Nottingham Prognostic Index Group Research Articles

Abstract PO1-14-05: A comparison of chemotherapy recommendations by NPI, Predict, and Oncotype DX testing in UK women with early node positive breast cancer

Abstract Introduction: Gene expression testing is expensive and, unless it changes the chemotherapy (CT) decision, unnecessary. Both Nottingham Prognostic Index (NPI) and Predict Breast Cancer (Predict) are free to use and based on clinico-pathological data. Each gives a guide to the prognosis. Many clinical teams in the UK have used these indices to guide treatment and more recently to help decide who should have access to gene expression testing. NPI scores of ≤2.4 have a cancer-specific ten-year survival of 96%, and >2.4 to ≤3.4, >3.4 to ≤5.4 and >5.4 have survivals of 93%, 78% and 44% respectively. UK oncologists use it as a guide in recommending adjuvant treatment. CT is not recommended for patients with NPI ≤3.4, is discussed as on option for NPI >3.4 to ≤5.4 and is recommended for NPI >5.4. Similarly, Predict can be used to guide CT decisions as follows: < 3% benefit, CT not recommended; 3-5% CT discussed as a possible option; >5% CT recommended. The OncotypeDX® Breast Recurrence Score® test has been assessed recently in the RxPONDER trial which concluded that postmenopausal women with a Recurrence Score (RS) result < 26 showed no benefit from the addition of CT. This study compares the clinical utility of three indices (NPI, Predict, and RS result) by assessing the distribution of NPI and Predict across RS result, evaluates changes in CT recommendations based on risk group, and by estimating the likelihood of CT recommendation. Methods: We recently conducted a prospective UK decision impact, decision conflict and economic analysis of Oncotype DX® test in early node positive, hormone receptor positive and HER2 negative breast cancer involving 664 women. Using these data, we calculated the NPI and the Predict score. Descriptive statistics, logistic regression and McNemar’s tests were used to assess the associations between NPI, Predict, RS result and change in CT decisions for all patients (n=664) and in the cohort of post-menopausal patients recruited after RxPONDER reported (n=176). Results: Table 1 shows similar stratification for all three indices within the low-risk groups, but not for the high-risk groups. Similar results were observed in the post-menopausal, post-RxPONDER cohort. The results of the CT decision change in the post-menopausal, post-RxPONDER patients by NPI and Predict demonstrate the utility of RS results across all NPI and Predict risk groups (Table 2). There was a stronger association between RS result (26-100 vs 0-25) and CT recommendation (OR152.8, 95% CI 53.9-433.2, p< 0.001) as compared to the association between either NPI or Predict (OR 8.7, 95% CI 3.8-19.8, p< 0.001 and OR 7.2, 95% CI 2.8-18.3, p=0.003 respectively), suggesting that UK Oncologists are predominantly using RS to guide their CT decisions. Conclusions: Either basing CT decisions or selecting which patients should undergo OncotypeDX testing by pre-screening with either NPI or Predict risks misclassifing many patients who either need potentially lifesaving CT or who can safely avoid chemotherapy altogether. Table 1. Predict and NPI risk groups by RS result for all patients and for the post-menopausal, post-RxPONDER cohort. Table 2. CT recommendation pre-and post-assay by risk group for post-menopausal, post-RxPONDER patients. Citation Format: Simon Holt, Paige Innis, Priyadharshini Sai-Giridhar, Satish Seerapu. A comparison of chemotherapy recommendations by NPI, Predict, and Oncotype DX testing in UK women with early node positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-05.

Association between pathological characteristics and recurrence score by OncotypeDX in resected T1-3 and N0-1 breast cancer: a real-life experience of a North Hungarian regional center.

Introduction: The 21-gene analysis (OncotypeDX) is validated test for pT1-3, pN0-1 with hormone receptor (HR) positive and normal expression of human epidermal growth factor receptor-2 (HER2) breast cancer (BC) to determine the aggressiveness of the disease based on the calculation of Recurrence Score (RS). Methods: In this retrospective study the authors correlated pathological characteristics and Recurrence Score (RS) by traditional statistical methods and Observed Oriented Modeling (OOM) in a realistic cohort of BC patients. Results: OncotypeDX tests were performed in 94 tumour specimens of 90 BC patients. >83% of node-negative (pN0) and >72% of node-positive (pN1) cases could avoid chemotherapy. For pN0 cases, non-parametric correlation and tests demonstrated significant association in eight types of characteristics [progesterone receptor (PR) expression, Ki-67 value, Ki-67 group, PR group, grade, estrogen receptor (ER) expression, Nottingham Prognostic Index (NPI) and Clinical Risk]. For pN1 cases, parametric correlation and tests showed significant association in six characteristic types (number of positive nodes, ER and PR expression, PR group, Ki-67 group and NPI). Based on OOM for pN0 cases, significant associations were established in three characteristics (Ki-67 group, grade and NPI group). For pN1 cases OOM found significant associations in seven characteristics (PR group, PNI, LVI, Ki-67 group, grade, NPI group and number of positive nodes). Conclusion: First in oncology, OOM was applied, which found some other significant characteristics associated with RS than traditional statistical methods. There were few patients, where no clinical associations were found between characteristics and RS contrary to statistically significant differences. Therefore, the results of these statistical analyses can be neither applied for individual cases nor able to provide the bases for screening patients, i.e., whether they need for OncotypeDX testing or not. OncotypeDX still provides a personalised approach in BC.

