Positive anterior margins in breast conserving surgery: Does it matter? A systematic review of the literature.

Positive margins are associated with an increased risk of ipsilateral breast tumor recurrence (IBTR); therefore re-excision of positive margins is recommended. Involvement of anatomically non-breast margins, such as anterior margins, has been associated to a lower risk of IBTR than radial margins. Although many surgeons do not re-excise positive anterior margins (PAM); there is no consensus regarding this approach. The objective of this study is to find evidence that assesses this practice. A systemic literature review was performed through six databases from January 1995 to July 2014. Studies that discussed anatomical location of involved margins in BCS were included. Six studies were identified evaluating PAM. One study reported a 2.5% rate of IBTR in patients with non-negative margins treated with radiotherapy (of which 23% had a PAM). Another study showed 4% of residual disease after re-excision of PAM, but did not report IBTR rates. A later observational study reported that 87.5% of positive anterior and posterior margins were re-excised. One survey from America and one from the UK showed that 47% and 71% of surgeons would not re-excise PAM, respectively. A later survey in the UK reported that 43.8% of surgeons would not re-excise PAM in DCIS, whilst 29.2% would not for invasive carcinoma. Common surgical practices to not re-excise PAM contradict current guidelines that recommend obtaining negative margins to reduce the risk of IBTR. However, there is little evidence detailing the relationship between PAM and IBTR rates. Low residual disease after re-excision of PAM supports the limited benefit of re-excise this margin; however further studies are required to evaluate this topic.

Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome.

AIMS: Triple-negative breast cancer (TNBC) patients generally have a poor outcome; there is a pressing need to identify more effective therapeutic strategies. Clinical trials targeting programmed death 1/programmed death ligand 1 (PD1/PDL1) in melanoma and non-small-cell lung cancer have reported high response rates, and tumoral PDL1 expression has been suggested as a potential biomarker to enrich for patient response to these treatments. There are only very limited data to date reporting the expression of PDL1 in TNBC. METHODS AND RESULTS: PDL1 immunohistochemistry was performed on 161 primary TNBCs and assessed in the tumour as well as immune cells in the stromal compartment. PDL1 expression was very common in TNBC, expressed in the tumour cell membrane (64%), cytoplasm (80%) and stromal (93%) cellular compartments. Cytoplasmic tumoral expression of PDL1 was associated with a lower risk of breast cancer-specific death [hazard ratio (HR) 0.45, P = 0.035] while stromal PDL1 expression was associated with a lower rate of deaths from all causes (HR 0.305, P = 0.0042). Membranous expression of PDL1 was not associated with outcome. While both PDL1 expression and tumour-infiltrating lymphocytes were associated with a better outcome, only lymphovascular invasion and high tumour-infiltrating lymphocytes were independently prognostic for breast cancer-specific death. CONCLUSION: While PDL1 expression is frequent in TNBC, it was not independently prognostic. There were differences in outcome depending on the cellular compartment of PDL1 expression. These data provide further impetus for investigating the utility of immune checkpoint therapies in TNBC, given the clinical significance of tumour-infiltrating lymphocytes (TILs) and PDL1 expression in this cohort.

MicroRNA-Related DNA Repair/Cell-Cycle Genes Independently Associated With Relapse After Radiation Therapy for Early Breast Cancer.

PURPOSE: Local recurrence and distant failure after adjuvant radiation therapy for breast cancer remain significant clinical problems, incompletely predicted by conventional clinicopathologic markers. We had previously identified microRNA-139-5p and microRNA-1274a as key regulators of breast cancer radiation response in vitro. The purpose of this study was to investigate standard clinicopathologic markers of local recurrence in a contemporary series and to establish whether putative target genes of microRNAs involved in DNA repair and cell cycle control could better predict radiation therapy response in vivo. METHODS AND MATERIALS: With institutional ethics board approval, local recurrence was measured in a contemporary, prospectively collected series of 458 patients treated with radiation therapy after breast-conserving surgery. Additionally, independent publicly available mRNA/microRNA microarray expression datasets totaling >1000 early-stage breast cancer patients, treated with adjuvant radiation therapy, with >10 years of follow-up, were analyzed. The expression of putative microRNA target biomarkers--TOP2A, POLQ, RAD54L, SKP2, PLK2, and RAG1--were correlated with standard clinicopathologic variables using 2-sided nonparametric tests, and to local/distant relapse and survival using Kaplan-Meier and Cox regression analysis. RESULTS: We found a low rate of isolated local recurrence (1.95%) in our modern series, and that few clinicopathologic variables (such as lymphovascular invasion) were significantly predictive. In multiple independent datasets (n>1000), however, high expression of RAD54L, TOP2A, POLQ, and SKP2 significantly correlated with local recurrence, survival, or both in univariate and multivariate analyses (P<.001). Low RAG1 expression significantly correlated with local recurrence (multivariate, P=.008). Additionally, RAD54L, SKP2, and PLK2 may be predictive, being prognostic in radiation therapy-treated patients but not in untreated matched control individuals (n=107; P<.05). CONCLUSIONS: Biomarkers of DNA repair and cell cycle control can identify patients at high risk of treatment failure in those receiving radiation therapy for early breast cancer in independent cohorts. These should be further investigated prospectively, especially TOP2A and SKP2, for which targeted therapies are available.

