conventional clinical parameters. Consequently, we present here a candidate serum biomarker signature able to classify patients with primary breast cancer according to their risk of developing distant recurrence, with an accuracy outperforming current procedures.
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Project description:Synchronous liver metastasis (SLM) remains a major challenge for rectal cancer. Early detection of SLM is a key factor to improve the survival rate of rectal cancer. In this radiomics study, we predicted the SLM based on the radiomics of primary rectal cancer. A total of 328 radiomics features were extracted from the T2WI images of 194 patients. The least absolute shrinkage and selection operator (LASSO) regression was used to reduce the feature dimension and to construct the radiomics signature. after LASSO, principal component analysis (PCA) was used to sort the features of the surplus characteristics, and selected the features of the total contribution of 85%. Then the prediction model was built by linear regression, and the decision curve analysis was used to judge the net benefit of LASSO and PCA. In addition, we used two independent cohorts for training (n?=?135) and validation (n?=?159). We found that the model based on LASSO dimensionality construction had the maximum net benefit (in the training set (AUC [95% confidence interval], 0.857 [0.787-0.912]) and in the validation set (0.834 [0.714-0.918]). The radiomics nomogram combined with clinical risk factors and LASSO features showed a good predictive performance in the training set (0.921 [0.862-0.961]) and validation set (0.912 [0.809-0.97]). Our study indicated that radiomics based on primary rectal cancer could provide a non-invasive way to predict the risk of SLM in clinical practice.
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Project description:The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p > 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p > 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer.
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Project description:It has been debated for decades how cancer cells acquire metastatic capability. It is unclear whether metastases are derived from distinct subpopulations of tumor cells within the primary site with higher metastatic potential, or whether they originate from a random fraction of tumor cells. Here we show, by gene expression profiling, that human primary breast tumors are strikingly similar to the distant metastases of the same patient. Unsupervised hierarchical clustering, multidimensional scaling, and permutation testing, as well as the comparison of significantly expressed genes within a pair, reveal their genetic similarity. Our findings suggest that metastatic capability in breast cancer is an inherent feature and is not based on clonal selection.
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Project description:Whether the expression status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) receptor and Ki-67 show concordance between the primary tumors and the synchronous axillary lymph node (ALN) metastases has been discussed in numerous studies. However, to date, the results of these studies remain controversial. Therefore, the present study aimed to investigate whether the expression of ER, PR, HER-2 and Ki-67 was in concordance between the primary tumors and synchronous ALN metastases in patients with operable breast cancer (BC). A total of 60 tissue samples were collected from patients with primary operable BC diagnosed with primary tumors and synchronous ALN metastases. The expression levels of the four biomarkers, ER, PR, HER-2 and Ki-67, were assessed in primary lesions and synchronous ALN metastases samples using immunohistochemistry. The cut-off values were set to 10% for ER and PR, while the labeling index of Ki-67 was set to 14%. The immunostaining intensity of ER and PR was scored as negative (?), 1+, 2+ and 3+. The criteria for HER-2 testing in BC were implemented according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines. The concordance rates for ER, PR and HER-2 were 96.7 (58/60), 96.7 (58/60) and 90% (54/60), respectively. In addition, the kappa values of consistency in the primary lesions and the synchronous ALN metastases were 0.773 for ER, 0.654 for PR and 0.785 for HER-2. Furthermore, the P-values of ER, PR and Ki-67 numerical variables between the two groups were 0.393, 0.400 and 0.331, respectively, as demonstrated using a non-parametric Wilcoxon signed rank test. The findings of the present study demonstrated a high degree of concordance between the expression of ER, PR, HER-2 and Ki-67 in the primary tumors and that in the synchronous ALN metastases, suggesting that the BC primary tumor biomarkers may be used for the prognosis of synchronous ALN metastases in patients with operable BC.
