John R Benson

Early breast cancer

Adoption of urbanised lifestyles together with changes in reproductive behaviour might partly underlie the continued rise in worldwide incidence of breast cancer. Widespread mammographic screening and effective systemic therapies have led to a stage shift at presentation and mortality reductions in the past two decades. Loco-regional control of the disease seems to affect long-term survival, and attention to surgical margins together with improved radiotherapy techniques could further contribute to mortality gains. Developments in oncoplastic surgery and partial-breast reconstruction have improved cosmetic outcomes after breast-conservation surgery. Optimum approaches for delivering chest-wall radiotherapy in the context of immediate breast reconstruction present special challenges. Accurate methods for intraoperative assessment of sentinel lymph nodes remain a clinical priority. Clinical trials are investigating combinatorial therapies that use novel agents targeting growth factor receptors, signal transduction pathways, and tumour angiogenesis. Gene-expression profiling offers the potential to provide accurate prognostic and predictive information, with selection of best possible therapy for individuals and avoidance of overtreatment and undertreatment of patients with conventional chemotherapy. Short-term presurgical studies in the neoadjuvant setting allow monitoring of proliferative indices, and changes in gene-expression patterns can be predictive of response to therapies and long-term outcome.

The global breast cancer burden.

Breast cancer now represents the most common female malignancy in both the developing and developed world, and is the primary cause of death among women globally. Despite well-documented reductions in mortality from breast cancer during the past two decades, incidence rates continue to increase and do so more rapidly in countries that historically had low rates. This has emphasized the importance of survivorship issues and optimal management of disease chronicity. This article reviews current trends of incidence and mortality in both a western and global context, and considers pertinent changes in underlying etiological risk factors. The latter not only offer clues regarding changes in incidence patterns, but also provides rationale and guidance for strategies that could potentially reduce the burden of this disease. The relevance of lifestyle adjustments and screening interventions for primary and secondary prevention, respectively, are discussed with reference to different healthcare resource settings.

Can breast MRI help in the management of women with breast cancer treated by neoadjuvant chemotherapy

Contrast-enhanced (CE) MRI was used to monitor breast cancer response to neoadjuvant chemotherapy. Patients underwent CE MRI before and after therapy, together with conventional assessment methods (CAM). CE MRI was carried out at 1.5 T in the coronal plain with 3D sequences before and after bolus injection. An expert panel determined chemotherapy response using both CE MRI and CAM. Histopathological response in the surgical specimen was then used to determine the sensitivity and specificity of CE MRI and CAM. In total, 67 patients with 69 breast cancers were studied (mean age of 46 years). Tumour characteristics showed a high-risk tumour population: median size 49 mm: histopathological grade 3 (55%): oestrogen receptor (ER) negative (48%). Histopathological response was as follows: – complete pathological response (pCR) 17%; partial response (pPR) 68%; no response (NR) 15%. Sensitivity of CAM for pCR or pPR was 98% (CI 91–100%) and specificity was 50% (CI 19–81%). CE MRI sensitivity was 100% (CI 94–100%), and specificity was 80% (CI 44–97%). The absolute agreement between assessment methods and histopathology was marginally higher for CE MRI than CAM (81 vs 68%; P=0.09). In 71%, CE MRI increased diagnostic knowledge, although in 20% it was judged confusing or incorrect. The 2nd MRI study significantly increased diagnostic confidence, and in 19% could have changed the treatment plan. CE MRI persistently underestimated minimal residual disease. In conclusion, CE MRI of breast cancer proved more reliable for predicting histopathological response to neoadjuvant chemotherapy than conventional assessment methods.

Alternative mechanisms of action of anti-oestrogens

SummaryThe molecular mechanism of action of anti-oestrogens such as tamoxifen appears to be a complex mixture of antagonism of the mitogenic action of oestradiol at the level of the oestrogen receptor, plus a range of other activities from enzyme inhibition to growth factor modulation. This article will concentrate on two specific areas: 1) the inhibition of protein kinase C and calmodulin-dependent cAMP phosphodiesterase; and 2) the regulation by tamoxifen of peptide regulators of breast cancer epithelial cell growth such as insulin-like growth factor I (IGF I) and transforming growth factor beta (TGF-β). The elucidation of these mechanisms is potentially important in the treatment and chemoprevention of breast cancer — the quantitative contribution of each individual mechanism of the overall antineoplastic action of anti-oestrogens is central to developing new and possibly more effective anti-oestrogens and optimizing strategies for their use.

