Prediction of outcome of early ER+ breast cancer is improved using a biomarker panel, which includes Ki-67 and p53.

BACKGROUND: The aim of this study is to determine whether immunohistochemical (IHC) assessment of Ki67 and p53 improves prognostication of oestrogen receptor-positive (ER+) breast cancer after breast-conserving therapy (BCT). In all, 498 patients with invasive breast cancer from a randomised trial of BCT with or without tumour bed radiation boost were assessed using IHC. METHODS: The ER+ tumours were classified as 'luminal A' (LA): ER+ and/or PR+, Ki-67 low, p53-, HER2- or 'luminal B' (LB): ER+ and/or PR+and/or Ki-67 high and/or p53+ and/or HER2+. Kaplan-Meier and Cox proportional hazards methodology were used to ascertain relationships to ispilateral breast tumour recurrence (IBTR), locoregional recurrence (LRR), distant metastasis-free survival (DMFS) and breast cancer-specific survival (BCSS). RESULTS: In all, 73 patients previously LA were re-classified as LB: a greater than four-fold increase (4.6-19.3%) compared with ER, PR, HER2 alone. In multivariate analysis, the LB signature independently predicted LRR (hazard ratio (HR) 3.612, 95% CI 1.555-8.340, P=0.003), DMFS (HR 3.023, 95% CI 1.501-6.087, P=0.002) and BCSS (HR 3.617, 95% CI 1.629-8.031, P=0.002) but not IBTR. CONCLUSION: The prognostic evaluation of ER+ breast cancer is improved using a marker panel, which includes Ki-67 and p53. This may help better define a group of poor prognosis ER+ patients with a greater probability of failure with endocrine therapy.

Interobserver variability in clinical target volume delineation in tangential breast irradiation: a comparison between radiation oncologists and radiation therapists.

AIMS: The delineation of target volumes has been radiation oncologist led. If radiation therapists were to undertake this task, work processes may be more efficient and the skills set of radiation therapy staff broadened. This study was undertaken to quantify interobserver variability of breast target volumes between radiation oncologists and radiation therapists. MATERIALS AND METHODS: The planning computed tomography datasets of 30 patients undergoing tangential breast radiotherapy were utilised. Four radiation oncologists and four radiation therapists independently contoured the clinical target volume (CTV) of the breast on planning computed tomography using a written protocol. The mean CTV volumes and the mean distance between centres of volume (COV) were determined for both groups to determine intergroup variation. Each of the radiation oncologists' readings in turn has been used as the gold standard and compared with that of the radiation therapists. The concordance index for each patient's CTV was determined relative to the gold standard for each group. A paired t-test was used for statistical comparison between the groups. An intraclass correlation coefficient was calculated to measure the agreement between the radiation oncologist and radiation therapist groups. RESULTS: The mean concordance index was 0.81 for radiation oncologists and 0.84 for radiation therapists. The intraclass correlation coefficient for the mean volume was 0.995 (95% confidence interval 0.981-0.998) between radiation oncologist- and radiation therapist-contoured volumes. The intraclass correlation for the mean difference between radiation oncologists' and radiation therapists' COV was 0.999 (95% confidence interval 0.999-1.000). CONCLUSIONS: Interobserver variability between radiation oncologists and radiation therapists was found to be low. Radiation therapists could potentially assume the role of CTV voluming for breast radiotherapy provided a standardised contouring protocol is in place.

ATM induction insufficiency in a radiosensitive breast-cancer patient.

The ataxia telangiectasia (A-T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology.

Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a.

Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximately 50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.

Probability of axillary node involvement in patients with tubular carcinoma of the breast.

BACKGROUND: The aim of this study was to investigate the frequency of axillary metastasis in women with tubular carcinoma (TC) of the breast. METHODS: Women who underwent axillary dissection for TC in the Western Sydney area (1984--1995) were identified retrospectively through a search of computerized records. A centralized pathology review was performed and tumours were classified as pure tubular (22) or mixed tubular (nine), on the basis of the invasive component containing 90 per cent or more, or 75--90 per cent tubule formation respectively. A Medline search of the literature was undertaken to compile a collective series (20 studies with a total of 680 patients) to address the frequency of nodal involvement in TC. A quantitative meta-analysis was used to combine the results of these studies. RESULTS: The overall frequency of nodal metastasis was five of 31 (16 per cent); one of 22 pure tubular and four of nine mixed tumours (P = 0.019). None of the tumours with a diameter of 10 mm or less (n = 16) had nodal metastasis compared with five of 15 larger tumours (P = 0.018). The meta-analysis of 680 women showed an overall frequency of nodal metastasis in TC of 13.8 (95 per cent confidence interval 9.3-18.3) per cent. The frequency of nodal involvement was 6.6 (1.7--11.4) per cent in pure TC (n = 244) and 25.0 (12.5--37.6) per cent in mixed TC (n = 149). CONCLUSION: A case may be made for observing the clinically negative axilla in women with a small TC (10 mm or less in diameter).