R. Douglas Macmillan

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival.

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P=0.0061), whereas cyclin D1 mRNA overexpression was not (P=0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P=0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P=0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P=0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P=0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age >50 years (P=0.0001), postmenopausal status (P=0.0008), lymph node negativity (P=0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.

Objective assessment of lymphatic and blood vascular invasion in lymph node‐negative breast carcinoma: findings from a large case series with long‐term follow‐up

In a previous study on a small series of breast cancers, we developed objective methods for the assessment of vascular invasion (VI), using immunohistochemical staining. We found that VI was predominantly lymphovascular invasion (LVI), with minimal contribution of blood vascular invasion (BVI). The aims of the current study were: (a) to assess the frequency, extent and prognostic role of LVI and BVI in a large, well‐characterized series of LN‐negative breast cancers; and (b) to assess the ability of VI to stratify early breast cancer into different prognostic groups. Paraffin‐embedded sections from 1005 lymph‐node (LN)‐negative primary invasive breast cancers were stained for CD34, CD31 and podoplanin/D240 to detect BVI and LVI. VI lesions were assessed and the results were correlated with clinicopathological criteria and survival. VI was detected in 218 (22%); 211/218 (97%) were LVI, while BVI was detected in 7/218 (3%). The frequency of LVIs/section ranged from 1 to 79, with no significant difference between the frequency of LVI and outcome. The presence of LVI was significantly associated with adverse disease‐free interval (DFI) and poor overall survival (OS) in both univariate and multivariate analyses. The results from the study indicated that VI in early stage breast cancer is predominantly LVI and that its objective assessment is a powerful independent prognostic factor. Efforts to detect early metastatic activity, such as diligent pathological examination of sentinel LN biopsies would be complimented by the objective evaluation of VI status of the primary tumour. VI status should be included routinely in breast cancer staging systems. Copyright

Is immediate autologous breast reconstruction with postoperative radiotherapy good practice?: a systematic review of the literature.

BACKGROUND There remains controversy as to whether immediate autologous breast reconstruction with postoperative radiotherapy is associated with acceptable complications and aesthetic outcomes. This systematic review analyses the literature regarding outcomes of immediate autologous breast reconstruction with postoperative radiotherapy compared with no radiotherapy, as well as with delayed autologous breast reconstruction following post-mastectomy irradiation. METHODS Pubmed (1966 to October 2012), Ovid MEDLINE (1966 to October 2012), EMBASE (1980 to October 2012), and the Cochrane Database of Systematic Reviews (Issue 10, 2012) were searched. Overall complications (including fat necrosis), fat necrosis, revisional surgery, loss of volume, and aesthetic outcome, were analysed individually. Comparable data from observational studies were combined for meta-analysis where possible and quality assessment of the studies was performed. RESULTS The majority of studies of immediate autologous breast reconstruction and postoperative radiotherapy reported satisfactory outcomes (19 of 25 studies; n=1,247 patients). Meta-analysis of observational studies demonstrated no significant differences in total prevalence of complications (p=0.59) or revisional surgery (p=0.38) and a summary measure for fat necrosis favouring the group without radiotherapy (OR 2.82, 95% CI 1.35-5.92, p=0.006). The majority of studies comparing immediate reconstruction and postoperative radiotherapy with delayed reconstruction following post-mastectomy radiotherapy (10 of 12 observational studies; n=1,633 patients) reported satisfactory outcomes following immediate reconstruction. Meta-analysis of observational studies demonstrated no significant difference in overall incidence of complications (p=0.53) and fat necrosis (OR 0.63, 95% CI 0.29-1.38, p=0.25), and a summary measure for revisional surgery (OR 0.15, 95% CI 0.05-0.48, p=0.001) favouring the delayed surgery group. No randomised-controlled trials met the inclusion criteria, and all of the observational studies included were missing more than one important component for reporting of observational studies. DISCUSSION The majority of studies reported satisfactory outcomes and a similar incidence of complications for immediate autologous breast reconstruction and adjuvant radiotherapy when compared with no radiotherapy or delayed reconstruction following radiotherapy; the proportion that required revisional surgery was higher though for immediate than delayed breast reconstruction. The findings are limited by the paucity of high quality data in the published literature, and until better data is available the findings of this review suggest that immediate autologous breast reconstruction should at least be considered when adjuvant chest wall radiotherapy is anticipated.

