Pattern of metastatic spread in triple-negative breast cancer

Purpose The prognosis of women with triple-negative breast cancers (defined as cancers that are estrogen receptor-negative, progesterone receptor-negative and HER2/neu negative) is poor, compared to women with other subtypes of breast cancer. It is proposed that the underlying difference in recurrence rates may be explained in part by different routes of metastatic spread. Experimental design We studied a cohort of 1608 patients diagnosed with breast cancer, diagnosed between January 1987 and December 1997 at Women’s College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor-negative, progesterone receptor-negative and HER2/neu-negative. We compared the incidence rates of metastatic spread to bone and to other (non-bone) organs in women with triple-negative and other forms of breast cancer. Results Of the 1,608 patients, 180 (11.2%) had triple-negative breast cancer. The 1608 women were followed for a median of 9.0 years (range 0.1–19 years). Compared to other patients, those with triple-negative breast cancer had an increased likelihood of distant recurrence over the study period (adjusted hazard ratio (HR) 1.9; 95% CI: 1.5–2.5, P < 0.0001). The relatively poor prognosis was apparent in the five years after diagnosis (HR 2.9; 95% CI: 2.1–3.9; P = 0.0001) but not thereafter (HR 0.5; 95% CI: 0.2–1.1; P = 0.07). In particular, women with triple-negative breast cancer were four times more likely to experience a visceral metastasis within five years of diagnosis than those with other types of cancer (HR 4.0; 95% CI: 2.7–5.9; P < 0.0001). The rates of bone metastases were comparable for triple-negative and for other forms of cancer in this time period (HR 0.8; 95% CI: 0.4–1.6 P = 0.5). Conclusions The excess risk of distant recurrence in triple-negative breast cancers, versus other forms of cancer, is attributable in large part to an excess of visceral metastases in the first five years following diagnosis.     

Pretreatment haemoglobin levels significantly predict the tumour response to primary chemotherapy in human breast cancer

The purpose of this study was to evaluate whether tumour response to primary chemotherapy in human breast cancer is influenced by baseline haemoglobin (Hb) status. A total of 157 patients with T2-4, N0-1 M0 breast cancer were treated with chemotherapy consisting of either the CMF regimen + tamoxifen (the first 76 cases) or the single-agent epirubicin (the subsequent 81) before definitive surgery. In total, 144 patients were fully assessable. Ki67, p53, bcl-2, c-erbB2, steroid hormone receptor, and microvessel density were evaluated immunohistochemically in tumour specimens obtained before chemotherapy and at surgery. Tumour shrinkage >50% occurred in 72.1% of patients. Responding patients had higher baseline Hb levels and red blood cell counts than nonresponders (P<0.01 and <0.003, respectively). The distribution of disease response according to increasing cutoffs of baseline Hb status showed that from 12.5 mg l(-1) onwards, patients with Hb levels above the cutoff obtained a greater response rate than those with lower Hb values. The difference attained the statistical significance at 12.5 (76.1 vs 59.5%, P<0.05) and 13.0 g/dl(-1) (81.0 vs 57.6%, P<0.002) cutoffs, respectively. The predictive role of Hb levels was maintained in multivariate analysis after adjustment for clinical and biological characteristics and treatment regimen. Patients with baseline Hb levels 相似文献   

An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models

Background

Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.

Methods

Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively.

Results

Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells.

Conclusions

Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.     

Behaviour of breast cancer molecular subtypes through tumour progression

Introduction

Breast cancer (BC) becomes more aggressive throughout disease progression. Clinical stage is correlated with patient outcome. We hypothesised that BC molecular subtypes are associated with a poor prognosis in advanced clinical stages. We analysed the distribution and behaviour of molecular subtypes at different BC tumour size and variation of molecular subtype in recurrent lesions.

Patients and methods

We studied 1647 consecutive patients with non-metastatic invasive and microinvasive (Tmi) BC treated from January 1997 to December 2007. Patients were categorised by tumour size and molecular subtype. A chi-square method was used for multiple group comparisons. Kaplan-Meier product limit method was used to calculate overall survival and disease-free survival.

