BACKGROUND:The incidence of local recurrence (LR) after conservative surgery for early breast cancer without adjuvant therapy is unacceptably high even with favourable tumours. The aim of this study was to examine the effect of adjuvant therapies in tumours with excellent prognostic features. METHODS:Patients with primary invasive breast cancer <2 cm diameter, grade 1 or good prognosis special type, and node negative, treated by wide local excision (WLE) with clear margins were randomised into a 2 × 2 clinical trial of factorial design with or without radiotherapy and with or without tamoxifen. Trial entry was allowed to either comparison or both. FINDINGS:The actuarial breast cancer specific survival in 1135 randomised patients at 10 years was 96%. Analysis by intention to treat showed that LR after WLE was reduced in patients randomised to radiotherapy (RT) (HR 0.37, CI 0.22-0.61 p<0.001) and to tamoxifen (HR 0.33, CI 0.15 - 0.70 p<0.004). Actuarial analysis of patients entered into the four-way randomisation showed that LR after WLE alone was 1.9% per annum (PA) versus 0.7% with RT alone and 0.8% with tamoxifen alone. No patient randomised to both adjuvant treatments developed LR. Analysis by treatment received showed LR at 2.2%PA for surgery alone versus 0.8% for either adjuvant radiotherapy or tamoxifen and 0.2% for both treatments. CONCLUSIONS:Even in these patients with tumours of excellent prognosis, LR after conservative surgery without adjuvant therapy was still very high. This was reduced to a similar extent by either radiotherapy or tamoxifen but to a greater extent by the receipt of both treatments.

Background: The Nottingham Elderly Primary Series I (EPSI), in which patients were randomised to primary tamoxifen or initial surgery, found that in oestrogen receptor (ER) unselected cases surgery achieved better local control but no overall survival advantage. However, analysis of EPSI by ER status suggested that the selection of patients with ER-rich tumours may lead to comparable local control and survival rates. Nottingham EPSII is a randomised trial designed to test this hypothesis, and we now present its final analysis at 20 years.

BACKGROUND Long-term analysis of a randomised trial in Nottingham comparing tamoxifen versus surgery as initial treatment demonstrated that in oestrogen receptor (ER)-unselected cases, surgery achieved better local control, with no difference in overall survival. It was suggested that for patients with ER-rich tumours, local control and survival may be comparable. We now present long-term follow-up of a randomised trial designed to address this clinical scenario. PATIENTS AND METHODS One hundred and fifty three fit elderly (≥70 years) women with clinically node-negative primary invasive breast carcinoma <5 cm of high ER content [histochemical (H) score ≥100] were randomised 2:1 to primary tamoxifen (Tam) (N = 100) or mastectomy with adjuvant tamoxifen (Mx + Tam) (N = 53). RESULTS With median follow-up of 78 months, there was no statistically significant difference in 10-year rates of regional recurrence (9.0% versus 7.5%), metastasis (8.0% versus 13.2%), breast cancer-specific survival (89.0% versus 86.8%) or overall survival (64.0% versus 66.0%) between Tam and Mx + Tam; however, local control was inferior with Tam (local failure rates 43.0% versus 1.9%; P < 0.001). CONCLUSION Irrespective of the degree of ER positivity, surgery achieved better local control. However, there was excellent and similar survival in both groups. Tam could be considered in those who are 'frail', refuse or prefer not to initially undergo surgery.

Abstract Introduction: Axillary lymph node status is an important predictor of overall survival (OS), hence its inclusion in clinical prognostic tools. The Nottingham Prognostic Index (NPI) which incorporates Lymph Node (LN) stage, tumor size and grade generates a score which predicts a percentage 10-year survival. Despite its status as a benchmark model for breast cancer prognosis, newer prognostic factors do exist. Lymph Node Ratio (LNR) is a superior prognostic indicator compared to absolute positive lymph node number, warranting re-evaluation of breast cancer prognostication. The aims of this study were threefold: identify the strength of LNR as a prognostic indicator compared to LN stage and NPI; establish a new prognostic index (Galway Index of Survival [GAINS]), taking into account the effect of LNR and breast cancer subtype on traditional clinicopathological features in breast cancer prognostication; and evaluate the prognostic efficacy of the new index compared to NPI. Methods: Two cohorts were used: Galway Cohort-a prospectively compiled cohort of 1668 cases with histologically proven Stage 1, 2 and 3 primary operable breast cancer treated between 1990–2010 in a single institution; and ONCOPOOL-a retrospectively compiled database of 16944 cases treated across 12 European breast cancer units between 1990–1999. A Cox Proportional Hazards model was fitted to evaluate the strength of LNR compared to LN stage (within the NPI model) in both cohorts. The effect of clinicopathological variables on OS was analyzed using multivariable analysis in the Galway cohort. Three models were created (Model 1: Traditional prognostic variables excluding NPI and LNR; Model 2: Model 1 and LNR; Model 3: Model 1 and NPI) and compared using Likelihood-ratio tests. Stepwise variable selection was used to identify the best model to create a prognostic index and performance of the two indices was evaluated using Receiver Operating Curves (ROC). Results: Controlling for tumor size and histological grade, LNR is a stronger prognostic factor than LN Stage in both the Galway (β values of 1.2 and 0.3 respectively) and ONCOPOOL (b values of 1.3 and 0.3 respectively) cohorts, with LNR rendering LN stage non significant (p=0.135) in the former. In the Galway cohort, separate comparisons of Model 2 and 3 with Model 1 demonstrated that traditional clinicopathological variables in addition to LNR (Model 2) best predicted OS (p=0.019). Within Model 2, LNR was a significant predictor of survival (p=0.014, Hazard Ratio 7.4). Age, LNR, stage and molecular subtype were significant prognostic factors, and corresponded to distinct survival patterns when included in the new prognostic index. GAINS performed almost identically to NPI, with similar areas under the curve (AUC) (GAINS AUC=0.745 [95%CI0.67−0.82]; NPI AUC=0.742 [95%CI0.67−0.82]). Conclusion: LNR is a better prognostic indicator compared to LN Stage. GAINS performs just as well as NPI as a prognostic index and has the potential for clinical utility given further validation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-15.