Prediction of the Nottingham prognostic index and molecular subtypes of breast cancer through multimodal magnetic resonance imaging

PurposeTo explore the ability of intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI) and background parenchyma enhancement (BPE) to predict the Nottingham prognostic index (NPI) and molecular subtypes of breast cancer (BC). Materials and MethodsIn this study, 93 patients with BC were included, and they all underwent DKI, IVIM and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examinations. The corresponding mean kurtosis value (MK), pure diffusion (MD), perfusion fraction (f), pseudo diffusion coefficient (D*), true diffusion coefficient (D), and BPE were measured. We used logistic regression analysis to investigate the relevance between the NPI, molecular subtypes and variables. The diagnostic efficacy was analyzed using receiver operating characteristic curves (ROC). ResultsThe MD and D values of the high-level NPI group were significantly lower than those of the low-level NPI group (p < 0.01), and the f value of the high-level NPI group was obviously higher than that of low-level NPI group (p < 0.001). The area under curve (AUC) of the combined model (f + D) was 0.824. Comparing with non-Luminal subtypes, the Luminal subtypes showed obviously lower MK, f and D*, and the AUC of the combined model (MK + f + D*) was 0.785. In comparison to other subtypes, the MK and D* values of triple-negative subtype were higher than other subtypes, and the combined model (MK + D*) represented an AUC of 0.865. ConclusionThe quantitative parameters of DKI and IVIM have vital value in predicting the NPI and molecular subtypes of BC, while BPE could not provide additional information. Besides, these combined models can obviously improve the prediction performance.

Comparison of diffusion kurtosis imaging and dynamic contrast enhanced MRI in prediction of prognostic factors and molecular subtypes in patients with breast cancer

PurposeTo explore the clinical value of diffusional kurtosis imaging (DKI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for predicting genotypes and prognostic factors of breast cancer. Materials and methodsA total of 130 female patients with pathologically-confirmed breast cancer and DKI and DCE-MRI data were reviewed retrospectively. Two radiologists independently evaluated mean diffusivity (MD) and mean kurtosis (MK) for the DKI model and volume transfer constant (Ktrans), reverse rate constant (Kep), and extracellular extravascular volume ratio (Ve) for the DCE-MRI model for post-processing analyses. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic efficacies. ResultsMK, Ktrans, and Kep values were significantly higher in the high-grade Nottingham prognostic index (NPI) group (NPI ≥ 3.4) than in the low-grade NPI group (NPI < 3.4) (p < 0.01). The Ktrans had significantly greater area under ROC curve (AUC) than Kep and MK in predicting the NPI (p = 0.038 and 0.0217, respectively). Higher Ktrans, Kep, and MK values were observed in the high Ki-67 expression (≥14%) group than in the low Ki-67 expression (<14%) group (p < 0.05). Moreover, the MK value had better diagnostic performance than the Ktrans and Kep values in identifying Ki-67 expression status (p = 0.0097 and 0.0008, respectively). The combined model (MD + MK + Ktrans + Ve) had a significantly higher AUC than the single parameters for differentiating between luminal A/B and non-luminal subtypes (p = 0.003, < 0.001, 0.001, and < 0.001, respectively). The Human epidermal growth factor receptor 2-positive group had higher MD and Ve values than the other subtype groups (p < 0.05), and the Ve had a sensitivity of 100%. Moreover, the Ve AUC was significantly higher than that for MD in the identification of the triple-negative subtype (p = 0.048). ConclusionKtrans of DCE-MRI and MK of DKI demonstrated good diagnostic performance in predicting the prognostic factors of breast cancer. Additionally, the combination of the DCE-MRI and DKI models can improve the efficiency of predicting breast cancer genotypes.