The prognostic significance of steroid receptor co-regulators in breast cancer: co-repressor NCOR2/SMRT is an independent indicator of poor outcome

BackgroundAdvances in understanding the molecular basis of breast cancer has necessitated a definition of improved indicators of prognosis that are central to the underlying cancer biology and that reflect the heterogeneous nature of the disease. This study investigates the pattern of expression of the steroid receptor co-regulators NCOA1/SRC1, NCOA3/RAC3, NCOR2/SMRT, and CBP/p300 in breast cancer. The aims were to identify whether their expression was related to patient outcome, their relationships to known prognostic factors and to provide a basis for further research into the mechanistic significance of such associations.MethodsThe protein levels of steroid receptor co-regulators were assessed by immunohistochemistry in a large well-characterised series of breast carcinomas prepared as tissue microarrays. Relationships between these targets, other clinicopathological variables and patients’ outcome were examined.ResultsNCOR2/SMRT was an independent prognostic indicator of overall patient survival (OS) and disease free interval (DFI) and was significantly correlated with distant metastases and local recurrence whereas tumours expressing NCOA1/SRC1 had a significantly longer OS and DFI. There were also significant correlations between co-regulator expression of NCOA1/SRC1, CBP/p300 and NCOA3/RAC3, which were associated with lower tumour grade. NCOA1/SRC1 was also correlated with smaller tumour size. Furthermore, the co-activators had a significant association with steroid receptors, particularly ERα.ConclusionsNCOR2/SMRT is associated with poor patient outcome, independent of other prognostic factors. In contrast, steroid receptor co-activator expression is generally associated with a good prognosis. Further investigations are needed to establish the mechanisms of these links between the steroid receptor co-regulator system and patient outcome.

Growth fraction as a predictor of response to chemotherapy in node-negative breast cancer

Accurate predictive markers of chemotherapeutic response in early breast cancer are still lacking. The role of tumour growth fraction as a predictor of response to chemotherapy was assessed in early breast cancer. In this study, immunohistochemical expression of MIB1 was studied in a well‐characterised series of early (Stages I and II) node‐negative breast carcinoma cases (n = 100) with long‐term follow‐up that have received adjuvant chemotherapy (cyclophosphamide/methotrexate/5‐fluorouracil regimen). In addition, 728 cases who did not receive adjuvant chemotherapy were used as a control group. Increased tumour growth fraction was associated with a better response to adjuvant chemotherapy in terms of longer breast cancer specific survival and disease‐free interval [hazard ratio (HR) = 0.354, 95% CI = 0.177–0.688, p = 0.003 and HR = 0.396, 95% CI = 0.205–0.768, p = 0.006, respectively]. In contrast to the control group, patients with high growth fraction tumour (>70%) showed an excellent outcome with infrequently reported events during the period of follow‐up. Importantly, patients with a low growth fraction (≤10%) showed frequent recurrences and shorter survival time with outcome comparable to those of high growth fraction who did not receive chemotherapy. Therefore, tumour growth fraction can be used to assign patients into distinct groups showing differential response to adjuvant chemotherapy. Patients with a high growth fraction appear to be ideal candidates for adjuvant chemotherapy while those with low growth fraction are less likely to benefit and are prone to the potential serious side effects of adjuvant chemotherapy.

Training in oncoplastic surgery: An international consensus. The 7th Portuguese Senology Congress, Vilamoura, 2009

Oncoplastic Breast Surgery (OPBS) is becoming an integral part of breast cancer management, but few surgeons have received formal training in these techniques. An International Symposium has recently debated the key issues which impact on training and specialisation in OPBS, as well as patient access to these procedures. The Symposium concluded that increasing the availability of OPBS is a major challenge, which demands much closer collaboration and cooperation between breast and plastic surgeons, backed up by new training schemes, new curricula and new guidelines.

MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours

Background:MYC is amplified in approximately 15% of breast cancers (BCs) and is associated with poor outcome. c-MYC protein is multi-faceted and participates in many aspects of cellular function and is linked with therapeutic response in BCs. We hypothesised that the functional role of c-MYC differs between molecular subtypes of BCs.Methods:We therefore investigated the correlation between c-MYC protein expression and other proteins involved in different cellular functions together with clinicopathological parameters, patients’ outcome and treatments in a large early-stage molecularly characterised series of primary invasive BCs (n=1106) using immunuohistochemistry. The METABRIC BC cohort (n=1980) was evaluated for MYC mRNA expression and a systems biology approach utilised to identify genes associated with MYC in the different BC molecular subtypes.Results:High MYC and c-MYC expression was significantly associated with poor prognostic factors, including grade and basal-like BCs. In luminal A tumours, c-MYC was associated with ATM (P=0.005), Cyclin B1 (P=0.002), PIK3CA (P=0.009) and Ki67 (P<0.001). In contrast, in basal-like tumours, c-MYC showed positive association with Cyclin E (P=0.003) and p16 (P=0.042) expression only. c-MYC was an independent predictor of a shorter distant metastases-free survival in luminal A LN+ tumours treated with endocrine therapy (ET; P=0.013). In luminal tumours treated with ET, MYC mRNA expression was associated with BC-specific survival (P=0.001). In ER-positive tumours, MYC was associated with expression of translational genes while in ER-negative tumours it was associated with upregulation of glucose metabolism genes.Conclusions:c-MYC function is associated with specific molecular subtypes of BCs and its overexpression confers resistance to ET. The diverse mechanisms of c-MYC function in the different molecular classes of BCs warrants further investigation particularly as potential therapeutic targets.