A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer

BACKGROUND There is now increasing evidence to support the use of indocyanine green (ICG) for sentinel lymph node (SLN) detection in early breast cancer. The primary objective of this feasibility study (ICG-10) was to determine the sensitivity and safety of ICG fluorescence imaging in sentinel lymph node identification when combined with blue dye and radiocolloid. METHODS One hundred women with clinically node negative breast cancer (95 unilateral; 5 bilateral) had sentinel lymph node (SLN) biopsy using blue dye, radioisotope and ICG. One patient was excluded from analysis and sensitivity, or detection rate, of ICG alone, and in combination with blue dye and/or radioisotope, was calculated for the remaining 104 procedures in 99 patients. RESULTS Transcutaneous fluorescent lymphography was visible in all 104 procedures. All 202 true SLNs, defined as blue and/or radioactive, were also fluorescent with ICG. Detection rates were: ICG alone 100%, ICG & blue dye 95.0%, ICG & radioisotope 77.2%, ICG & blue dye & radioisotope 73.1%. Metastases were found in 25 of 201 SLNs (12.4%) and all positive nodes were fluorescent, blue and radioactive. The procedural node positivity rate was 17.3%. CONCLUSION The results of this study confirm the high sensitivity of ICG fluorescence for SLN detection in early breast cancer. The combination of ICG and blue dye had the highest nodal sensitivity at 95.0% defining a dual approach to SLN biopsy that avoids the need for radioisotope.

Management of the axilla in women with breast cancer.

The approach towards axillary surgery should be selective and flexible, with its management tailored to patient choice and tumour characteristics, and concordant with local practice guidelines and available resources. Sentinel-lymph-node biopsy has been embraced as a standard of care in many centres around the world and has revolutionised management of the axilla during the past decade. Nonetheless, data for long-term outcomes remain scarce, and there are persistent variations in practice and inconsistencies in methodology. An international perspective has been sought on important issues relating to management of the axilla, which includes not only the indications and techniques for sentinel-lymph-node biopsy, but also lymph-node sampling, axillary-lymph-node dissection, and observation alone. In this Review, we initially present an overview, which focuses on biological models of lymphatic networks within the breast and patterns of tumour dissemination. A set of key questions are posed with preliminary comments from the authors, followed by a series of collective viewpoints from experts within several different countries.

A systematic review of the clinical evidence to guide treatment recommendations in breast reconstruction based on patient- reported outcome measures and health-related quality of life.

Background: Advances in breast cancer diagnosis and management have produced significant improvements in disease-free and breast cancer related survival. Consequently, there is increasing focus on the quality of long-term cancer survivorship. Of the 44,000 women diagnosed annually in the United Kingdom, 30% to 40% are required to undergo mastectomy. During the past 30years, significant technical advances in breast reconstruction have increased performance of this surgical practice as a means to potentially improve health-related quality of life (HRQoL) for breast cancer survivors. Breast reconstruction studies increasingly aim to assess more discriminating outcomes based on the patients’ own perception of the surgical result and its effect on HRQoL. This incremental output in HRQoL evaluation is being fuelled by both healthcare providers and official bodies such as the Food and Drug Administration, together with demands for more comprehensive comparative effectiveness data to permit fully informed consent by patients. Methods: In this systematic review, the authors apply inclusion and exclusion criteria to effectively screen 1012 abstracts identified in the field of HRQoL in breast reconstruction between 1978 and 2009. Each study was evaluated with respect to its design and statistical methodology. Each was reviewed with a recommended standard checklist of methodological requirements as described by Efficace et al (J Clin Oncol. 2003;21:3502–3511). Results: A total of 34 papers that included HRQL outcomes in breast reconstruction were identified and reviewed in detail. The majority of studies were retrospective in nature with significant inherent limitations. Specifically, they were compromised by potentially biased patient recall. Most of these studies lacked both an a priori outcome of interest and statistical rigor jeopardizing estimations of potential effect size. In addition, more than 90% of the studies failed to report or describe missing data. Thirteen studies provided level I (n = 2) and II (n = 11) evidence. While these studies benefited from more robust design, the majority used generic instruments such as 36-item short form (SF-36), which may not be sufficiently sensitive to measure changes consequent to breast reconstruction (ie, effect on body image or psychosocial well-being). Furthermore, these studies were generally underpowered to detect meaningful clinical difference or to permit subgroup analyses. Further limitations included reliance on single center design that may negatively impact generalizability and deficiencies in reporting the number and types of surgical complications, which potentially has an effect on HRQoL outcomes. Conclusions: This systematic review reveals tendency for sound scientific methodology in HRQoL to be undermined by poorly designed and underpowered studies. In the current healthcare environment, patients and providers increasingly seek meaningful data to guide clinical decisions; policy makers are similarly in need of a rigorous patient-centered, comparative effectiveness data to inform national level decision-making. In light of this and the limitations of the existing published data, there is a pressing need for further Level I and II evidence in the form of randomized controlled trials as well as well-designed, multicenter prospective longitudinal studies in breast reconstruction. Such studies should incorporate sensitive and condition–specific patient-report outcome measures, provide adequate sample sizes, and respect established guidelines for rigorous HRQoL methodology.

