Poor Nottingham Prognostic Index Research Articles

Expression of Lamin A/C in early-stage breast cancer and its prognostic value.

Lamins A/C, a major component of the nuclear lamina, play key roles in maintaining nuclear integrity, regulation of gene expression, cell proliferation and apoptosis. Reduced lamin A/C expression in cancer has been reported to be a sign of poor prognosis. However, its clinical significance in breast cancer remains to be defined. This study aimed to evaluate expression and prognostic significance of lamin A/C in early-stage breast cancer. Using immunohistochemical staining of tissue microarrays, expression of lamin A/C was evaluated in a large well-characterised series of early-stage operable breast cancer (n = 938) obtained from Nottingham Primary Breast Carcinoma Series. Association of lamin A/C expression with clinicopathological parameters and outcome was evaluated. Positive expression rate of lamin A/C in breast cancer was 42.2% (n = 398). Reduced/loss of expression of lamin A/C was significantly associated with high histological grade (p < 0.001), larger tumour size (p = 0.004), poor Nottingham Prognostic Index score (p < 0.001), lymphovascular invasion (p = 0.014) and development of distant metastasis (p = 0.027). Survival analysis showed that reduced/loss of expression of lamin A/C was significantly associated with shorter breast cancer-specific survival (p = 0.008). This study suggests lamin A/C plays a role in breast cancer and loss of its expression is associated with variables of poor prognosis and shorter outcome.

Connexin 43 is an independent predictor of patient outcome in breast cancer patients

PurposeGap junctions are specialized membrane structures that form channels between adjacent cells allowing cell communication. Gap junctions and specifically Connexin 43 (Cx43) are down-regulated in cancer; however, there are contrasting reports on how this effects breast cancer patient survival. This paper is the first large-scale tissue microarray analysis of Cx43 expression in breast cancer patients with an associated clinical long-term follow-up.MethodsUsing a validated TMA of 1118 primary breast cancers, coupled to a comprehensive database of clinicopathological variables, the expression levels and subcellular localisation of Cx43 was assessed by immunohistochemistry. Its impact in terms of survival, distant metastasis-free survival, and clinicopathological variables was determined.ResultsPatients whose tumors expressed high levels of Cx43 had significantly better survival (p < 0.001) than patients with low levels. High Cx43 expression within tumors was associated with an 18-month survival advantage. Loss of Cx43 expression was associated with markers of poor prognosis, namely large tumor size, high grade, high proliferation status, high pleomorphism, high mitosis, poor Nottingham Prognostic Index (NPI), and triple negative tumors. Cx43 expression was independent of tumor size, grade, stage and ER-status in predicting poor survival on multivariate analysis (p = 0.004).ConclusionConnexin 43 (Cx43) is an independent predictor of breast cancer survival and distant metastasis-free survival. High expression of Cx43 was seen in only 13% of tumors, suggesting that drugs to increase Cx43 expression may result in prolonged patients survival.

Low serum 25-hydroxy vitamin D levels are associated with aggressive breast cancer variants and poor prognostic factors in patients with breast carcinoma.

This study was conducted to assess the serum 25-hydroxy (OH) vitamin D levels in patients with breast cancer compared to healthy controls and to identify its association with aggressive breast cancer phenotypes. Serum 25-OH vitamin D levels of 78 breast cancer patients and 78 matched healthy controls were estimated using ELISA. The cases and controls were matched with respect to age, menopausal status, parity, weight, height and co-morbidities. Prognostic factors like grade of tumour, hormone receptor status, HER2 neu status and lymphovascular invasion were compared with 25-OH vitamin D levels. The mean serum 25-OH vitamin D levels of cases were significantly lower compared to the controls (22.33 ± 8.19 vs. 37.41 ± 12.9 ng/mL; p = 0.0001). Patients with higher grades of tumour, non-luminal types of breast cancer and breast cancers with estrogen receptor negativity had significantly lower serum 25-OH vitamin D levels than their opposing groups. Patients with excellent and good Nottingham's prognostic Index (NPI) had significantly higher serum 25-OH vitamin D levels than the moderate and poor NPI groups. Newly diagnosed breast cancer patients have significantly lower serum 25-OH vitamin D levels than healthy controls. Lower level of serum 25-OH vitamin D correlates with aggressive breast cancer phenotypes.