Pleomorphic lobular carcinoma of the breast: is it a prognostically significant pathological subtype independent of histological grade?

Pleomorphic lobular carcinoma is regarded as a biologically aggressive variant of invasive lobular carcinoma of the breast. However, there is no consensus on the definition and whether this subtype adds useful information to histological grade. Two-hundred and two grade 2 or grade 3 invasive lobular carcinomas were studied. Tumours were categorised according to the components of histological grade: tubules, pleomorphism and mitoses. Pleomorphic lobular carcinoma was defined as a carcinoma with a lobular growth pattern and marked nuclear pleomorphism (pleomorphism 3). Breast cancer-specific survival was used in analysis of prognosis. Grade 3 pleomorphic lobular carcinomas (tubules 3, pleomorphism 3, mitoses 2 and tubules 3, pleomorphism 3, mitoses 3) had a worse prognosis than grade 2 (tubules 3, pleomorphism 2, mitoses 1) carcinomas. Grade 2 lobular carcinomas with marked nuclear pleomorphism (tubules 3, pleomorphism 3, mitoses 1) had a similar prognosis to grade 2 carcinomas with moderate pleomorphism (tubules 3, pleomorphism 2, mitoses 1). Survival was associated with mitotic score, but not with nuclear pleomorphism on both univariate and multivariate analysis. A non-classical growth pattern was seen more frequently in all subgroups with marked nuclear pleomorphism and was associated with worse survival. Histological grade and nodal status were independent of prognostic factors. This study shows that histological grade (in particular the mitotic component) in invasive lobular carcinomas is of prognostic importance, but pleomorphic type does not provide useful additional prognostic information.

The microRNA maturation regulator Drosha is an independent predictor of outcome in breast cancer patients

Drosha is a protein that plays a key role in the biogenesis of microRNAs which are well known to be deranged in human breast cancer (BC). The purpose of the current study was to assess the biological and prognostic value of Drosha protein expression in BC. Drosha protein expression was assessed immunohistochemically in two sets of BC: (1) full-face sections of selected BC series with distinct stages of tumour progression (Normal parenchymal cells, ductal carcinoma in situ (DCIS), primary invasive BC and nodal metastases) to evaluate its differential expression, (2) tissue microarray comprising a large and well-characterised series of unselected clinically annotated invasive BC to investigate its correlation with clinicopathological features and patient outcome. A gradual loss of Drosha cytoplasmic expression was observed along tumour progression from DCIS, to invasive and to metastatic cancer cells. In invasive BC, loss of Drosha cytoplasmic expression was associated with BRCA1 and ER expression and with shorter BC specific survival (BCSS), disease free interval (DFI) and distant metastasis free interval (DMFI). This correlation was maintained in ER negative, HER2 negative, triple negative and LN negative cases. Moreover, loss of cytoplasmic Drosha was predictive of better response to chemotherapy and endocrine therapy. This study provides evidence that Drosha protein potentially plays an important role in BC progression and assessment of its expression provides an independent predictor of patient outcome. These observations provide further evidence that alterations in miRNA regulation influence tumour behaviour.

Lateral thoracic artery perforator (LTAP) flap in partial breast reconstruction.

BACKGROUND Partial breast reconstruction using pedicled perforator flaps from the thoracodorsal (TDAP) and lateral intercostal arteries (LICAP) is well described. The article introduces the lateral thoracic artery perforator (LTAP) flap as an additional valuable option from the lateral chest wall and reports clinical experience and outcomes. METHODS The anatomy of the LTAP flap is reviewed and the results of a consecutive series are reported. RESULTS In a series of 75 consecutive cases of lateral chest wall perforator flaps used for reconstruction of partial breast defects, 12 (17%) were raised as pure LTAP flaps, and a further 19 (27%) as combined LTAP/LICAP flaps. The LTAP was therefore used in 44% of flaps overall. One LTAP flap (delayed case) had early venous compromise that settled spontaneously. DISCUSSION The LTAP flap is a reliable option for partial breast reconstruction from the lateral chest wall, particularly in the immediate setting. It allows comparable flap size to be harvested compared to LICAP flaps. The LTAP flap can be raised on its own pedicle allowing greater mobilization or it can be incorporated into the more commonly used LICAP flap to augment perfusion.