Simon Cawthorn

First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial.

BACKGROUND Three clinical trials on the use of tamoxifen to prevent breast cancer have reported mixed results. The overall evidence supports a reduction in the risk of breast cancer, but whether this benefit outweighs the risks and side-effects associated with tamoxifen is unclear. METHODS We undertook a double-blind placebo-controlled randomised trial of tamoxifen, 20 mg/day for 5 years, in 7152 women aged 35-70 years, who were at increased risk of breast cancer. The primary outcome measure was the frequency of breast cancer (including ductal carcinoma in situ). Analyses were by intention to treat after exclusion of 13 women found to have breast cancer at baseline mammography. FINDINGS After median follow-up of 50 months (IQR 32-67), 69 breast cancers had been diagnosed in 3578 women in the tamoxifen group and 101 in 3566 in the placebo group (risk reduction 32% [95% CI 8-50]; p=0.013). Age, degree of risk, and use of hormone-replacement therapy did not affect the reduction. Endometrial cancer was non-significantly increased (11 vs 5; p=0.2) and thromboembolic events were significantly increased with tamoxifen (43 vs 17; odds ratio 2.5 [1.5-4.4], p=0.001), particularly after surgery. There was a significant excess of deaths from all causes in the tamoxifen group (25 vs 11, p=0.028). INTERPRETATION Prophylactic tamoxifen reduces the risk of breast cancer by about a third. Temporary cessation of tamoxifen should be considered and the use of appropriate antithrombotic measures is recommended during and after major surgery or periods of immobilisation. Prophylactic use of tamoxifen is contraindicated in women at high risk of thromboembolic disease. The combined evidence indicates that mortality from non-breast-cancer causes is not increased by tamoxifen. The overall risk to benefit ratio for the use of tamoxifen in prevention is still unclear, and continued follow-up of the current trials is essential.

Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study

BACKGROUND Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. METHODS Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2-3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website . FINDINGS Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm(3) (2.7%; 95% CI 2.0-3.4; p<0.0001) at the lumbar spine and 0.025 g/cm(3) (1.4%; 0.8-1.9; p<0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; p=0.002) and 0.8% (0.3-1.4; p=0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0.001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13-1.87]; p=0.003). INTERPRETATION These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial

BACKGROUND Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. METHODS Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40-70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. FINDINGS 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0-7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32-0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836). INTERPRETATION Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. FUNDING Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.

Tamoxifen-Induced Reduction in Mammographic Density and Breast Cancer Risk Reduction: A Nested Case–Control Study

BACKGROUND Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug. METHODS We conducted a nested case-control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12-18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided. RESULTS In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction. CONCLUSION The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.

The psychological effect of mastectomy with or without breast reconstruction: A prospective, multicenter study

&NA; A multicenter, prospective study (n = 103) examined the psychological implications of womens decisions for or against breast reconstruction. Recognized measures of anxiety, depression, body image, and quality of life were completed before the operation, and 6 and 12 months later. A reduction in psychological distress over the year following the operation was evident in each surgical group (mastectomy alone or immediate or delayed reconstruction). indicating that reconstructive surgery can offer psychological benefits to some women: however, others report improved psychological functioning without this surgical procedure. In contrast to existing retrospective research, the prospective design enabled the process of adjustment during the first year after the operation to be examined. The results indicate that breast reconstruction is not a universal panacea for the emotional and psychological consequences of mastectomy. Women still reported feeling conscious of altered body image 1 year postoperatively, regardless of whether or not they had elected breast reconstruction. Health professionals should be careful of assuming that breast reconstruction necessarily confers psychological benefits compared with mastectomy alone.

Referral patterns, cancer diagnoses, and waiting times after introduction of two week wait rule for breast cancer: prospective cohort study.

Objective To investigate the long term impact of the two week wait rule for breast cancer on referral patterns, cancer diagnoses, and waiting times. Design Prospective cohort study. Setting A specialist breast clinic in a teaching hospital in Bristol. Participants All patients referred to breast clinic from primary care between 1999 and 2005. Main outcome measures Number, route, and outcome of referrals from primary care and waiting times for urgent and routine appointments. Results The annual number of referrals increased by 9% over the seven years from 3499 in 1999 to 3821 in 2005. Routine referrals decreased by 24% (from 1748 to 1331), but two week wait referrals increased by 42% (from 1751 to 2490) during this time. The percentage of patients diagnosed with cancer in the two week wait group decreased from 12.8% (224/1751) in 1999 to 7.7% (191/2490) in 2005 (P<0.001), while the number of cancers detected in the “routine” group increased from 2.5% (43/1748) to 5.3% (70/1331) (P<0.001) over the same period. About 27% (70/261) of people with cancer are currently referred in the non-urgent group. Waiting times for routine referrals have increased with time. Conclusion The two week wait rule for breast cancer is failing patients. The number of cancers detected in the two week wait population is decreasing, and an unacceptable proportion is now being referred via the routine route. If breast cancer services are to be improved, the two week wait rule should be reviewed urgently.