The multifunctional solute carrier 3A2 (SLC3A2) confers a poor prognosis in the highly proliferative breast cancer subtypes

Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity and patient outcome. This study aimed to evaluate the biological and prognostic value of the membrane solute carrier, SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. SLC3A2 was assessed at the genomic level, using METABRIC data (n = 1980), and at the proteomic level, using immunohistochemistry on tissue microarray (TMA) sections constructed from a large well-characterised primary BC cohort (n = 2500). SLC3A2 expression was correlated with clinicopathological parameters, molecular subtypes and patient outcome. SLC3A2 mRNA and protein expression were strongly correlated with higher tumour grade and poor Nottingham prognostic index (NPI). High expression of SLC3A2 was observed in triple-negative (TN), HER2+ and ER+ high-proliferation subtypes. SLC3A2 mRNA and protein expression were significantly associated with the expression of c-MYC in all BC subtypes (p < 0.001). High expression of SLC3A2 protein was associated with poor patient outcome (p < 0.001), but only in the ER+ high-proliferation (p = 0.01) and TN (p = 0.04) subtypes. In multivariate analysis SLC3A2 protein was an independent risk factor for shorter BC-specific survival (p < 0.001). SLC3A2 appears to play a role in the aggressive BC subtypes driven by MYC and could act as a potential prognostic marker. Functional assessment is necessary to reveal its potential therapeutic value in the different BC subtypes.

Association of Histopathological Markers with Clinico- Pathological Factors in Mexican Women with Breast Cancer.

Breast cancer (BCa) is the most common malignancy in Mexican women. A set of histopathological markers has been established to guide BCa diagnosis, prognosis and treatment. Nevertheless, in only a few Mexican health services, such as that of the Secretariat of National Defense (SEDENA for its acronym in Spanish), are these markers commonly employed for assessing BCa. The aim of this study was to explore the association of Ki67, TP53, HER2/neu, estrogenic receptors (ERs) and progesterone receptors (PRs) with BCa risk factors. Clinical histories provided background patient information. Immunohistochemical (IHC) analysis was conducted on 48 tissue samples from women diagnosed with BCa and treated with radical mastectomy. The Chi square test or Fisher exact test together with the Pearson and Spearman correlation were applied. On average, patients were 58±10.4 years old. It was most common to find invasive ductal carcinoma (95.8%), histological grade 3 (45.8%), with a poor Nottingham Prognostic Index (NPI; 80.4%). ERs and PRs were associated with smoking and alcohol consumption, metastasis at diagnosis and Ki67 expression (p<0.05). PR+ was also related to urea and ER+ (p<0.05). Ki67 was associated with TP53 and elevated triglycerides (p<0.05), and HER2/neu with ER+, the number of pregnancies and tumor size (p<0.05). TP53 was also associated with a poor NPI (p <0.05) and CD34 with smoking (p<0.05). The triple negative status (ER-/PR-/HER2/neu-) was related to smoking, alcohol consumption, exposure to biomass, number of pregnancies, metastasis and a poor NPI (p<0.05). Moreover, the luminal B subtype was associated with histological type (p=0.007), tumor size (p=0.03) and high cholesterol (p=0.02). Ki67, TP53, HER2/neu, ER and PR proved to be related to several clinical and pathological factors. Hence, it is crucial to determine this IHC profile in women at risk for BCa. Certain associations require further study to understand physiological/biochemical/molecular processes.

Classification of patients with breast cancer according to Nottingham prognostic index highlights significant differences in immunohistochemical marker expression.

BackgroundPrognosis and treatment of patients with breast carcinoma of no special type (NST) is dependent on a few established parameters, such as tumor size, histological grade, lymph node stage, expression of estrogen receptor, progesterone receptor, and HER-2/neu, and proliferation index. The original Nottingham Prognostic Index (NPI) employs a three-tiered classification system that stratifies patients with breast cancer into good, moderate, and poor prognostic groups. The aim of our study was to use robust immunohistochemical methodology for determination of ER, PR, HER-2/neu, Ki-67, p53, and Bcl-2, and to observe differences in the expression of these markers when patients are stratified according to the original, three-tiered Nottingham Prognostic Index.MethodsParaffin blocks from 120 patients diagnosed with breast carcinoma, NST, were retrieved from our archive. Cases included in the study were female patients previously treated with modified radical mastectomy and axillary dissection.ResultsOur study demonstrates that expression of markers of good prognosis, such as ER, PR, and Bcl-2, is seen with higher frequency in good and moderate NPI groups. In contrast, overexpression of HER-2/neu, a marker of adverse prognosis, is more frequent in moderate and poor NPI groups. High proliferation index, as measured by Ki-67, is seen in moderate and poor NPI groups, whereas low proliferation index is seen in good NPI groups.ConclusionsThese data confirm that the original, three-tiered NPI statistically correlates with the expression of prognostic immunohistochemical markers in breast carcinoma NST.

