An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis.

BACKGROUND: Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. METHODS: The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. RESULTS: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. CONCLUSIONS: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

Patient and tumour characteristics, management, and age-specific survival in women with breast cancer in the East of England.

BACKGROUND: Breast cancer relative survival (BCRS), which compares the observed survival of women with breast cancer with the expected survival of women for the whole population of the same age, time period, and geographical region, tends to be poorer in older women, but the reasons for this are not clear. We examined the influence of patient and tumour characteristics, and treatment on BCRS to see whether these could explain the age-specific effect. METHODS: Data for 14,048 female breast cancer patients diagnosed from 1999 to 2007, aged 50 years or over were obtained from the Eastern Cancer Registration and Information Centre. We estimated relative 5- and 10-year survival for patients in four age groups (50-69, 70-74, 75-79, and 80+ years). We also modelled relative excess mortality (REM) rate using Poisson regression adjusting for patient characteristics and treatment. The REMs derived from these models quantify the extent to which the hazard of death differs from the hazard in the reference category, after taking into account the background risk of death in the general population. We compared the results with those obtained for breast cancer-specific mortality, analysed using multivariate Cox regression. RESULTS: Median follow-up time was 4.7 years. Relative 5-year survival was 89, 81, 76, and 70% for patients aged 50-69, 70-74, 75-79, and 80+ years, respectively. Corresponding relative 10-year survival was 84, 77, 67, and 66%. Unadjusted REM was 1.93, 2.74, and 3.88 for patients aged 70-74, 75-79, and 80+ years, respectively, (50-69 years as reference). The equivalent hazard ratios from the Cox model were 1.88, 2.45, and 3.81. These were attenuated after adjusting for confounders (REM - 1.49, 1.36, and 1.23; Cox - 1.47, 1.50, and 1.76). CONCLUSION: We confirmed poorer BCRS in older women in our region. This was partially explained by known prognostic factors. Further research is needed to determine whether biological differences or suboptimal management can explain the residual excess mortality.

Treatment and survival in breast cancer in the Eastern Region of England.

BACKGROUND: The reasons for variation in survival in breast cancer are multifactorial. METHODS: From 1999 to 2003, the vital status of 9051 cases of invasive breast cancer was identified in the Eastern Region of England. Survival analysis was by Cox proportional hazards regression. Data were analysed separately for patients aged <70 years and those older due to differences in treatment policies. RESULTS: Overall 5-year survival was 78%. In patients aged <70 years, significant differences in survival lost their formal significance after adjustment for detection mode and node status, although this remained close to statistical significance with some residual differences between relative hazards. There was significant negative ecological correlation between proportion with nodes positive or not examined and 9-year survival rates. Patients with estrogen receptor (ER) status unknown were at significantly higher risk of dying than ER-positive patients. There was a clear trend of increasing hazard of dying with increasing deprivation. Survival differences in women aged > or =70 years were related to whether surgery was included as part of treatment. CONCLUSION: This variation in treatment and survival may be attributed to lack of information, in particular nodal and ER status, thereby impacting on staging and prescription of adjuvant therapy.

Measuring performance in clinical breast examination.

BACKGROUND: Clinical breast examination (CBE) remains an essential part of triple assessment of breast lumps, but to date there are no performance measures for clinicians using this technique. The aim of this retrospective audit was to compare the performance and accuracy of CBE to identify key indicators that could be used to monitor performance prospectively. METHODS: Clinical examination findings (E1, normal, to E5, malignant) for 16,585 patients who had CBE as part of triple assessment were obtained from electronic medical records. The performance of CBE, by age group, mammographic density and clinician, was assessed by calculating the sensitivity, specificity and area under the receiver operating characteristic (ROC) curve. RESULTS: There was marked variation in sensitivity between clinicians (range 44.6-65.9 per cent). There was a strong downward trend in the percentage classified as E5 as sensitivity for breast cancer detection decreased, and a corresponding strong downward trend in the proportion of E4 and E5 cancers classified as E5. Both of these measures could be used as indicators to monitor CBE performance. CONCLUSION: The performance measures outlined here could help to identify clinicians who have a lower sensitivity for CBE and who may therefore require feedback and further training.

Tamoxifen: the drug that came in from the cold.