Titanium clip placement to allow accurate tumour bed localisation following breast conserving surgery – Audit on behalf of the IMPORT Trial Management Group

INTRODUCTION Accurate tumour bed (TB) localisation is a key requirement for the UK IMPORT (Intensity Modulated Partial Organ Radiotherapy) trial. We audited the value of titanium clips for TB localisation following breast conserving surgery (BCS) in breast radiotherapy (RT) planning. PATIENTS AND METHODS At surgery, paired clips were positioned around the TB as follows: 1. Medial, lateral, superior and inferior: half-way between skin and fascia; 2. Posterior: at the pectoral fascia; 3. Anterior: close to the suture line. Thirty consecutive patients with clips inserted were audited at the time of RT planning. Audit standards were set as follows: (i) 5/6 pairs of clips identified on RT planning computed tomography (CT) scan - 100%; (ii) possible clip migration: <10%; (iii) TB localisation improved with clips: >50%. Inter- and intra-observer variability in clinician outlining of the TB was studied in a subset of 12 randomly selected patients to see if this impacted on positioning of radiotherapy field borders. RESULTS Five or six pairs of clips were identified in all 30 cases. The TB could be successfully identified using CT seroma alone in only 8/30 (27%) patients. Clips were essential for the TB localisation of the other 22/30 (73%) patients. There was no evidence of clip migration. TB localisation led to modified RT field borders in 18/30 (60%) patients. Five of these patients had highly visible seromas, so the addition of clips modified field borders in 13/30 (43%) patients. Both inter- and intra-observer variability was reasonable and did not impact on positioning of radiotherapy field borders. CONCLUSION Titanium clips provide an accurate and reliable method of TB localisation following BCS. We anticipate that the audit results will lead to clips being adopted as best practice by the Association of Breast Surgeons (ABS) at BASO (British Association of Surgical Oncology).

Predictors of recurrence for ductal carcinoma in situ after breast-conserving surgery

Ductal carcinoma in situ (DCIS) constitutes a major public health problem, with up to half of screen-detected cancers representing pure forms of DCIS without evidence of invasion. A proportion of cases detected with routine screening would not have progressed to a life-threatening form of breast cancer during the patients lifetime, and overdiagnosis of breast cancer is a cause for concern. Once DCIS has been detected, treatment is obligatory and present technologies do not allow accurate risk stratification such that intensity of treatment can be tailored to risk of recurrence and progression to invasive disease. Present management strategies are based on prognostic and predictive information derived from conventional histopathological and host factors. With increasing molecular characterisation of these preinvasive lesions, data will be available for how factors such as oestrogen receptor, progesterone receptor, HER2, and indicators of proliferative activity can provide additional information about both prognosis and benefit from adjuvant treatments such as radiotherapy and hormonal therapy. Low-risk patients are especially poorly defined in terms of need for adjuvant therapies, which can be associated with both short-term adverse sequelae and long-term effects (eg, cardiotoxicity) that can affect all-cause mortality. Optimum risk prediction in the future is likely to be achieved by integration of both conventional and molecular factors, which should be incorporated into a validated predictive model to help with clinical decision making.

Ultrasound guided percutaneous axillary lymph node core biopsy: how often is the sentinel lymph node being biopsied?

Patients with breast cancer now frequently undergo axillary ultrasound and core biopsy (CB) in an attempt to reduce the number of unnecessary sentinel lymph node (SLN) biopsies. This study aimed to establish the frequency of successful targeting of the SLN by ultrasound guided biopsy. A total of 137 patients had axillary ultrasound of which 121 underwent CB. 73 (60%) patients proceeded to SLN after negative CB. All SLNs were examined for evidence of metastases and previous CB. Of the 73 patients, 51 had no evidence of malignancy in the SLN (true negative=70%). However nodal deposits were found in the remaining 22 patients, representing a false negative rate for CB of 30%. Overall histopathological evidence of previous CB was identified in 47 (64%) of 73 patients undergoing SLN biopsy. The reason for false negative findings in the 22 (30%) patients was failure to sample the sentinel lymph node in 10 (45%) and failure to sample the metastatic disease in the sentinel node in 11 (55%). This study suggests that both better methods of identifying the sentinel lymph node and more adequate sampling are required.