Results

Median follow-up was 7.2 years. For patients with invasive BC the median age was 56 years. Four hundred and fifteen patients recurred and 225 died. Larger tumours were more frequently of triple-negative (TN) subtype than small ones or Tmi lesions. Any molecular subtype change from primary tumour to recurrent lesions is more likely to happen from a good prognosis to a subtype of worse prognosis than the opposite. Larger tumours of luminal A, luminal B and TN, but not HER2 subtype, are more likely to carry aggressive markers and to have worse outcomes than small ones.

Conclusion

We found accumulation of TN subtype, migration to a poor prognosis subtype and increasing aggressiveness of luminal and TN subtypes throughout tumour progression. Tumours belonging to the HER2 subtype behave aggressively regardless of the primary size.     

The relation of flow cytometry to clinical and biologic characteristics in women with node negative primary breast cancer

Flow cytometry (FC) analysis including DNA index (ploidy status) and cell kinetics (%S and %S + G2/M) was done on frozen tissue of the primary lesions of 101 women with node negative (N-) breast cancer who were studied prospectively. Currently, 19% (19/101) of the patients have recurred. No significant relations have been found between recurrence or survival and age, estrogen/progesterone receptor status, tumor size, and tumor type. The DNA index (ploidy) was not related to any clinical variable, time to recurrence, or survival. Aneuploid tumors did, however, have significantly higher %S phase activity. Patients with %S activity less than or equal to the median value were significantly different from those patients with %S above the median. They were older and had a higher frequency of ER/PR positive and well- or moderately differentiated tumors. Patients with %S + G2/M greater than the median value showed shorter time to recurrence (P = .055) and shorter survival (P = .006), whereas %S alone was significantly associated only with survival. Multivariate analysis showed that neither DNA index nor cell kinetics was significantly associated with time to relapse. DNA index was not significantly associated with survival; %S was of borderline significance whereas %S + %G2/M was a significant independent predictor of survival. Although FC data may provide independent information related to survival in N-women, additional research in a larger number of patients is needed to define its precise role in patient management.     

Pattern of metastases in human breast carcinoma in relation to estrogen receptor status

The distribution of metastases at the first recurrence of breast cancer was studied in 57 estrogen receptor (ER) positive and in 23 ER negative patients, who constituted a subset of 460 patients with operable breast cancer. The pattern of metastases with respect to localization of metastases and the dominant site of first recurrence was similar in patients with ER positive and ER negative tumours. The recurrence-free survival (RFS) and the overall survival were associated with the ER status in the 460 patients. ER positive patients had both a significantly longer RFS (p = 0.0024) and survival (p = 0.0001) compared to ER negative patients. Survival after recurrence was prolonged in patients with soft tissue recurrences only, and the proportion of dead patients was highest in receptor negative patients with metastases to bone and viscera. In conclusion, we could not demonstrate that ER positive and negative tumours have a propensity for recurrence at specific sites.     

c-myc over-expression in human primary ovarian tumours: its relevance to tumour progression.

Expression of the c-myc gene was analyzed in 56 human primary ovarian cancer tissues, including 51 common epithelial and 5 non-epithelial tumours to determine molecular events in the carcinogenic process in ovaries. Over-expression of the c-myc gene was found in 37.3% of all ovarian tumour tissues, and in 63.5% of serous adenocarcinoma tissues. Significant over-expression of the c-myc gene at Stage III compared with other stages, and one remarkable case of over-expression in a serous tumour of low malignant potential suggest that c-myc expression is temporarily activated at some stage(s) during tumorigenesis of ovarian cancer, especially of serous tumours.     