Despite the perception of many oncologists that tamoxifen is an inferior drug, and should be substituted by an aromatase inhibitor in post-menopausal women, the current evidence strongly supports the view that AIs should be used 2-3 years after tamoxifen to achieve the maximal overall survival (OS) advantage.

Radiological staging in breast cancer: which asymptomatic patients to image and how.

BACKGROUND: Approximately 4% of patients diagnosed with early breast cancer have occult metastases at presentation. Current national and international guidelines lack consensus on whom to image and how. METHODS: We assessed practice in baseline radiological staging against local guidelines for asymptomatic newly diagnosed breast cancer patients presenting to the Cambridge Breast Unit over a 9-year period. RESULTS: A total of 2612 patients were eligible for analysis; 91.7% were appropriately investigated. However in the subset of lymph node negative stage II patients, only 269 out of 354 (76.0%) investigations were appropriate. No patients with stage 0 or I disease had metastases; only two patients (0.3%) with stage II and < or =3 positive lymph nodes had metastases. Conversely, 2.2, 2.6 and 3.8% of these groups had false-positive results. The incidence of occult metastases increased by stage, being present in 6, 13.9 and 57% of patients with stage II (> or =4 positive lymph nodes), III and IV disease, respectively. CONCLUSION: These results prompted us to propose new local guidelines for staging asymptomatic breast cancer patients: only clinical stage III or IV patients require baseline investigation. The high specificity and convenience of computed tomography (chest, abdomen and pelvis) led us to recommend this as the investigation of choice in breast cancer patients requiring radiological staging.

One-stop diagnostic breast clinics: how often are breast cancers missed?

The aim of this study was to estimate the number of patients discharged from a symptomatic breast clinic who subsequently develop breast cancer and to determine how many of these cancers had been 'missed' at initial assessment. Over a 3-year period, 7004 patients were discharged with a nonmalignant diagnosis. Twenty-nine patients were subsequently diagnosed with breast cancer over the next 36 months. This equates to a symptomatic 'interval' cancer rate of 4.1 per 1000 women in the 36 months after initial assessment (0.9 per 1000 women within 12 months, 2.6 per 1000 women within 24 months). The lowest sensitivity of initial assessment was seen in patients of 40-49 years of age, and these patients present the greatest imaging and diagnostic challenge. Following multidisciplinary review, a consensus was reached on whether a cancer had been missed or not. No delay occurred in 10 patients (35%) and probably no delay in 7 patients (24%). Possible delay occurred in three patients (10%) and definite delay in diagnosis (i.e., a 'missed' cancer) occurred in only nine patients (31%). The overall diagnostic accuracy of 'triple' assessment is 99.6% and the 'missed' cancer rate is 1.7 per 1000 women discharged.

Molecular characteristics of screen-detected vs symptomatic breast cancers and their impact on survival.

BACKGROUND: Several recent studies have shown that screen detection remains an independent prognostic factor after adjusting for disease stage at presentation. This study compares the molecular characteristics of screen-detected with symptomatic breast cancers to identify if differences in tumour biology may explain some of the survival benefit conferred by screen detection. METHODS: A total of 1379 women (aged 50-70 years) with invasive breast cancer from a large population-based case-control study were included in the analysis. Individual patient data included tumour size, grade, lymph node status, adjuvant therapy, mammographic screening status and mortality. Immunohistochemistry was performed on tumour samples using 11 primary antibodies to define five molecular subtypes. The effect of screen detection compared with symptomatic diagnosis on survival was estimated after adjustment for grade, nodal status, Nottingham Prognostic Index (NPI) and the molecular markers. RESULTS: Fifty-six per cent of the survival benefit associated with screen-detected breast cancer was accounted for by a shift in the NPI, a further 3-10% was explained by the biological variables and more than 30% of the effect remained unexplained. CONCLUSION: Currently known biomarkers remain limited in their ability to explain the heterogeneity of breast cancer fully. A more complete understanding of the biological profile of breast tumours will be necessary to assess the true impact of tumour biology on the improvement in survival seen with screen detection.

Use of ultrasound-guided axillary node core biopsy in staging of early breast cancer.