Hormone receptor status, Her 2- neu amplification and their correlation with prognostic indices in patients with invasive ductal carcinoma of breast in Jaffna

Knowing the tumour biology can help to stratify patients for prognostic and therapeutic purposes. Expression of estrogen and progesterone receptors (ER, PR), amplification of human epidermal growth factor receptor 2 (Her 2 neu), size and histological grading of tumour , axillary lymph node state and NPI ( Nottingham Prognostic Index) are well established parameters that have influence on prognosis and treatment of breast carcinoma. It is an institutional based retrospective cross sectional analytic study.181 female patients who underwent primary mastectomy and axillary clearance for invasive ductal carcinoma of breast in Teaching Hospital Jaffna from 2014 to 2018 were included in this study.ER/PR status and amplification of Her 2 neu in the infiltrating ductal carcinoma of breast and the prognostic indices were recorded. SPSS was used for statistical analysis and correlation between the receptor status and prognostic indices were calculated using Spearman’s correlation, chi-square and Kruskal- Wallis tests. Of the 181 patients with invasive ductal carcinoma of breast, 132 patients (72.9%) were above 45 years old. A total of 87 patients had ER + (48.1%), 76 had PR + (41.9%) and, 62 had Her 2-neu + (34.3%). The mean ages of patients with expression of ER, PR and Her 2-neu amplification were 56.43, 54.36 and 52.95 years respectively. Triple negative tumour was found in 38 patients (21%). NPI 1 indicating good prognosis, NPI 2 with moderate and NPI 3 with poor prognostic categories were seen in 57 (31.5%), 74 (40.9%) and 50 (27.6%) patients respectively. Stage T2 sized tumour was identified in 88 patients (48.6%).A total of 110 patients (60.8%) had grade 2 tumours. 89 patients (49.1%) had axillary lymph node involvement. Statistically significant correlation was found between the expression of ER and PR (Spearman’s correlation coefficient (r) = 0.136, p value &lt; 0.0001). Statistically significant inverse correlation existed between the expression of hormone receptors (ER&amp;PR) and Her 2-neu amplification (chi square=12.93, p value &lt; 0.0001). Kruskal-Wallis test revealed statistically significant association between the expression of ER and the favourable NPI groups and also with low grade tumours ((p value 0.046 and 0.006) and a statistically significant association between Her2-nue amplification and axillary lymph node involvement (p value = 0.0001).

Abstract 677: Progranulin/GP88 tumor tissue expression further stratifies survival outcomes of patients classified by their Nottingham Prognostic Index

Abstract Background: The Nottingham Prognostic Index (NPI) combines nodal status, tumor size and histological grade and is used to provide predictive value information on survival for patients with primary breast cancer. Attempts to improve the performance of NPI have been carried out by inclusion of other factors, such as biomarker expression as well as addition of other structural features such as vascular invasion. In the present study, we investigated whether expression of the survival factor GP88 (progranulin), known to be overexpressed in breast cancer, would improve NPI’s predictive value. GP88/Progranulin is an 88 kDa autocrine growth and survival factor that is overexpressed in estrogen receptor positive (ER+) invasive ductal carcinoma (IDC) in association with resistance to anti-estrogens and aromatase inhibitor while the cells remain ER+. Previous training and validation pathological studies totaling 600 cases of ER+ IDC had demonstrated that GP88/Progranulin tissue expression was an independent prognostic marker od recurrence and mortality for early stage ER+ IDC. Methods: We examined by immunohistochemistry the GP88 tumor tissue expression of 508 formalin fixed paraffin embedded cases of ER+ IDC with known clinical outcomes and for which NPI had been determined. GP88 IHC expression was scored by two board certified pathologists and classified into two score groups of GP88 &amp;lt; 3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) and overall survival outcomes (OS) was then examined by Kaplan Meier analysis, Cox proportional Hazard ratio and Pearson’s X2 test. Results: Patients were categorized into three NPI groups (&amp;lt; 3.4, 3.4-5.4, &amp;gt;5.4). Kaplan-Meier survival graphs of cases categorized by their NPI scores and GP88 expression showed that for each NPI subgroup, patients having tumors with a high GP88 expression (GP88 IHC score of 3+) had a worse DFS than patients within the same NPI subgroup with low GP88 expression (GP88 IHC score &amp;lt; 3+). When adjusted for NPI, high GP88 score was highly significantly associated with recurrence. Its hazard ratio is 3.30 (95% CI 2.12 to 5.14). Conclusions: These data suggest that the determination GP88 tumor expression at time of diagnosis for early stage breast cancer patients could provide additional survival information than the ones provided by NPI alone that maybe useful for improving the risk management of patients. Citation Format: Ginette Serrero, Douglas Hawkins, Olga Ioffe, Pablo Bejarano, Binbin Yue. Progranulin/GP88 tumor tissue expression further stratifies survival outcomes of patients classified by their Nottingham Prognostic Index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 677. doi:10.1158/1538-7445.AM2017-677

Correlation of various histopathologic prognostic factors with Nottingham prognostic index and microvessel density in invasive breast carcinoma: A study of 100 cases.