Protein profiling of angiogenesis-related growth factors in laryngeal carcinoma: Pattern of protein expression in relation to tumour progression

The expression of angiogenesis-related proteins was determined in laryngeal tumour tissue, associated tumour involved lymph nodes, apparently normal mucosa and control tissue and were related to tumour stage. Both laryngeal tumour tissue and associated metastatic nodes were obtained from seven patients undergoing surgical resection; in four cases apparently normal mucosa was also dissected from the tumour specimen margins. Control uvula mucosa was obtained from five healthy volunteers undergoing uvulopalatopharyngoplasty. The relative expression of 55 angiogenesis-related proteins was determined in tissue lysates using a Proteome Profiler human angiogenesis array kit. The level of 32/55 angiogenesis-related proteins was higher in tumour tissue compared with controls. Furthermore, in these tumour biopsies higher levels of proteins were associated with increasing tumour stage. A similar trend was seen for 29/32 of these proteins in the nodal tissue. In T4 stage tumour tissue samples, 29/55 angiogenensis-related proteins were more highly expressed compared with the adjacent normal mucosa from the same patient, and this decreased to 8 proteins in tumour tissue from the T1 stage patients. In contrast, the expression of 23 angiogenesis-related proteins in metastatic lymph node tissue from T4 stage patients was lower compared with that found in the normal mucosa adjacent to the tumour. In conclusion, this study has identified a number of factors involved in angiogenesis that are likely to contribute to the growth and metastasis of laryngeal tumours. Furthermore, a number of factors were also substantially altered in metastatic deposits compared with the primary tumour mass or adjacent normal tissue. This study requires confirmatory analysis of the selected key factors in a larger cohort of patients.     

Mathematical modelling of tumour response in primary breast cancer.

Although breast cancer is perceived to be relatively chemosensitive, cytotoxic drug therapy only leads to cure in the adjuvant setting. In advanced disease, primary resistance and inadequate cell kill may be important in determining the lack of a durable response to cytotoxics, but for an individual patient''s tumour there is no consistent way of determining the importance of these two factors. An adaptation of Skipper''s log cell kill model of tumour response to chemotherapy was applied to serial tumour measurements of 46 locally advanced primary breast carcinomas undergoing neoadjuvant chemotherapy. Assuming a log-normal distribution of errors in the clinically measured volumes, the model produced, for each tumour separately, in vivo estimates of proportional cell kill, initial resistance and tumour doubling times during therapy. After 4 weeks'' treatment, these data could then be used to predict subsequent tumour volumes with good accuracy. In addition, for the 13 tumours that became operable after the neoadjuvant chemotherapy, there was a significant association between the final volume as predicted by the model and the final pathological volume (P < 0.05). This approach could be usefully employed to determine those tumours that are primarily resistant to the treatment regimen, permitting changes of therapy to more effective drugs at a time when the tumour is clinically responding but destined to progress.     

Family history and breast cancer tumour characteristics in screened women

Women with a family history of breast cancer have an increased risk of the disease. However, since they tend to experience greater surveillance for the disease, their breast cancers may be detected at an earlier stage, thus making it difficult to assess reliably whether tumour characteristics vary by family history. Information on 9,731 Million Women Study participants with screen-detected breast cancer, diagnosed in 1996-2003, and 37,983 matched controls, who also attended routine screening but were not diagnosed with breast cancer, was used to estimate adjusted relative risks (RRs) of screen-detected breast cancer in women with a family history of the disease. Women with a family history of breast cancer had an increased risk of screen-detected breast cancer (RR 1.57; 95% CI:1.47-1.68) compared with those without such a family history. The RRs were 1.58 (1.46-1.71) and 1.55 (1.34-1.80) for invasive and in situ breast cancer; 1.63 (1.49-1.79) and 1.55 (1.32-1.83) for node-negative and node-positive disease; and 1.56 (1.42-1.70), 1.75 (1.39-2.21) and 1.71 (1.28-2.29) for ductal, lobular and tubular cancers. There was no significant difference in the RR of screen-detected breast cancer associated with a family history of the disease according to invasiveness, size, nodal status, malignancy grade or morphological type of the breast cancer.     

Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer

Allele loss on a specific chromosome has implied the existence of a tumor suppressor gene such as the p53 gene and the RB gene. In order to determine which chromosome(s) carries a tumor suppressor gene(s) that contributes to tumor progression in primary breast cancer, we analyzed the loss of heterozygosity for each autosomal chromosome arm by using 39 restriction fragment length polymorphism markers including 25 variable numbers of tandem repeat probes. In 79 primary breast cancers, we found the frequent loss on the long arm of chromosome 13 (21%), the long arm of chromosome 16 (45%), and the short arm of chromosome 17 (56%). Interestingly, breast cancers in which loss of both chromosomes 13q and 17p was detected showed more malignant histopathological features, and a group of the tumors in which chromosome 16q loss was detected presented with frequent lymph node metastasis. Furthermore, the result of the deletion mapping on chromosome 17p implied the existence of a tumor suppressor gene distal to the p53 gene as well as the p53 gene itself for primary breast cancer. These results suggest that at least 4 tumor suppressor genes exist on chromosomes 13q, 16q, and 17p for primary breast cancer.     

Relation of risk of contralateral breast cancer to the interval since the first primary tumour

Background:

There is no consensus on how to separate contralateral breast cancer (CBC) occurring as distant spread of the primary breast cancer (BC) from an independent CBC.

Methods:

We used standardised incidence ratios (SIRs) to analyse the variations in the risk of CBC over time among 6629 women with BC diagnosed between 1954 and 1983. To explore the most appropriate cutoff to separate the two types of CBC, we analysed the deviance between models including different cutoff points as compared with the basal model with no cutoff date. We also performed a prognostic study through a Cox model.

Results:

The SIR was much higher during the first 2 years of follow-up than afterwards. The best cutoff appeared to be 2 years. The risk of early CBC was linked to tumour spread and the risk of late CBC was linked to age and to the size of the tumour. Radiotherapy was not selected by the model either for early or late CBC risk.

Conclusion:

A clearer pattern of CBC risk might appear if studies used a similar cutoff time after the initial BC.     

The role of microRNAs in human breast cancer progression

Over the past decade, microRNAs (miRNAs) have become a new paradigm of gene regulation. miRNAs are involved in a wide array of carcinogenic processes. Indeed, increasing evidence has shown the importance of miRNAs in cancer, suggesting their possible use as diagnostic, predictive and prognostic biomarkers, leading to miRNA-based anti-cancer therapies, either alone or in combination with current targeted therapies, with the goal of improving cancer treatment responses and increasing cure rates. The advantage of using a miRNA approach is based on the ability to concurrently target multiple effectors of pathways involved in cell proliferation, migration and survival. This review sheds new light on miRNA regulation of genes that play critical roles in the process of malignant transformation and tumour metastasis, the dysregulation of miRNA expression in cancer development and the development of miRNA-based diagnostics and therapeutics.     

The process of malignant progression in human breast cancer

Malignant progression in breast cancer represents the processes through which localized, hormone-dependent tumor cells become resistant to endocrine manipulations and metastasize to sites distant from the primary tumor. By selection in ovariectomized athymic nude mice, we have isolated a variant (MIII) of the hormone-dependent, poorly invasive, human breast cancer cell line MCF-7. MIII cells have lost their absolute requirement for estrogen to form proliferating tumors in nude mice. Furthermore, these tumors are significantly more invasive than the parental MCF-7 cell line. MIII cells retain some responsivity to estrogens and antiestrogens, indicating that they have progressed to a hormone-independent but hormone-esponsive phenotype. In an attempt to determine the nature of this process, we have compared the phenotype of MIII cells with that of other MCF-7 variants. These comparisons strongly suggest that the factors contributing to perturbations in antiestrogen sensitivity, hormone-dependent growth, metastatic potential and tumorigenicity are essentially independent of each other and acquired in a random manner. Loss of estrogen receptor expression and overexpression of EGF receptors tend to occur later in the process of malignant progression.     