Abstract P2-11-14: Does the Nottingham prognostic index further refine survival within the breast cancer subtypes?

Abstract Background The Nottingham Prognostic Index (NPI), based on tumor size, lymph node status, and histologic grade, is a well established method of predicting survival of operable breast cancer. Breast cancer survival of the luminal, triple negative, and HER2 overexpressing subtypes has been previously described. The purpose of this study is to determine if the NPI can further refine survival of these subtypes within the AJCC stages of breast cancer. Method We identified 118,923 cases of stages 1-3 first primary female invasive breast cancer from the California Cancer Registry diagnosed between January 1, 2000 and December 31, 2010 with known ER/PR/HER2 status. The subtypes were classified as Luminal A (ER and/or PR-positive, HER2-negative), Luminal B (ER and/or PR-positive, HER2-positive), triple negative (ER-/PR-/HER2-), or HER2-overexpressing (ER-/PR-/HER2+). The NPI was computed and cases were stratified as having good (NPI &amp;lt;3.4), moderate (3.4-5.4) or poor (&amp;gt;5.4) prognosis. Kaplan Meier survival analysis (95% CIs) was used to compare survival among the NPI categories within each subtype and stage. Results The table shows that in stage 1, there was a statistically significant difference in survival between the good versus the moderate and poor NPI categories for luminal A, luminal B, and the triple negative subtypes. For the HER2-overexpressing subtype, the only difference was between the good and poor NPI category. For stage 2, the only difference in survival was for Luminal A where both the moderate (94.6%; 93.4%, 95.8%) and poor (84.3%; 83.6%, 85.0%) NPI categories had worse survival than the good category (99.9%; 97.1%, 100.0%). For stage 3, there were no differences among the NPI categories for any of the subtypes. Eight year survival of stage 1 breast cancer subtypes within the NPI categories 8-Year Survival95% LCL*95% UCL*Luminal A Good95.695.196.2Moderate94.493.994.9Poor90.389.191.5Luminal B Good95.894.097.5Moderate94.393.195.5Poor88.686.291.0Triple Negative Good93.690.197.0Moderate88.186.090.1Poor86.084.287.8HER2-overexpressing Good92.387.697.1Moderate89.786.992.4Poor86.483.389.5*CL = Confidence Limit For stage 2, the only difference in survival was for Luminal A where both the moderate (94.6%; 93.4%, 95.8%) and poor (84.3%; 83.6%,85.0%) NPI categories had worse survival than the good category (99.9%; 97.1%, 100.0%). For stage 3, there were no differences among the NPI categories for any of the subtypes. Conclusion The NPI is a valuable addition to AJCC stage 1 for all breast cancer subtypes. The NPI and AJCC staging systems both incorporate lymph node status and tumor size. However, histologic grade, found only in the NPI, may improve the accuracy of survival, especially in stage 1. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-14.

Abstract P5-12-08: Survival differences by stage and race/ethnicity using the Nottingham prognostic index