A recent Cochrane review of trials involving elderly women with operable primary breast cancer showed no significant difference in overall survival between surgery (±adjuvant tamoxifen) and primary endocrine therapy using tamoxifen. We report the final results of a randomised pilot trial comparing primary tamoxifen and wedge mastectomy as initial treatment in this population. One hundred and thirty-one women >70 years with early operable primary breast cancer (<5 cm), unselected for oestrogen receptor (ER), entered the trial in 1982-1987. Sixty-eight patients were allocated to tamoxifen only and 67 to wedge mastectomy only, as primary treatment. At 20 years of follow-up, the median time to local failure was significantly shorter in the tamoxifen arm though approximately one-fifth of patients in this group did not develop local failure requiring mastectomy. There was no difference in regional recurrence, distant metastases or overall survival between the mastectomy and tamoxifen arms. In this small study, primary endocrine therapy achieved local control in 30% of those surviving at 5 years and 20% at 10 years, unselected for ER. The primary therapy used did not significantly affect regional recurrence, incidence of distant metastases or overall survival. Primary endocrine therapy should certainly be considered in those patients with ER positive tumours and who are unfit (based on life expectancy) for or refuse surgery.

Gene expression microarrays allow for the high throughput analysis of huge numbers of gene transcripts and this technology has been widely applied to the molecular and biological classification of cancer patients and in predicting clinical outcome. A potential handicap of such data intensive molecular technologies is the translation to clinical application in routine practice. In using an artificial neural network bioinformatic approach, we have reduced a 70 gene signature to just 9 genes capable of accurately predicting distant metastases in the original dataset. Upon validation in a follow-up cohort, this signature was an independent predictor of metastases free and overall survival in the presence of the 70 gene signature and other factors. Interestingly, the ANN signature and CA9 expression also split the groups defined by the 70 gene signature into prognostically distinct groups. Subsequently, the presence of protein for the principal prognosticator gene was categorically assessed in breast cancer tissue of an experimental and independent validation patient cohort, using immunohistochemistry. Importantly our principal prognosticator, CA9, showed that it is capable of selecting an aggressive subgroup of patients who are known to have poor prognosis.

ONCOPOOL is a retrospectively compiled database of primary operable invasive breast cancers treated in the 1990s in 10 European breast cancer Units. Sixteen thousand and nine hundred and forty four cases were entered, with tumours less than 5 cm diameter in women aged 70 or less (mean age 55).Data: Data were date of birth, mode of diagnosis, pathology (size, lymph node status, grade, type, lympho-vascular invasion and hormone receptor) and therapies and outcome measures: first local, regional or distant recurrences, contralateral primary, date and cause of death.Tumour characteristics: Mean diameter 1.8 cm, 66% lymph node negative, 24% 1-3 lymph nodes involved and 10% had 4 or more involved. Grade 1, 29%; Grade 2, 41%; and Grade 3, 30%. Polynomial relationships were established between grade, stage and size.Seventy-five percent were oestrogen receptor (ER) positive. ER closely related to grade.Outcomes: Overall Survival was 89% at S years from diagnosis, 80% 10 years and 73% 15 years; Breast Cancer-Specific survivals were 91%, 84% and 79%.Survival strongly related to the Nottingham Prognostic index (NPI).Cases detected at screening had 84% 10-year survival, those presenting symptomatically 76%.ER positive cases treated with adjuvant hormone therapy had a reduction in risk of death of 13% over those not receiving adjuvant therapy (p = 0.000). ER negative cases treated with chemotherapy showed a risk reduction of 23% over those not receiving chemotherapy (p = 0.000). (C) 2009 Elsevier Ltd. All rights reserved.