Nottingham prognostic index (NPI) is a widely used integrated prognostic variable in patients with breast cancer. NPI has been correlated with tumor size, grade, lymph node stage and patient survival. The present study aimed at evaluating and correlating the various clinical and pathologic features of breast carcinoma with NPI. This study included 100 consecutive cases of primary breast carcinoma over a period of 2 years. Demographic data was noted and histomorphological features like tumor size, grade, lymph node involvement, necrosis, vascular invasion etc., were assessed. NPI was calculated as reported in the literature. Immunohistochemical staining for hormone receptors and CD34 (to calculate microvessel density [MVD]) was performed. Statistical analysis was used for correlation. Of the 100 cases, 54% of the tumors were in T2 tumor size category (2-5 cm) and lymph node metastasis in 48% of the cases. NPI ranged from 2.3 to 7.3 with 54% of the cases in the intermediate NPI group (3.41-5.4). The mean MVD was 160.93 (±69.4/mm2). On statistical analysis, tumor size and grade, lymph node stage, mitotic rate, nuclear pleomorphism, necrosis and MVD showed a correlation with NPI (P < 0.05). NPI is an important and useful prognostic indicator for breast cancer patients, which shows the correlation with other histomorphological prognostic features as well.

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.

P4-09-24: Correlation of Aurora Family Member Expression with Clinical Breast Cancer Prognosis.

Abstract Introduction: Aurora-A, Aurora-B and Aurora-C are a family of protein kinases which have been identified as key regulators of the mitotic cell division process. Members of this group have been linked with pro-tumorigenic effects and have been reported as being up-regulated in certain cancers. Our current study examines the expression profile of the Aurora-A, Aurora-B and Aurora-C members in a breast cancer cohort in relation to a number of predictive factors. Materials and Methods: The expression of Aurora-A, Aurora-B and Aurora-C was examined in a breast cancer cohort using quantitative real time PCR (normal samples n = 34, tumour samples n = 109) and immunhistochemistry (IHC). Expression of the aurora members was related to clinical parameters such as staging and Nottingham prognostic index (NPI). Results: Examination of Aurora-A levels in the breast cancer cohort revealed an association of Aurora-A expression with NPI grouping. High levels of Aurora-A levels were seen in NPI-1 and NPI-2 stages (NPI-1 median = 66.0, NPI-2 median = 64.3), with expression reducing significantly at the higher NPI-3 group (NPI-3 median = 20.3; p = 0.029 vs NPI-2 and p = 0.009 vs NPI-1 respectively). Additionally, Aurora-A levels were found to be significantly lower in grade 3 cancers compared to grade 1 (median grade 1 = 86.5 vs median grade 3 levels = 52.6, p = 0.04). In contrast to this, examination of Aurora-C levels in the cohort identified a relatively low level of Aurora-C in NPI-1 and NPI-2 group (median values NPI-1 = 88, NPI-2 = 34.4) compared to a substantial increase in Aurora-C expression in NPI-3 (median value = 1602, p = 0.05 vs NPI-1 and p = 0.06 vs NPI-2). Aurora-B expression levels did not exhibit any significant differences within the breast cancer cohort. Conclusions: Differential expression of Aurora-A, Aurora-B and Aurora-C were observed within the breast cancer cohort. Higher Aurora-A expression was associated with low NPI groups and grades and potentially with better patient prognosis whereas lower levels were seen in the poorer prognostic NPI-3 group and higher grades. An opposite trend was seen in Aurora-C where lower levels were associated with the NPI-1 and NPI-2 groups and significantly higher levels were seen in the NPI-3 group. Aurora-B levels appeared to have no predictive function. This data suggests that together Aurora-A and Aurora-C levels, within a patient may be useful for predicting patient outcome. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-24.

Are symptomatic guidelines for chemotherapy appropriate to ER-positive screen-detected breast cancer (SDBC)?

Oncologists recommend chemotherapy to postmenopausal women with adverse prognostic factors, but predictors of the benefit of chemotherapy are mainly based on mortality from symptomatic cancer trials. From 1990 to 1998, 1475 breast cancers (875 screen detected cancers [SDBCs]: 600 symptomatic) were treated in women aged 50-65years and prognostic factors compared with cancer mortality. Median follow-up was 110months. The Nottingham Prognostic Index (NPI) was calculated for 6737 breast cancers which were part of the Association of Breast Surgery (ABS) 2001/2002 Audit of SDBCs to validate survival figures. Ten year survival was 92.1% for SDBC and 77.6% for symptomatic cancers. Adjusting for baseline factors, SDBCs had a reduced mortality (RR=0.42 (0.31-0.57), independent of grade, node status and tumour size. Oestrogen receptor (ER) positive SDBC had a lower annual mortality rate (0.6%) compared with symptomatic (4.3%: P<0.001) or ER negative SDBC (1.8%). Epithelial proliferation was lower in SDBC in all NPI groups compared with symptomatic cancers (P≤0.001). Grade, node status, ER status, size and mode of detection predicted survival. Survival for each NPI group was better for SDBC. For ER positive SDBC in the Moderate Prognostic Group 1 (MPG1), 10year mortality was 6.4% compared with 17.6% in symptomatic (P=0.001). NPI on 6,737 operable SDBC confirmed similar mortality in all groups (4% mortality in MPG1 group). SDBC have lower mortality than symptomatic due to a lower proliferative index. The use of adjuvant chemotherapy is over-treatment for ER positive SDBCs with Good Prognostic Group (GPG) and MPG1 NPI scores.

