Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

Breast-conserving surgery with intra-operative radiotherapy: the right approach for the 21st century?

Wide local excision followed by external beam radiation therapy (EBRT) to the whole breast has become the standard of care for most patients with localised 'early' breast cancer in the UK, Europe, and the USA. Local relapse rates are low, and overall survival figures have improved during the past decade, with the advent of more effective systemic endocrine- and chemo-therapy. A policy of EBRT for every patient undergoing breast conserving surgery (BCS) is however associated with a number of practical difficulties, acute radiation side effects and longer term toxicity, all of which detract from the obvious benefits of EBRT. In addition, with a disease as common as early breast cancer and a treatment programme typically requiring sophisticated radiation planning and many fractions of treatment, the policy of BCS plus EBRT has enormous resource implications within departments of oncology, greatly contributing to lengthy pre-treatment delays. For all these reasons, we and others have developed an increasing interest in techniques of partial breast irradiation, with an emphasis in our own Department on the emerging technique of intra-operative radiotherapy (IORT), which we initially employed as a boost to the tumour bed for use in conjunction with EBRT to the whole breast. To test the possibility of replacing the whole of the EBRT 3-6 week programme by a single application of IORT at the time of surgery, we and others have commenced a large scale prospectively randomised clinical trail in selected patients. Nine international centres are currently participating, and 350 patients have now been randomised to receive either IORT as part of the initial surgical excision or conventional EBRT with a pragmatic dose policy according to the preference of the contributing centre. The majority of patients undergoing IORT receive this at the time of initial surgery but it is also permissible within the trial programme to randomise suitable patients after the excised specimen has been histologically examined, thus avoiding any unsuitable patients - for example, those with a lobular carcinoma. These patients will be stratified and assessed separately from the 'pre-pathology' group, whose surgery and IORT is completed within a single session; if the latter patients are found to have unfavourable histology we have the facility, within the trial, to add EBRT. The trial is ongoing and our early experience has been encouraging. We have also recently assessed the long term local failure rate in patients offered IORT as a tumour bed boost, in conjunction with conventional EBRT. This methodology will also be the subject of a future randomised clinical trial.

Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway.

In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF-EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation.

Prediction of nipple and areola involvement in breast cancer.

AIMS: To find a pre-operative test for nipple and areola involvement in breast cancer. METHODS: Areola-tumour distance was measured in 140 consecutive patients (median age 45, range: 23-83) undergoing a mastectomy. We analysed whether nipple and areola correlated with areola-tumour distance, tumour size, nodal status, perinodal involvement and lymphatic embolization. RESULTS: The nipple was involved in 22 (16%) cases and this correlated with tumour size, number of lymph nodes, perinodal extension and presence of lymphatic emboli. In all these 22 cases, the tumour was within 2.5 cm of the areola. Tumour size, however, could not predict nipple involvement in tumours within 2.5 cm of the areolar edge. CONCLUSIONS: In the one-fifth of cases where the tumour is over 2.5 cm from the areola, preserving the nipple and areola for reconstruction may be worthwhile. In remaining cases, some other predictive test for nipple involvement would be necessary.

Role of ultrasonography to detect axillary node involvement in operable breast cancer.

Prompted by the concern about unnecessary axillary dissections, we prospectively studied the accuracy of clinical examination (CE) and conventional ultrasonography (USG, 7.5 MHz), to diagnose pre-operatively metastatic axillary lymph nodes in 200 operable breast cancer patients. USG had higher specificity (90% vs 77%, P = 0.025) and higher positive predictive value (ppv = 90% vs 76%, P = 0.02) than CE. Together, CE + USG had higher sensitivity (82% vs 58%, P = 0.00005) and higher negative predictive value (npv = 76% vs 58%, P = 0.008) than CE alone. In women < 45 years, CE + USG had higher sensitivity (91% vs 76%, P = 0.037) and npv (89% vs 67%, P = 0.018) than in older women. The sensitivity and npv of CE + USG to detect > 1 positive node were 97% (for both) in women < 45 years compared to 81% and 79% in older women. The high sensitivity of CE + USG (82% for the whole group) is probably due to the higher proportion of young women (median age = 45) in our population. It suggests that using CE + USG to avoid axillary dissection in some patients is feasible.

Influence of lateral posture on sweating: does posture alter the sympathetic outflow to the sweat glands?

Our unpublished observation that a lateral decubitus posture influences the pattern of sweating was systematically tested by measuring galvanic skin resistance (GSR). Changes in the GSR between two electrodes placed on skin was used to quantify the degree of sweating. In the lateral posture, sweating is inhibited on the lower half and stimulated on the upper half and reversal of the lateral posture induces sweating on the opposite half of the body. This observation suggests that the autonomic nervous system is controlled at least in part, by body posture.