Abstract Background It is well documented that race/ethic disparities in breast cancer survival exist. The Nottingham Prognostic Index (NPI), based on tumor size, lymph node status, and histologic grade, is a well established method of predicting survival of operable breast cancer. The purpose of this investigation is to determine if race/ethnic disparities also exist among the NPI categories. Method We identified 157, 865 cases of stages 1-3 first primary female invasive breast cancer from the California Cancer Registry diagnosed between January 1, 2000 and December 31, 2010. The NPI was computed and cases were stratified as having good (NPI &amp;lt;3.4), moderate (3.4-5.4) and poor (&amp;gt; 5.4) prognosis. Kaplan Meier Survival analysis (95% CIs) was used to compare survival at eight years for patients who were white, black, Hispanic, or Asian/Pacific Islander (API) within each AJCC stage and NPI category. Results The distribution of cases by stage, race/ethnicity and good, moderate, and poor NPI categories is seen in the table. Distribution of cases by stage, race/ethnicity and NPI categories WhiteBlackHispanicAPITotalStage 1 Good15,8287442,4432,16921,184Moderate28,9841,8025,1954,20040,181Poor9,7701,0152,4351,85515,075Stage 2 Good237234842350Moderate4,0872567315155,589Poor37,1094,00710,8937,18659,195Stage 3 Good803112Moderate56216983Poor9,4511,2793,7021,76416,196Total 157,865 Stage 1: There were no significant differences in survival within the good category. In the moderate category, APIs (95.5; 94.5, 96.6) had better survival than whites (93.6; 93.2, 94.0) whereas blacks (90.1; 87.8; 92.3) had worse survival. In the poor NPI category, APIs (92.6; 90.8, 94.4) also had better survival than whites (88.7; 87.8, 89.6). Stage 2: In the moderate NPI category, blacks (92.8; 89.0, 96.7) had worse survival than whites (94.0; 93.0, 95.1) and in the poor category, blacks (73.8; 71.9, 75.8) and Hispanics (80.7; 79.5, 81.8) both had worse survival than whites (81.8; 81.2, 82.3) while APIs had better survival (84.6; 83.3, 85.8). Stage 3: There were too few patients in the good and moderate NPI categories. In the poor category, blacks (47.8, 43.4, 52.1) had worse survival than whites (60.1; 58.4, 61.8) while APIs (64.2; 60.2, 68.2) had better survival. Conclusion The NPI provides further refinement of the disparities in survival among race/ethnicity. It appears that APIs have better survival than whites in all stages of disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-12-08.

Clinicopathologic Implications of EpCAM and Sox2 Expression in Breast Cancer

BackgroundThe purpose of this study was to investigate the clinicopathologic significance of EpCAM and Sox2 expression in breast cancer and to study their correlation during breast cancer progression. Patients and MethodsEpCAm and Sox2 expression were assessed using immunohistochemistry in ductal carcinoma insitu (DCIS), invasive breast cancer (IBC) and matched lymph node metastasis (LNM), if present. ResultsEpCAM overexpression was found in 63.2% of DCIS, 72.2% of IBC and 74.4% of LNM. In IBC cases, EpCAM overexpression was associated with high grade (P < .001), large tumor size (P = .051), poor Nottingham Prognostic Index (NPI) (P = .006), histological tumor types (P = .044) and the triple negative phenotype (P = .008). LNM frequently reflected the expression phenotype of the matched primary tumors with no significant differences between LNM and their primary tumors (P = .564). Sox2 expression was detected in 47.4%, 33.3% and 54.7% of DCIS, IBC and LNM respectively. In DCIS group, Sox2 expression was significantly associated with comedo type (P = .037), negative ER (P = .012) and PR (P = .037) and the triple negative phenotype (P = .006). In IBC cases, Sox2 expression showed significant associations with high grade (P = .045), nodal spread (P = .037), poor NPI (P = .018) and the triple negative phenotype (P < .001). LNM showed significantly higher Sox2 expression rates than primary tumors (P < .001). Significant positive associations between EpCAM overexpression and Sox2 positivity in DCIS (P = .027), IBC (P = .001) and LNM (P < .001) were found. ConclusionThis study emphasized the potential role of EpCAM and Sox2 in breast carcinogenesis and revealed their involvement during breast cancer progression and LN metastases.

Chromosome 17 polysomy: correlation with histological parameters and HER2NEU gene amplification

AimsHER2NEU gene amplification is present in the majority of invasive breast carcinomas that have HER2 protein overexpression. A subset of breast cancers harbour an increased chromosome 17 (CEP17) copy number...