Expression of ras oncogene p21 protein in relation to regional spread of human breast carcinomas

The oncogenes most frequently detected in human tumors belong to the ras gene family (Ha-ras, Ki-ras, and N-ras). These genes encode a group of closely related 21,000 dalton proteins termed p21. An immunohistochemical study of ras p21 expression was carried out on paraffin sections of 54 human breast carcinomas using monoclonal antibodies to p21. The control group consisted of ten cases of benign fibrocystic disease. The p21 expression was significantly higher in cancer cells than in epithelial cells of control specimens. No correlations, however, were observed between oncogene product expression and tumor size, histologic type, or grade. As a group, tumors with axillary lymph node metastases expressed higher levels of ras p21 than nonmetastasizing tumors. However, because of the significant overlap in individual p21 values, it is unlikely that the immunohistochemical assay for p21 could be used to predict the behavior of mammary carcinomas.     

Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression

The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S (<3 mm from IDC), DCIS-S (<3 mm from DCIS) and breast cancer associated-normal stroma (BC-NS; >10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1. In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1, COL5A2 and MMP13) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1, COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development.     

Accumulation of genetic alterations and progression of primary breast cancer.

In order to detect common regions of deletion, 219 breast tumors were examined for loss of heterozygosity at several loci on chromosomes 3p, 16q, and 17 by restriction fragment length polymorphism analysis. Allelic deletions of loci on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, were analyzed and compared with histopathological and clinical features. Common regions of deletion were detected within chromosomal bands 3p13-14.3, 16q22-23, 17p13 (two separated loci), and 17q21. Concordant losses of alleles on chromosomes 3p, 13q, 16q, 17p, and 17q were observed. A significant association was detected between loss of heterozygosity on chromosomes 17p and 17q and amplification of the erbB2 oncogene (17p, P = 0.000721, by Fisher's exact test; 17q, P less than 0.001, chi 2 = 12.135). Furthermore, tumors showing highly malignant phenotypes had accumulated more genetic changes at the loci studied than those having less malignant phenotypes on the basis of histopathological classification, lymph node metastasis, and tumor size. These results suggested that accumulation of genetic alterations, including loss of function of tumor suppressor genes on chromosomes 3p, 13q, 16q, and 17, and amplification of the erbB2 oncogene, may contribute to tumor development and/or progression in primary breast cancer.     

Early primary breast cancer in the elderly - Pattern of presentation and treatment

Introduction

The incidence of primary breast cancer in elderly patients is increasing. However, little is known about their biological profile and most appropriate clinical management, as most studies have been conducted in the younger population. This study aimed to identify a profile of characteristics in elderly women with operable primary breast cancer and investigate the dynamics influencing the treatment decision-making process.

Methods

A review of 268 consecutive female patients >70 years of age, diagnosed with early operable primary breast cancer (<5 cm) over a 30-month period at the Nottingham Breast Institute, was conducted. Age, co-morbidity, cancer characteristics, treatment offered and undertaken, and reason for patient choice were recorded and analysed.

Results

The median age was 78 (range 70-100) years. In our study, 82% of the patients had one or more co-morbidities, with 34% of them having three or more co-morbidities. The commonest pathological diagnosis (from needle core biopsies) was invasive ductal carcinoma of no special type (76%) with histological grade 2 (64%). Majority of them were oestrogen receptor (ER)-positive (84%) and had a high histochemical (H)-score (83% with H-score >200).Most of the patients (60%) underwent primary surgical management, of which 45.4% received breast-conserving surgery. Among the patients who had breast-conserving surgery, 68% of them received adjuvant radiotherapy. When offered genuine choice in treatment options, most patients chose non-operative treatment. Patients who underwent non-operative treatment were on average seven years older and had significantly more co-morbidities than those who had surgery.

Conclusion

The elderly population evidently have demographic and cancer characteristics distinct from their younger counterparts, with less patients receiving surgical management. Further work is underway to correlate this with their clinical outcomes and to examine the factors behind the treatment decision-making process.