H Hamed

Risk reducing mastectomy: outcomes in 10 European centres

Background: Increasingly women at high risk of breast cancer are opting for risk reducing surgery. The aim of this study was to assess the effectiveness of this approach in women at high risk in both carriers and non-carriers of BRCA1/2. Methods: Data from 10 European centres that offer a genetic counselling and screening service to women at risk were obtained prospectively from 1995. Breast cancer risks were estimated from life tables and a control group of women at risk who did not undergo surgery. Results: The combined centres have data on 550 women who have undergone risk reducing mastectomy with greater than 3334 women years of follow-up. Operations were carried out on women with lifetime risks of 25–80%, with an average expected incidence rate of 1% per year. No breast cancers have occurred in this cohort in the “at risk” unaffected breast, whereas >34 would have been expected. A high rate (2–3.6%) of occult disease was identified in the at risk breast at the time of surgery. Interpretation: We conclude that risk reducing surgery is highly effective.

Intraoperative assessment of tumor resection margins in breast-conserving surgery using 18F-FDG cerenkov luminescence imaging: A first-in-human feasibility study

In early-stage breast cancer, the primary treatment option for most women is breast-conserving surgery (BCS). There is a clear need for more accurate techniques to assess resection margins intraoperatively, because on average 20% of patients require further surgery to achieve clear margins. Cerenkov luminescence imaging (CLI) combines optical and molecular imaging by detecting light emitted by 18F-FDG. Its high-resolution and small size imaging equipment make CLI a promising technology for intraoperative margin assessment. A first-in-human study was conducted to evaluate the feasibility of 18F-FDG CLI for intraoperative assessment of tumor margins in BCS. Methods: Twenty-two patients with invasive breast cancer received 18F-FDG (5 MBq/kg) 45–60 min before surgery. Sentinel lymph node biopsy was performed using an increased 99mTc-nanocolloid activity of 150 MBq to facilitate nodal detection against the γ-probe background signal (cross-talk) from 18F-FDG. The cross-talk and 99mTc dose required was evaluated in 2 lead-in studies. Immediately after excision, specimens were imaged intraoperatively in an investigational CLI system. The first 10 patients were used to optimize the imaging protocol; the remaining 12 patients were included in the analysis dataset. Cerenkov luminescence images from incised BCS specimens were analyzed postoperatively by 2 surgeons blinded to the histopathology results, and mean radiance and margin distance were measured. The agreement between margin distance on CLI and histopathology was assessed. Radiation doses to staff were measured. Results: Ten of the 12 patients had an elevated tumor radiance on CLI. Mean radiance and tumor-to-background ratio were 560 ± 160 photons/s/cm2/sr and 2.41 ± 0.54, respectively. All 15 assessable margins were clear on CLI and histopathology. The agreement in margin distance and interrater agreement was good (κ = 0.81 and 0.912, respectively). Sentinel lymph nodes were successfully detected in all patients. The radiation dose to staff was low; surgeons received a mean dose of 34 ± 15 μSv per procedure. Conclusion: Intraoperative 18F-FDG CLI is a promising, low-risk technique for intraoperative assessment of tumor margins in BCS. A randomized controlled trial will evaluate the impact of this technique on reexcision rates.

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study

Summary Background Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. Methods We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. Findings Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5–98·4] vs 96·6% [95·8–97·3]; at 5 years: 83·8% [79·3–87·5] vs 85·0% [83·5–86·4]; at 10 years: 73·4% [67·4–78·5] vs 70·1% [67·7–72·3]; hazard ratio [HR] 0·96 [95% CI 0·76–1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89–97] vs 91% [88–94]; HR 0·59 [95% CI 0·35–0·99]; p=0·047) but not 5 years (81% [73–87] vs 74% [70–78]; HR 1·13 [0·70–1·84]; p=0·62) or 10 years (72% [62–80] vs 69% [63–74]; HR 2·12 [0·82–5·49]; p= 0·12). Interpretation Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. Funding Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

PSYCHOSOCIAL ADJUSTMENT OF WOMEN WITH MASTALGIA

Abstract Psychosocial adjustment of 54 women with mastalgia referred to a breast unit has been assessed using standardized interviews and questionnaires. Patients with severe mastalgia (n = 33) experienced significantly more depression, anxiety and social dysfunction than those with non-severe mastalgia (n = 21). The levels of anxiety and depression observed among patients with severe mastalgia were similar to those of a group of patients with operable breast cancer on the morning of their operation (n = 32). 29 of the patients with severe mastalgia, who were treated with the GnRH analogue, goserelin (3.6 mg given monthly for 6 courses), underwent further psychosocial assessment after treatment. Patients experiencing severe pain 10 months after starting treatment showed no improvement in their psychosocial functioning. Levels of depression and social impairment were statistically significantly improved among those patients who had pain reduction. Their levels of anxiety also improved, but remained high after treatment and were similar to those in women who were still experiencing severe pain. Both psychosocial and physical needs of patients with severe mastalgia must be addressed as part of an effective and comprehensive management approach.

Paget's disease of the nipple: A multi-focal manifestation of higher risk disease

BACKGROUND The treatment of Paget disease by mastectomy has been challenged recently in favor of breast-conserving techniques. A large series of patients treated with mastectomy has been reviewed to assess the feasibility of less radical surgery. METHODS The cases of 70 women with a clinical diagnosis of Paget disease were reviewed. The type, grade, receptor and node status, and the mammographic and pathologic extent of the underlying breast malignancy were determined. The survival of patients with invasive disease was compared with matched controls without Paget disease. RESULTS The underlying malignancy was invasive in 58% of cases. Despite the fact that only one third of women presented with a palpable mass, the malignancy was frequently extensive, being confined to the retroareolar region in only 25% of cases. The true extent of the disease was underestimated by mammography in 43% of cases. Of the patients with ductal in situ carcinoma, 96.5% had high-grade carcinomas and 100% had invasive carcinomas of high cytonuclear grade. Overexpression of the c-erb-B2 oncogene was detectable in 83% of cases. Patients with Paget disease had a significantly worse survival than matched controls, but this difference was eliminated if they were also matched for c-erb-B2 status. CONCLUSIONS Paget disease is often associated with extensive underlying malignancy, which is difficult to assess accurately either clinically or mammographically. As a consequence, cone excision of the nipple would have resulted in incomplete excision in 75% of cases. The underlying disease is of high grade and is frequently c-erb-B2 positive with a resulting poor prognosis. Aggressive local and systemic treatment would seem to be merited.