This study suggests that the amount of prognostic information contained in four widely performed IHC assays is similar to that in the GHI-RS. Additional studies are needed to determine the general applicability of the IHC4 score.

PURPOSE To determine whether the Recurrence Score (RS) provided independent information on risk of distant recurrence (DR) in the tamoxifen and anastrozole arms of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial. PATIENTS AND METHODS RNA was extracted from 1,372 tumor blocks from postmenopausal patients with hormone receptor-positive primary breast cancer in the monotherapy arms of ATAC. Twenty-one genes were assessed by quantitative reverse transcriptase polymerase chain reaction, and the RS was calculated. Cox proportional hazards models assessed the value of adding RS to a model with clinical variables (age, tumor size, grade, and treatment) in node-negative (N0) and node-positive (N+) women. RESULTS Reportable scores were available from 1,231 evaluable patients (N0, n = 872; N+, n = 306; and node status unknown, n = 53); 72, 74, and six DRs occurred in N0, N+, and node status unknown patients, respectively. For both N0 and N+ patients, RS was significantly associated with time to DR in multivariate analyses (P < .001 for N0 and P = .002 for N+). RS also showed significant prognostic value beyond that provided by Adjuvant! Online (P < .001). Nine-year DR rates in low (RS < 18), intermediate (RS = 18 to 30), and high RS (RS > or = 31) groups were 4%, 12%, and 25%, respectively, in N0 patients and 17%, 28%, and 49%, respectively, in N+ patients. The prognostic value of RS was similar in anastrozole- and tamoxifen-treated patients. CONCLUSION This study confirmed the performance of RS in postmenopausal HR+ patients treated with tamoxifen in a large contemporary population and demonstrated that RS is an independent predictor of DR in N0 and N+ hormone receptor-positive patients treated with anastrozole, adding value to estimates with standard clinicopathologic features.

Quantitative expression of ER and PgR and HER-2 status did not identify patients with differential relative benefit from anastrozole over tamoxifen: TTR was longer for anastrozole than for tamoxifen in all molecular subgroups. Low ER or PgR or high HER-2 expression are associated with a high risk of recurrence with either anastrozole or tamoxifen.

Time to recurrence was longer for anastrozole- than tamoxifen-treated patients in both ER+/PgR+ and ER+/PgR- subgroups, but the benefit was substantially greater in the PgR- subgroup. As this was an "exploratory" analysis, this effect should be considered as hypothesis generating and assessed prospectively in other trials comparing the adjuvant use of an aromatase inhibitor with tamoxifen.

SummaryBackground Age-specifi c eff ects of mammographic screening, and the timing of such eff ects, are a matter of debate. The results of the UK Age trial, which compared the eff ect of invitation to annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no signifi cant diff erence in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up.

Study objective-The aim was to compare congenital malformation rates in twin births with those in singleton births.

Background:We recently reported that the GHI Recurrence score (GHI-RS) provided additional information regarding distant recurrence beyond that obtained from classical clinical factors (age, nodal status, tumour size, grade, randomised treatment) in 1231 patients with ER+ primary breast cancer in the ATAC trial who did not receive chemotherapy and were randomized between anastrozole vs. tamoxifen (Dowsett et al, SABCS 2008). Here we develop a score based on 4 standard laboratory assays (IHC4 score) and compare its prognostic value to that of the GHI-RS.Methods:Quantitative IHC scores were obtained for ER, PgR, and Ki67, and HER2 was scored as positive/negative in 1125 of those women from TransATAC for whom the GHI-RS and sections were available; 793 of those women were node negative. An IHC4 score was obtained by a proportional hazards regression using classical variables and the 4 IHC values. This was done separately for all patients and node negative patients for recurrence (TTR) and distant recurrence (TTDR), but the scores were very similar (pairwise correlation ρ &gt; 0.93). The data set was then split at random into two equal parts. Models were created on each half with the classical and IHC4 variables to create an IHC4 score, which was then applied to the other half (validation) and compared with the GHI-RS. Results were summarized by likelihood ratio (LR) χ2 test which combined results from the two halves. This was repeated for 100 random splits of the data.Results: Each of the 4 IHC variables added significantly to a model containing the classical variables and the overall model was highly significant (χ2(4df)=34.9, P &lt; 0.0001, for TTDR on all pts). Of the 4 variables PgR was the most predictive for all patients. When restricted to node negative patients, ER and HER2 were jointly the strongest predictors.The IHC4 score was modestly correlated with GHI-RS (ρ=0.70), and in sample splitting evaluations provided a similar amount of information as the GHI-RS score (GHI-RS slightly more for TTR and IHC4 slightly more for TTDR, see Table).Mean change in LR χ2 for addition of IHC4 or GHI-RS or both to classic model (C) in the validation halves of 100 random splits of the data. Higher values indicate more information. TTRTTDRModelAll PatientsNode Neg.All PatientsNode Neg.C+IHC4 vs C (1df)19.721.226.926.6C+GHI-RS vs C (1df)26.725.625.619.4C+IHC4+GHI-RS vs C (2df)30.029.932.529.7The predicted 9y distant recurrence proportion for an No, T&lt;2cm, poorly differentiated tumour receiving anastrozole at either the 25th or 75th percentile of each score was 6.7% vs 12.3% for IHC4 and 7.8% vs 11.2% for GHI-RS.None of these variables provided predictive information regarding the choice between tamoxifen or anastrozole.Conclusion:These data suggest that 4 standard IHC assays performed in a high quality laboratory can provide similar amounts of prognostic information for endocrine treated ER+ breast cancer patients as the GHI-RS. External validation in another data set is needed to confirm these results. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 74.