Benefits of biomarker selection and clinico-pathological covariate inclusion in breast cancer prognostic models

IntroductionMulti-marker molecular assays have impacted management of early stage breast cancer, facilitating adjuvant chemotherapy decisions. We generated prognostic models that incorporate protein-based molecular markers and clinico-pathological variables to improve survival prediction.MethodsWe used a quantitative immunofluorescence method to study protein expression of 14 markers included in the Oncotype DX™ assay on a 638 breast cancer patient cohort with 15-year follow-up. We performed cross-validation analyses to assess performance of multivariate Cox models consisting of these markers and standard clinico-pathological covariates, using an average time-dependent Area Under the Receiver Operating Characteristic curves and compared it to nested Cox models obtained by robust backward selection procedures.ResultsA prognostic index derived from of a multivariate Cox regression model incorporating molecular and clinico-pathological covariates (nodal status, tumor size, nuclear grade, and age) is superior to models based on molecular studies alone or clinico-pathological covariates alone. Performance of this composite model can be further improved using feature selection techniques to prune variables. When stratifying patients by Nottingham Prognostic Index (NPI), the most prognostic markers in high and low NPI groups differed. Similarly, for the node-negative, hormone receptor-positive sub-population, we derived a compact model with three clinico-pathological variables and two protein markers that was superior to the full model.ConclusionsPrognostic models that include both molecular and clinico-pathological covariates can be more accurate than models based on either set of features alone. Furthermore, feature selection can decrease the number of molecular variables needed to predict outcome, potentially resulting in less expensive assays.

Qualitative Assessment of the Progesterone Receptor and HER2 Improves the Nottingham Prognostic Index Up to 5 Years After Breast Cancer Diagnosis

To investigate whether the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) can improve the Nottingham Prognostic Index (NPI) in the classification of patients with primary operable breast cancer for disease-free survival (DFS). The analysis is based on 1,927 patients with breast cancer treated between 2000 and 2005 at the University Hospitals, Leuven. We compared performances of NPI with and without ER, PR and/or HER2. Validation was done on two external data sets containing 862 and 2,805 patients from Oslo (Norway) and Auckland (New Zealand), respectively. In the Leuven cohort, median follow-up was 66 months, and 13.7% of patients experienced a breast cancer-related event. Positive staining for ER, PR, and HER2 was detected, respectively, in 86.9%, 75.5%, and 11.9% of patients. Based on multivariate Cox regression modeling, the improved NPI (iNPI) was derived as NPI - PR positivity + HER2 positivity. Validation results showed a risk group reclassification of 20% to 30% of patients when using iNPI with its optimal risk boundaries versus NPI, in a majority of patients to more appropriate risk groups. An additional 10% of patients were classified into the extreme risk groups, where clinical actions are less ambiguous. Survival curves of reclassified patients resembled more closely those for patients in the same iNPI group than those for patients in the same NPI group. The addition of PR and HER2 to NPI increases its 5-year prognostic accuracy. The iNPI can be considered as a clinically useful tool for stratification of patients with breast cancer receiving standard of care.

Retrospective application of Nottingham Prognostic Index (NPI) and Adjuvant! Online tool in newly diagnosed patients with early breast cancer in mid-western Ireland.