The aim of this study was to see how effective ultrasound-guided needle biopsy was at detecting lymph node involvement in patients with early breast cancer. Patients with newly diagnosed invasive breast cancer underwent axillary ultrasound (US) where lymph node size and morphology were noted. A core biopsy (CB) was undertaken of any node greater than 5 mm in longitudinal section. Patients with benign CBs proceeded to sentinel lymph node (SLN) biopsy, whereas those with malignancy underwent axillary lymph node dissection (ALND). US and CB findings were correlated with final surgical histology in all cases. One hundred and thirty-nine patients were examined, of whom 52.5% had lymph node metastases on final histology. One hundred and twenty-one patients (87%) underwent axillary node CB. The overall sensitivity of CB for detecting lymph node metastases was 53.4% (60.3% for macrometastases; 26.7% for micrometastases). The US morphological characteristics most strongly associated with malignancy were absence of a hilum and a cortical thickness greater than 4 mm. However, one third of patients with normal lymph node morphology had nodal metastases, and only 12% of these were diagnosed on CB. CB of axillary lymph nodes can diagnose a substantial number of patients with lymph node metastases, allowing these patients to proceed directly to ALND, avoiding unnecessary SLN biopsy.

Screen-detected vs symptomatic breast cancer: is improved survival due to stage migration alone?

This paper examines whether screen-detected breast cancer confers additional prognostic benefit to the patient, over and above that expected by any shift in stage at presentation. In all, 5604 women (aged 50-70 years) diagnosed with invasive breast cancer between 1998 and 2003 were identified by the Eastern Cancer Registration and Information Centre (ECRIC) and mammographic screening status was determined. Using proportional hazards regression, we estimated the effect of screen detection compared with symptomatic diagnosis on 5-year survival unadjusted, then adjusted for age and Nottingham Prognostic Index (NPI). A total of 72% of the survival benefit associated with screen-detected breast cancer can be accounted for by age and shift in NPI. Survival analysis by continuous NPI showed a small but systematic survival benefit for screen-detected cancers at each NPI value. These data show that although most of the screen-detected survival advantage is due to a shift in NPI, the mode of detection does impact on survival in patients with equivalent NPI scores. This residual survival benefit is small but significant, and is likely to be due to differences in tumour biology. Current prognostication tools may, therefore, overestimate the benefit of systemic treatments in screen-detected cancers and lead to overtreatment of these patients.

Combination of acellular dermal matrix with a de-epithelialised dermal flap during skin-reducing mastectomy and immediate breast reconstruction.

Introduction Patients with large ptotic breasts undergoing immediate implant-based reconstruction often require skin-reducing mastectomy to optimise the aesthetic outcome. However, healing complications, especially at the resulting inverted T-junction, leading to wound dehiscence, infection, skin necrosis, implant exposure and failed reconstruction have been widely reported. We present an innovative approach for immediate implant-based reconstruction combining porcine- or bovine-derived acellular dermal matrices with a de-epithelialised dermal sling to protect and support the implant, while improving clinical outcomes in this challenging group of patients. Materials and methods Demographic, tumour and surgical data were reviewed for patients undergoing Wise pattern (T-scar) skin-reducing mastectomies with immediate implant-based reconstruction combining porcine- or bovine-derived acellular dermal matrices with a de-epithelialised dermal sling. Results This technique was successfully employed to reconstruct five large pendulous breasts in four breast cancer patients with a median age of 50.5 years (range 34-61 years) who were not suitable for, or had declined, flap-based reconstruction. The acellular dermal matrices used were SurgiMend®, StratticeTM and Braxon® and the expandable implants were placed in the sub-pectoral (n = 3) and pre-pectoral (n = 1) planes. The technical steps and clinical outcomes are presented. One patient experienced T-junction breakdown overlying the de-epithelialised dermis without implant loss. Conclusion The combination of an acellular dermal matrix and a dermal sling provides a double-layer 'water-proofing' and support for the implants inferiorly, avoiding T-junction breakdown complications, since any dehiscence is on to well-vascularised dermis. Furthermore, the acellular dermal matrix stabilises the implant in the large mastectomy cavity (pocket control). This approach provides a viable option which facilitates mastectomy and immediate implant reconstruction in large-breasted patients.

P-glycoprotein expression is associated with sestamibi washout in primary hyperparathyroidism.