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Project description:Purpose: Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy.Experimental Design: Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods.Results: Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including TP53, PIK3CA, and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2, and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases.Conclusions: Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. Clin Cancer Res; 23(15); 4402-15. ©2017 AACR.
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Project description:BACKGROUND:Bone is a preferential site for prostate cancer (PCa) metastasis. However, sites of synchronous distant metastases in PCa patients with bone metastases at initial diagnosis and their impacts on prognosis are still unclear, limiting our ability to better stratify and treat the patients. In this study, we examined the sites of synchronous extra-skeletal metastases in de novo PCa patients with bone metastases and their associated prognoses. METHODS:In total, 16,643 de novo PCa patients with bone metastases from the SEER database were included. After stratification of metastatic sites (bone, lung, liver, and brain) and treatment modalities, overall survival (OS) and independent predictors of OS, were analyzed. RESULTS:Lung was the most frequent site of synchronous metastases, followed by liver, while brain metastases were relatively uncommon. Patients with bone-only metastases showed the longest mean survival time (35.87 months, p?<?0.001), followed by patients with bone and lung metastases (30.74 months, p?<?0.001). Patients with bone and liver metastases had the shortest mean survival time (17.39 months, p?<?0.001). Age?>?70 years, unmarried status, high tumor grade, prostate-specific antigen (PSA)?>?50 ng/ml, and Gleason score???8 were associated with poor OS (all p?<?0.01). Asian or Pacific Islander ethnic background was associated with a favorable OS (all p?<?0.01). Chemotherapy improved OS in patients without brain metastases (all p?<?0.05). For patients with bone-only metastases, radical prostatectomy (RP) (HR, 0.339; 95% CI 0.231-0.495; p?<?0.001), brachytherapy (BT) (HR, 0.567; 95% CI 0.388-0.829; p?=?0.003), and chemotherapy (HR, 0.850; 95% CI 0.781-0.924; p?<?0.001) were associated with prolonged OS. CONCLUSIONS:Age, race, tumor grade, PSA, Gleason score, sites of synchronous extra-skeletal metastases, as well as treatment modalities affected OS in newly diagnosed PCa patients with bone metastases. Synchronous liver metastases were associated with poor OS. Chemotherapy improved OS in patients without brain metastases. RP and BT improved OS in patients with bone-only metastases. Further investigation is warranted to validate these findings.
| S-EPMC6884608 | biostudies-literature
Project description:Background and aimsThis study aimed to access possible relationships between breast cancer subtypes and sites of distant metastasis in breast cancer.ResultsA total of 243,896 patients, including 226,451 cases in control groups were identified. Bone metastasis was found in 8848 cases, compared with 1,000 brain metastasis cases, 3434 liver metastasis cases and 4167 lung metastasis cases. Patients with all subtypes were most prone to bone metastases, the incidence of bone metastasis in HR+/HER2+ subtype was up to 5.1 %. Further, HR-/HER2+ subtype patients had a higher probability of brain (OR = 1.978) metastasis compared to HR+/HER2- subtype patients. In addition, liver metastasis was more frequently observed in the HER2 positive subtypes compared with HER2 negative subtypes. Patients with TN primarily presented lung metastasis, but it made no difference in the probability of lung metastases of all subtypes.Materials and methodsUsing the 2010-2013 Surveillance, Epidemiology, and End Results Program(SEER) data, a retrospective, population-based cohort study to investigate tumor subtypes-specific differences in the sites of distant metastasis. Metastatic patterns information was provided for bone, brain, liver and lung. The breast cancer was classified into four subtypes: hormone receptor (HR) +/ human epidermal growth factor receptor 2 (HER2) -, HR+/HER2+, HR-/HER2+ and triple negative (TN).ConclusionsThe pathological subtypes of breast cancer are clearly different in metastatic behavior with regard to the sites of distant metastasis, emphasizing that this knowledge may help to determine the appropriate strategy for follow-up and guide personalized medicine.
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