Reporting Clinical Outcomes of Breast Reconstruction: A Systematic Review

BACKGROUND Breast reconstruction after mastectomy for cancer requires accurate evaluation to inform evidence-based participatory decision making, but the standards of outcome reporting after breast reconstruction have not previously been considered. METHODS We used extensive searches to identify articles reporting surgical outcomes of breast reconstruction. We extracted data using published criteria for complication reporting modified to reflect reconstructive practice. Study designs included randomized controlled trials, cohort studies, and case series. The Cochrane Risk of Bias tool was used to critically appraise all study designs. Other criteria used to assess the studies were selection and funding bias, statistical power calculations, and institutional review board approval. Wilcoxon signed rank tests were used to compare the breadth and frequency of study outcomes, and χ² tests were used to compare the number of studies in each group reporting each of the published criteria. All statistical tests were two-sided. RESULTS Surgical complications following breast reconstruction in 42,146 women were evaluated in 134 studies. These included 11 (8.2%) randomized trials, 74 (55.2%) cohort studies, and 49 (36.6%) case series. Fifty-three percent of studies demonstrated a disparity between methods and results in the numbers of complications reported. Complications were defined by 87 (64.9%) studies and graded by 78 (58.2%). Details such as the duration of follow-up and risk factors for adverse outcomes were omitted from 47 (35.1%) and 58 (43.3%) studies, respectively. Overall, the studies defined fewer than 20% of the complications they reported, and the definitions were largely inconsistent. CONCLUSIONS The results of this systematic review suggest that outcome reporting in breast reconstruction is inconsistent and lacks methodological rigor. The development of a standardized core outcome set is recommended to improve outcome reporting in breast reconstruction.

Use of briefings and debriefings as a tool in improving team work, efficiency, and communication in the operating theatre

Introduction Team work, communication, and efficiency in the operating theatre are widely recognised to be suboptimal. Poor communication is the single biggest cause of medical error. The surgical operating theatre is a potentially highly stressed environment where poor communication can lead to fatal errors. The objectives of this study were to assess the effects briefings and debriefings had on theatre start time, list lengths, and the staffs impression of these meetings. Materials and methods Briefings and debriefings were conducted before the start of theatre lists over a 6 month period in 2007 in a district general hospital in north Bristol, UK. Both quantitative and qualitative data were collected. Using the hospital theatre database, theatre start and finish time was found and list length calculated. A questionnaire was devised and used to assess staff attitude to the briefings and debriefings. Results Staff felt that the briefings highlighted potential problems, improved the team culture, and led to organisational change. Theatre start times tended to be earlier and lists lengths were shorter when briefings were conducted, although this only reached statistical significance on one type of list. Discussion Briefings and debriefings had a positive impact on teamwork and communication. The lists ran more efficiently and briefings did not delay the theatre start times—in fact, the lists tended to start earlier.

Evaluation of a one-stop breast lump clinic: a randomized controlled trial

S U M MA R Y. This randomized controlled trial compared the impact on patients (n = 791) of a one-stop clinic providing same-day diagnosis with a conventional system involving two appointments and a delay before results are available. Semi-structured interviews at first clinic attendance and postal questionnaires completed 6 days and 8 weeks later assessed psychological reactions. Six days after first clinic attendance the one-stop group showed significantly lower levels of anxiety (P < 0.05). However, the sub-group who had breast cancer had become more distressed in both groups, more so in the one-stop group. Eight weeks later, women receiving a speedier diagnosis of cancer reported higher levels of depression than women given this diagnosis in the two-stop system (P < 0.05). Same-day diagnosis appears to reduce psychological distress for the 90% of clinic attenders diagnosed with a benign lump. Nevertheless, it may have a detrimental effect on women diagnosed with cancer. The psychological care of these women needs particular consideration as the availability of same-day diagnosis increases.

Evaluation of a novel breast reconstruction technique using the Braxon(®) acellular dermal matrix: a new muscle-sparing breast reconstruction.

Implant‐based breast reconstruction is becoming increasingly popular because of the widespread adoption of acellular dermal matrix (ADM), which allows surgeons to obtain good aesthetic results with fewer operations. To develop more conservative surgical techniques, a retrospective, three‐centre, proof‐of‐concept study was performed to study the effectiveness of a new, immediate, muscle‐sparing breast reconstruction technique using the patented Braxon® ADM, which enables subcutaneous positioning of the breast implant without detaching the pectoralis major.