BACKGROUND: The detection of parathyroid adenomas by (99m)Tc-labelled hexakis 2-methoxyisobutyl isonitrile (sestamibi) scintigraphy is influenced by several factors, including tumour size and serum level of parathyroid hormone (PTH). This study examined the relationship between sestamibi accumulation and multidrug resistance (MDR)-related P-glycoprotein (P-gp) expression in a large series of surgically excised parathyroid tumours. METHODS: Seventy-eight patients underwent dual-phase sestamibi imaging before parathyroidectomy. Expression of P-gp within tumour cells was assessed by immunohistochemistry. Tumour size was measured and the ellipsoid volume calculated. Scan results were analysed in relation to preoperative serum levels of calcium and PTH, P-gp expression and tumour volume. RESULTS: Sixty-four of the 78 sestamibi scans were positive and 14 negative. Smaller adenomas (less than 0.5 cm(3)) were more likely to be sestamibi negative than larger lesions (P = 0.006). Ten of 14 adenomas with negative imaging showed strong P-gp membrane positivity and 45 of 64 lesions with a positive scan did not show P-gp membrane expression, indicating a significant association between high P-gp membrane immunoreactivity and negative sestamibi result (P = 0.006). CONCLUSION: These data suggest an association between P-gp membrane expression and false-negative sestamibi scan result. Inhibition of the P-gp transmembrane pump using MDR modulators may therefore improve the sensitivity of sestamibi scintigraphy.

Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial.

PURPOSE: To evaluate the effect of quinidine, a putative modulator of P-glycoprotein-mediated drug resistance, on the response rate and toxicity profile of epirubicin in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1989 and 1992, 223 eligible patients were randomized in double-blind fashion to receive epirubicin 100 mg/m2 by intravenous (i.v.) bolus and prednisolone 25 mg orally twice daily, along with either placebo or quinidine (250 mg) capsules, taken for 4 days before and 2 days after chemotherapy. Treatment was continued for a maximum of eight courses. RESULTS: Ten eligible patients did not complete the first cycle of treatment. Of the remaining patients, 106 in the placebo arm received 619 courses of treatment, and 107 in the quinidine arm received 612 courses. The median cumulative dose of epirubicin in both arms was 600 mg/m2. The median quinidine level (measured before epirubicin administration in 288 courses) was 5.5 mumol/L; at this concentration, the drug partially reverses anthracycline resistance in multidrug-resistant (MDR) breast carcinoma cells in vitro. There were no statistically significant differences in hematologic or gastrointestinal toxicity between the two arms. The response rate in the placebo arm was 44% (6% complete remission [CR], 38% partial remission [PR]), and in the quinidine arm was 43% (4% CR, 39% PR). Surviving patients have been monitored for a median time of 74 weeks, and there is no significant difference in the overall or progression-free survival between the two arms. The median survival times were 59 weeks for placebo and 47 weeks for quinidine patients. The estimated relative death rate (quinidine/placebo) was 1.2 (P = .247; 95% confidence interval [CI], 0.88 to 1.63). CONCLUSION: Quinidine at this dose does not significantly alter the toxicity profile, response rate, or survival after epirubicin chemotherapy in patients with advanced breast cancer. This may be due to ineffective modulation of P-glycoprotein by quinidine or the lack of expression of mdr-1 in a sufficient proportion of cells in these tumors, or alternative mechanisms underlying resistance to epirubicin.

Hormone receptor status in primary breast cancer--time for a consensus?

In a previous study, we demonstrated wide variability in the access to oestrogen receptor (ER) measurement, patient selection, choice of technique and the cut-off point for positivity. The aim of this study was to update information on the current use of ER and progesterone receptor (PR) measurement in the United Kingdom (UK). Questionnaires, asking about availability, use and technique of ER and PR measurement, were returned from 170 (74%) units in the UK. Where ER positivity was determined using the percentage of cells staining positive (33%), the absolute cut-off point for positivity varied widely from 5 to 80% of cells. Of the 170 responding units, 107 (63%) felt that PR measurement was important. This study confirms considerable variability in both the technique of ER measurement and the absolute cut-off point for positivity (5-80%). It is essential that a consensus be reached regarding the choice of technique, as well as the threshold for positivity.