Background There remains disagreement on the long-term effect of mammographic screening in women aged 40–49 years. Objectives The long-term follow-up of a randomised controlled trial that offered annual mammography to women aged 40–49 years. The estimation of the effect of these mammograms on breast cancer and other-cause mortality, and the effect on incidence, with implications for overdiagnosis. Design An individually randomised controlled trial comparing offering annual mammography with offering usual care in those aged 40–48 years, and thus evaluating the effect of annual screening entirely taking place before the age of 50 years. There was follow-up for an average of 23 years for breast cancer incidence, breast cancer death and death from other causes. We analysed the mortality and incidence data by Poisson regression and estimated overdiagnosis formally using Markov process models. Setting Twenty-three screening units in England, Wales and Scotland within the NHS Breast Screening Programme. Participants Women aged 39–41 years were recruited between 1990 and 1997. After exclusions, a total of 53,883 women were randomised to undergo screening (the intervention group) and 106,953 women were randomised to have usual care (the control group). Interventions The intervention group was invited to an annual breast screen with film mammography, two view at first screen and single view thereafter, up to and including the calendar year of their 48th birthday. The control group received no intervention. Both groups were invited to the National Programme from the age of 50 years, when screening is offered to all women in the UK. Main outcome measures The main outcome measures were mortality from breast cancers diagnosed during the intervention phase of the trial (i.e. before the first National Programme screen at 50 years), mortality from all breast cancers diagnosed after randomisation, all-cause mortality, mortality from causes other than breast cancer, and the incidence of breast cancer. Results There was a statistically significant 25% reduction in mortality from breast cancers diagnosed during the intervention phase at 10 years’ follow-up (relative rate 0.75, 95% confidence interval 0.58 to 0.97; p = 0.03). No reduction was observed thereafter (relative rate 0.98, 95% confidence interval 0.79 to 1.22). Overall, there was a statistically non-significant 12% reduction (relative rate 0.88, 95% confidence interval 0.74 to 1.03; p = 0.1). The absolute benefit remained approximately constant over time, at one death prevented per 1000 women screened. There was no effect of intervention on other-cause mortality (relative rate 1.02, 95% confidence interval 0.97 to 1.07; p = 0.4). The intervention group had a higher incidence of breast cancer than the control group during the intervention phase of the trial, but incidence equalised immediately on the first National Programme screen at the age of 50–52 years. Limitations There was 31% average non-compliance with screening and three centres had to cease screening for resource and capacity reasons. Conclusions Annual mammographic screening at the age of 40–49 years resulted in a relative reduction in mortality, which was attenuated after 10 years. It is likely that digital mammography with two views at all screens, as practised now, could improve this further. There was no evidence of overdiagnosis in addition to that which already results from the National Programme carried out at later ages. Future work There is a need for research on the effects of modern mammographic protocols and additional imaging in this age group. Trial registration Current Controlled Trials ISRCTN24647151. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 55. See the NIHR Journals Library website for further project information. Other funding in the past has been received from the Medical Research Council, Cancer Research UK, the Department of Health and Social Care, the US National Cancer Institute and the American Cancer Society.