6139 Background: Prognostic tools used in oncology, have been derived to help stratify patients into specific risk-related groupings. Before the widespread use of the internet, the St Gallens' recommendations and the Nottingham Prognostic Index (NPI) were used in patients with early breast cancer; however more recently, there has been the development of the web-based tool, Adjuvant! Online (www.adjuvantonline.com), which provides more detailed information. We herein report our experience with the retrospective application of these prognostic tools and the comparative outcome for patients in Mid-Western Regional Hospital (MWRH), Limerick, Ireland. Methods: Study period: 01/01/2002-31/12/2002. Data was derived from (1) Mid-Western Cancer Centre (MWCC) Oncology Database (2) MWRH pathology records (3) MWRH patient files (4) MWRH Breast Multidisciplinary meeting records. Data was collated and entered into an Access database and exported into Predictive Analytics Software (PASW) for analysis. Results: Seventy seven patients with nonmetastatic breast cancer were analysed. Mean age: 53.4 years (range: 23-74 years). Median follow-up: 84 months. Patients were distributed into the following NPI groups, good, 26.0% (20/77), moderate, 50.6% (39/77) and poor risk, 23.4% (18/77); median survival did not show direct correlation with NPI risk, 83.3 months, good, 85.1 months, moderate and 76.2 months for poor-risk patients. Application of Adjuvant! Online showed a better correlation between the predicted survival (mean 72.9%, median 78.6%) versus the observed survival of our patient cohort (81.8%) and this was maintained within all sub-groups, including those who undertook no additional therapy, hormonal therapy and chemotherapy. Conclusions: Prognostic tools are useful in evaluating and predicting the possible outcome. Of the two tools used in this study, Adjuvant! Online was better able to predict overall survival for our cohort. These tools work well in the clinical setting, but should not be seen an alternative to good clinical judgement when assessing patients on an individual basis. No significant financial relationships to disclose.

Circulating Endothelial Cells and Circulating Progenitor Cells in Breast Cancer: Relationship to Endothelial Damage/Dysfunction/ Apoptosis, Clinicopathologic Factors, and the Nottingham Prognostic Index

BACKGROUND AND METHODS: Abnormal circulating endothelial cell (CEC) and circulating progenitor cell (CPC) numbers are present in cancer, but their relationship with angiogenesis, apoptosis, vascular biology, and prognosis is unclear. We prospectively studied 160 patients with breast cancer and 63 age-matched controls free of breast cancer, measuring CECs (CD45−/CD146+/CD34+) and CPCs (CD45−/CD133+/CD34+) by flow cytometry and plasma markers of endothelial damage/dysfunction (von Willebrand factor), apoptosis (Fas/Fas-L) and angiogenesis (vascular endothelial growth factor [VEGF], angiogenin) by ELISA. These were compared with clinicopathophysiologic features and the Nottingham Prognostic Index (NPI). An additional blood sample was taken 6 to 8 weeks after surgery from 15 women to test the effect of tumor removal. RESULTS: CECs were significantly higher in the NPI poor prognostic group compared with moderate and good prognostic groups, and the cancer-free controls, whereas CPCs were lower in the poor prognosis group (both P < .05). Levels of von Willebrand factor, VEGF, angiogenin, and Fas-L (but not soluble Fas) were abnormal in breast cancer compared with controls (P < .05), with no relationship to prognosis groups. VEGF (P = .04) and angiogenin (P = .001) were markedly different after surgery. In multivariate analysis, vascular invasion (P < .05) and tumor size (P < .001) were independently associated with CECs. CPCs did not significantly associate with NPI in a linear regression model; age (P < .05) was a negative predictor, whereas Her-2 status (P < .05) positively predicted CPCs. After adjustment, no variable independently predicted CPC levels. CONCLUSIONS: CECs and CPCs demonstrate a strong relationship with NPI groups, but only CECs positively predict higher NPI scores and correlate with tumor invasiveness and size, possibly reflecting total tumor vascular volume.

Improving NPI for breast cancer prognosis by including PR and HER-2 expression: own data and external validation set.

Abstract Abstract #1080 The Nottingham Prognostic Index (NPI) classifies primary operable breast cancer patients into good (NPI ≤ 3.4) , intermediate (NPI 3.4-5.4) and poor (NPI ≥ 5.4) prognostic risk groups [Br J Cancer 1987; 56: 489–92]. Studies indicate a significant short term prognostic role for estrogen (ER), progesterone (PR) and HER-2 receptor on disease free survival (DFS). We proposed at SABCS 2007 to add PR and HER-2 expression to the NPI called improved NPI (iNPI) defined as (NPI) + (HER-2) – (PR), with HER-2 and PR '1' in case of amplified HER-2 and any PR-expression and '0' otherwise.&amp;#x2028; Internal validation of the iNPI was performed on 1928 breast cancer patients, primary operated between Jan 2000 and June 2005 at Univ Hospital Leuven. All patients were classified into any of the three NPI or iNPI risk group. Mean follow-up was 3.5 yrs and DFS was defined as previously stated [Breast Cancer Research and Treatment 2007; 106: S247-S247]. Out of the 601 patients classified as NPI low risk, 59 shifted towards the intermediate iNPI group. Comparison of DFS for the 59 shifted with the non-shifted patients from the low NPI class did not reveal a significant difference (p=0.129, log-rank test). 57 patients out of 935 and 136 out of 392 respectively classified as intermediate and high NPI group became high and intermediate risk according to the iNPI. In both cases, DFS of the shifted patients differed significantly from DFS of the non-shifted patients (p=&amp;lt;.001 en p=0.029). DFS of the shifted patients with the iNPI group they where shifted to was not/marginally significant (p=0.856, p=0.462 and p=0.047 for low, intermediate and high NPI respectively).&amp;#x2028; For external validation a dataset from the Breast Cancer Micrometastasis group in Oslo with 677 patients and known NPI, PR and HER-2 was used. Figure 1 confirms a significant difference between DFS of the shifted and the non-shifted patients within the highest NPI risk group (p=0.021). The difference in DFS between shifted and non-shifted patients was marginally non-significant (p=0.068) in the intermediate and non-significant in the low NPI group (p=0.116). The non-significant difference between DFS of the shifted groups with the DFS of the group they were shifted to was confirmed, with exception of the low NPI group (difference in systemic treatment) (p=0.040, p=0.621 and p=0.076 for low, intermediate and high NPI respectively).&amp;#x2028; We confirm the results from an internal study at the Univ Hospital in Leuven on an external dataset. Inclusion of the PR and HER-2 status into the NPI results in more homogenate risk groups concerning DFS.&amp;#x2028; &amp;#x2028; Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1080.