Adequate tumour quinidine levels for multidrug resistance modulation can be achieved in vivo.

The multidrug resistance (MDR) phenotype can be reversed in vitro by a number of agents thought to interact with P-glycoprotein (P-gp). Although plasma levels, adequate for MDR modulation, can be achieved with certain modulators, concern has been expressed that tumour levels may be inadequate due to high plasma protein binding. Mice bearing an MDR-positive human tumour xenograft were injected intraperitoneally with quinidine (150 mg/kg). After 2 h the mean plasma quinidine level was 1.9 micrograms/ml (5.1 mumol/l) and the mean tumour quinidine effective in vitro. Three tumour biopsy specimens were obtained from patients who had received oral quinidine prior to surgery. Plasma and tumour levels were similar and were comparable with those measured in mice. This study should dispel fears of inadequate tumour levels of this and other modulators due to high plasma protein binding and encourage future clinical trials of modulators in MDR-positive human tumours.

Co-amplification of erbB2, topoisomerase II alpha and retinoic acid receptor alpha genes in breast cancer and allelic loss at topoisomerase I on chromosome 20.

The DNA topoisomerase enzymes are targets for the cytotoxic effects of a number of anticancer agents termed topoisomerase inhibitors. We have analysed breast cancer biopsy specimens for genetic alterations at and around topoisomerase loci in order to obtain molecular insight into factors which may determine how tumours respond to chemotherapy. We show that of 50 tumours examined, the topoisomerase II alpha locus is co-amplified in 3 cases out of 6 with erbB2 amplification and that amplification can be accompanied by high expression of topoisomerase II alpha. In our attempts to distinguish amplification from aneuploidy and define the limits of amplification, we also observed co-amplification of the retinoic acid-alpha receptor with erbB2 and topoisomerase II alpha in the same three samples. At the topoisomerase I locus on chromosome 20, we observed allelic loss in two out of 17 samples. Genetics abberations at topoisomerase loci, therefore, appear to be relatively common in breast cancer.

Identification of a multidrug resistance modulator with clinical potential by analysis of synergistic activity in vitro, toxicity in vivo and growth delay in a solid human tumour xenograft.

Circumvention of multidrug resistance in vitro by resistance modulators is well documented but their clinical use may be limited by effects on normal tissues. We have compared four resistance modifiers, both in terms of modulation of doxorubicin sensitivity in vitro and toxicity in vivo, in order to determine whether it is possible to select agents with clinical potential. Verapamil, D-verapamil and quinidine are all maximally active in the multidrug resistant cell line at about 7 microM and are not cytotoxic at this concentration. The tiapamil analogue Ro11-2933 is a highly potent resistance modulator such that at only 2 microM sensitization is greater than is seen with the other modulators at 7 microM. Since the ID50 concentration for Ro11-2933 is 17.7 microM (5-12-fold less than the other modifiers) we have used isobologram analysis to demonstrate that the interaction with doxorubicin is supra-additive and cannot be explained by additive toxicity. This method of analysis also revealed that when resistance modulation is related to the cytotoxicity of the modulator itself, all four modulators show comparable activity. On the other hand, measurement of the acute toxicity in mice of the modulators did reveal differences. The LD10 for verapamil (51 mg/kg) was about one third of that for quinidine (185 mg/kg) and this is consistent with the known maximum tolerated plasma levels in patients. Furthermore, whilst epirubicin alone was unable to reduce the growth rate of a multidrug resistant human tumour xenograft, the addition of quinidine, but not verapamil, at the maximum tolerated dose did do so. D-Verapamil was only about half as toxic as racemic verapamil and this too is consistent with clinical observations. The LD10 for Ro11-2933 (152 mg/kg) was comparable with that for quinidine. In the human tumour xenograft model maximal growth inhibition was observed with the combination of epirubicin and Ro11-2933 (45 mg/kg) and this degree of growth inhibition was comparable to that obtained with epirubicin alone in the drug sensitive xerografts. Ro11-2933 had no measurable effects on the plasma or tumour pharmacokinetics of epirubicin. These results suggest that it is possible to predict the clinical potential of a resistance modulator. Furthermore, Ro11-2933 is a promising agent for use in the clinic since maximal resistance modulation in vivo is observed at about one third of the LD10 dose.