Expression of e-cadherin, n-cadherin and snail and their correlation with clinicopathological variants: an immunohistochemical study of 132 invasive ductal breast carcinomas in Egypt

OBJECTIVE:To evaluate the expression of the cell adhesion molecules E-cadherin and N-cadherin and the transcription factor Snail in invasive ductal breast carcinomas and to determine their relationships with clinicopathological features.METHODS:Immunohistochemistry was used to examine E-cadherin, N-cadherin, and Snail protein expression in 132 invasive breast carcinomas.RESULTS:The expression of E-cadherin was decreased (negative or weak) in 37.1% of invasive carcinomas, while N-cadherin and Snail overexpression were detected in 51.9% and 40.9% of carcinomas, respectively. Low E-cadherin expression was significantly correlated with poorly differentiated carcinoma (53.1%), positive node status (80.9%), poor Nottingham Prognostic Index (64.7%), and the presence of estrogen and progesterone receptors. Overexpression of N-cadherin and Snail were also significantly correlated with poorly differentiated carcinoma, positive node status, and poor Nottingham Prognostic Index but were correlated with the absence of hormone receptors. Loss of E-cadherin immunoexpression was strongly associated with the presence of membranous N-cadherin (87.8%) and nuclear Snail (69.4%).CONCLUSION:Loss of E-cadherin and overexpression of N-cadherin and Snail in breast carcinomas may play a central role in the development of invasive ductal breast carcinoma. These biomarkers may provide a valuable reference for the study of invasive ductal carcinoma progression and to characterize the biological behavior of the tumor. In the future, increased N-cadherin and decreased E-cadherin expression may be used as indicators of the progression and prognosis of invasive ductal carcinoma.

CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis

C-terminal tensin-like (CTEN) gene is a member of the TENSIN gene family, involved in cell migration and localised at focal adhesion sites. This study was designed to explore the prevalence and clinical significance of CTEN expression in a large and well-characterised series (n = 1,409) invasive breast cancer (BC) cases with long term follow-up (median 11 years), using immuno-histochemistry and tissue microarray. Moderate to strong cytoplasmic immunoreactivity for CTEN was observed in 90% of the studied cases. CTEN expression was significantly associated with poor prognostic variables including larger tumour size (P = 0.044), higher histological grade (P = 0.019), axillary nodal involvement (P = 0.035) and poor Nottingham Prognostic Index (P = 0.016). Significant associations were observed between increased CTEN expression and up-regulation of phosphorylated-Akt (P-Akt), PIK3 and N-cadherin proteins (P\0.001). Kaplan-Meier survival analysis demonstrated that patients with high CTEN expression had significantly shorter Breast Cancer Specific Survival (P = 0.004) and Metastasis-Free Survival (P = 0.041) than those with low-CTEN expression. Multivariate analysis showed that CTEN was not an independent prognostic marker in BC. In conclusion, our results demonstrated the oncogenetic role of increased CTEN expression and its association with poor prognostic parameters. These data could help in prognostic assessment in BC patients.

Differential Expression and Prognostic Implications of the CCN Family Members WISP-1, WISP-2, and WISP-3 in Human Breast Cancer

The CCN family has three Wnt-inducted secreted proteins named WISP-1, WISP-2 and WISP-3. These molecules are known to play a diverse role in cells, but their role in cancer cells remains controversial. In this study, we analyzed the expression of the three WISP molecules at the mRNA and protein levels in a cohort of 122 human breast tumors and 32 normal breast tissues, and we correlated these findings with patients' clinical outcomes. WISP-1 transcripts were found in lower levels in node-positive tumors compared with node-negative tumors (P < .05); were lower in patients with a moderate (P = .01) and poor Nottingham Prognostic Index prognosis (P < .05) compared with good prognostic groups; were of significantly lower level in grade 3 differentiated tumors (P < .05) compared with grade 1; and were of lower levels in patients who developed metastasis and died from breast cancer-related causes (P < .05 in both comparisons). Almost the reverse was found to be true for WISP-2, which had greater levels of expression in node-positive tumors (P = .0043); higher levels in both moderate and poor prognostic groups compared with the good prognostic group (both P < .05); greater level in both grade 2 and 3 when compared with grade 1 (both P < .05); and higher levels in patients who went on to develop metastases (P < .01). WISP-3 transcript levels showed no statistically significant differences between groups. WISPs may play important but contrasting roles in breast cancer. WISP-1 seems to act as a tumor suppressor and WISP-2 as a factor that stimulates aggressiveness; WISP-3 has no definable beneficial or detrimental role.