Comparison between two prognostic index: Nottingham index (NPI) and an alternative index based on log of nodal involvement (Lpi)

22146 Background: Residual disease is an important,but rarely studied, parameter. In a database of 710 operable breast cancer patients treated by prospective phase II neoadjuvant trials (1982 to 2004), our study compared two prognostic index according to Vinh-Hung et al (SABCS 2006, 5023): Nottingham prognostic index (NPI) versus Lpi, an index based on log of nodal involvement. In Vinh-Hung series, the two index were assessed after primary surgery versus at surgery after neoadjuvant chemotherapy for us. We previously showed that the residual tumour in breast and nodes confers a determinant prognosis significance (Chollet BJC, 89: 1185, 2003). Methods: Median diameter of the invasive tumour was 40 mm [10–130]. 555 (78%) patients had a canalar and 90 (13%) a lobular carcinoma. 25.6% were grade III SBR. Calculated on residual disease: NPI = 0.2 × tumour size (cm) + lymph-node stage (1, node negative; 2, 1–3 positive lymph nodes; 3, ≥ 4 positive lymph nodes) + SBR grade (1, good; 2, moderate; 3, poor). Lpi = tumour size (cm) + 1 if SBR grade 3 or 4 (0 otherwise) + Log ((positive lymph nodes + 0.5)/(negative lymph nodes + 0.5)) NPI and Lpi distributions were divided into quartiles: NPI was categorized into low (NPI<3.4), intermediate (NPI<4.2 and NPI<4.8) and high risk (NPI≤7.6); as for Lpi: low (Lpi<0.6), intermediate (Lpi<1.5 and Lpi<2.5) and high risk (Lpi≤10.3). Results: The complete pathological response (pCR) rate was 14.2%. On 656 patients operated, 470 (72%) had a conservative surgery. On 520 patients with an axillary dissection, 272 (52.3%) had involved nodes. The ten-year OS and DFS were calculated in each risk group. The OS and DFS boundaries between low and high risk NPI groups were wider than for Lpi groups: 35.8% (NPI) versus 23.1% (Lpi) for OS and 37.8% (NPI) versus 23.7% (Lpi) for DFS. Conclusions: Conversely to Vinh-Hung et al (2006) at surgery, NPI after neoadjuvant chemotherapy, was better linked than Lpi to patient prognosis. As primary chemotherapy induces modifications in tumour parameters, could this explain the different results obtained? No significant financial relationships to disclose.

Postoperative wound complications and systemic recurrence in breast cancer

Many factors involved in wound healing can stimulate tumour growth in the experimental setting. This study examined the relationship between wound complications and the development of systemic recurrence after treatment of primary breast cancer. One thousand and sixty-five patients diagnosed with operable primary invasive breast cancer between 1994 and 2001 were assessed for development of systemic recurrence according to whether or not a wound complication occurred after surgery, with a median follow-up of 54 months (range 15–119). There were 93 wound complications (9%). There was a statistically significant greater risk of developing systemic recurrence in patients with wound problems than those without (hazard ratio (HR) 2.87; 95% CI: 1.97, 4.18; P<0.0001). This remained in a multivariate analysis after adjustment for case mix variables, including Nottingham Prognostic Index (NPI) and oestrogen–progesterone receptor status (HR: 2.52; 95% CI: 1.69, 3.77; P<0.0001). In the good prognostic NPI group, 4 out of 27 patients (15%) with wound problems vs 11 out of 334 (3%) without wound problems developed systemic recurrence. The corresponding figures were 10 out of 35 (29%) vs 48 out of 412 (12 %) in the moderate prognostic group and 18 out of 29 (62%) vs 75 out of 199 (38%) in the poor prognostic group. In 29 patients NPI could not be calculated. Smokers at the time of diagnosis were more likely to develop metastatic disease than the non-smokers (HR: 1.50; 95% CI: 1.04, 2.15; P=0.03) after adjustment for other factors. The results suggest that patients with wound complications at primary surgery have increased rates of systemic recurrence of breast cancer.

Survival of invasive breast cancer according to the Nottingham Prognostic Index in cases diagnosed in 1990–1999

The Nottingham Prognostic Index (NPI) is a well established and widely used method of predicting survival of operable primary breast cancer. Aims Primary: To present the updated survival figures for each NPI Group. Secondary: From the observations to suggest reasons for the reported fall in mortality from breast cancer. Methods The NPI is compiled from grade, size and lymph node status of the primary tumour. Consecutive cases diagnosed and treated at Nottingham City Hospital in 1980–1986 ( n = 892) and 1990–1999 ( n = 2238) are compared. Changes in protocols towards earlier diagnosis and better case management were made in the late 1980s between the two data sets. Results Case survival (Breast Cancer Specific) at 10 years has improved overall from 55% to 77%. Within all Prognostic groups there are high relative and absolute risk reductions. The distribution of cases to Prognostic groups shows only a small increase in the numbers in better groups. Conclusion The updated survival figures overall and for each Prognostic group for the NPI are presented.

Reading the prognosis of the individual with breast cancer

The well-established Nottingham Prognostic Index (NPI) places patients with primary breast cancer into Prognostic Groups with significantly differing survivals. However, mean survival of two adjacent groups may differ by a maximum of 22%, so that patients with NPI’s with only a 0.1 difference but lying in different prognostic groups may apparently have large differences in prognosis, whereas two patients lying in the same NPI group but with NPI’s differing by 0.9 are given the same prognoses. Aim To obtain better survival estimates for the individual than is provided by placement in an NPI group. Method Consecutive primary operable breast cancers treated at Nottingham City Hospital 1990–1999. Ten year % actuarial survivals plotted for 10 ranges of NPI from 2.0 to 6.9. There is an excellent inverse correlation between median NPI value for each range and survival at 10 years. To enable estimation of survival for all individual values of NPI, a curve fitting technique applied to these results (by G.B.) gave the formula to estimate survival from the individual’s NPI score: 10 year % survival for the individual = −3.0079 × NPI 2 + 12.30 × NPI + 83.84. This gave an r 2 of 0.98. Results and conclusion Greater accuracy in individual survival prediction is obtained by dividing women into 10 groups by NPI scores than in the originally described six groups; rank order of survival in relation to NPI score is preserved. A curve fitting technique has been applied to these data to give a formula for the prediction of 10 year survival for every 0.1 value of NPI.

Expression of inhibitor of apoptosis proteins and their relationships with clinicopathologic prognostic factors in breast cancer

BACKGROUND AND METHODS: Abnormal circulating endothelial cell (CEC) and circulating progenitor cell (CPC) numbers are present in cancer, but their relationship with angiogenesis, apoptosis, vascular biology, and prognosis is unclear. We prospectively studied 160 patients with breast cancer and 63 age-matched controls free of breast cancer, measuring CECs (CD45−/CD146+/CD34+) and CPCs (CD45−/CD133+/CD34+) by flow cytometry and plasma markers of endothelial damage/dysfunction (von Willebrand factor), apoptosis (Fas/Fas-L) and angiogenesis (vascular endothelial growth factor [VEGF], angiogenin) by ELISA. These were compared with clinicopathophysiologic features and the Nottingham Prognostic Index (NPI). An additional blood sample was taken 6 to 8 weeks after surgery from 15 women to test the effect of tumor removal. RESULTS: CECs were significantly higher in the NPI poor prognostic group compared with moderate and good prognostic groups, and the cancer-free controls, whereas CPCs were lower in the poor prognosis group (both P < .05). Levels of von Willebrand factor, VEGF, angiogenin, and Fas-L (but not soluble Fas) were abnormal in breast cancer compared with controls (P < .05), with no relationship to prognosis groups. VEGF (P = .04) and angiogenin (P = .001) were markedly different after surgery. In multivariate analysis, vascular invasion (P < .05) and tumor size (P < .001) were independently associated with CECs. CPCs did not significantly associate with NPI in a linear regression model; age (P < .05) was a negative predictor, whereas Her-2 status (P < .05) positively predicted CPCs. After adjustment, no variable independently predicted CPC levels. CONCLUSIONS: CECs and CPCs demonstrate a strong relationship with NPI groups, but only CECs positively predict higher NPI scores and correlate with tumor invasiveness and size, possibly reflecting total tumor vascular volume.