Phyllodes tumour with heterologous sarcomatous differentiation: Case series with literature review.

INTRODUCTION: Phyllodes tumours are rare fibroepithelial malignancies of the breast, accounting for less than 1% of malignant breast tumours. Further malignant differentiation of phyllodes tumours can occur, resulting in cases of extremely rare heterologous sarcomatous differentiation. PRESENTATION OF CASE: Two females in their fifties were diagnosed with malignant phyllodes tumour associated with heterologous sarcomatous differentiation. The first patient, aged 50 had phyllodes tumour with chondrosarcoma, osteosarcoma and ductal carcinoma-in-situ. The second patient, aged 53 had phyllodes tumour with osteosarcoma and liposarcoma. DISCUSSION: The association of phyllodes tumour and heterologous sarcomatous differentiation is rare, with only 4 previously reported cases in English literature. The paucity of evidence presents challenges in its management with uncertain prognosis and monitoring requirements for two aforementioned patients. CONCLUSION: Further case series and long-term follow up is required for accurate characterisation of phyllodes tumours with heterologous sarcomatous differentiation.

Tubular carcinoma of the breast: axillary involvement and prognostic factors.

BACKGROUND: Tubular carcinoma (TC) of the breast has a very favourable prognosis. The role for axillary staging in small TC was questioned. This study investigated the frequency of axillary metastases and prognostic factors in pure TC of the breast. It involved a retrospective review of prospectively collected data. METHODS: A consecutive series of patients presenting to The Strathfield Breast Centre (TSBC) between 1988 and 2011 were reviewed. Only pure TC was included. Information collected included demographics, surgery, pathology, adjuvant therapy and survival. RESULTS: Pure TC accounted for 146 out of 6110 cases of operable breast cancer. Ninety-five per cent were node negative (micrometastases and isolated tumour cells excluded). Ninety-eight per cent of those with known oestrogen receptor status were oestrogen receptor positive. Median tumour size was 10 mm (range 1-52 mm). Ten-year survival was 97%. Twelve per cent of patients had more than one tumour (either ipsilateral or contralateral). Eight patients had recurrent disease. All were node negative. Three of these patients died of their disease. CONCLUSION: Axillary metastases are uncommon in pure TC. Recurrent disease is not readily predicted by tumour size or node status.

Cell cycle marker expression in benign and malignant intraductal papillary lesions of the breast.

AIMS: The diagnosis of intraductal papillary lesions of the breast on core biopsy remains challenging in pathology, with most patients requiring formal surgical excision for a definitive diagnosis. The aim of this study was to determine whether a representative panel of proliferative cell cycle immunohistochemical markers (cyclin A2, cyclin B1 and cyclin D1) could improve the specificity of pathological diagnosis of these lesions. METHODS: A series of 68 surgically excised intraductal papillary lesion cases were retrospectively selected, and immunohistochemistry for cyclin A2, cyclin B1 and cyclin D1 was performed. RESULTS: Cyclin B1 (OR 1.80, 95% CI 1.01 to 3.2, p=0.046) and cyclin D1 (OR 1.13, 95% CI 1.05 to 1.22, p=0.002) expression was independently associated with a diagnosis of malignancy in papillary lesions, although expression was frequently heterogeneous and only focal. Cyclin A2 expression (OR 0.76, 95% CI 0.41 to 1.4, p=0.38) was not associated with a malignant diagnosis in multivariable logistic regression models. All three cyclins displayed high sensitivity (80%-95%) for a diagnosis of malignancy, although cyclin B1 showed a superior specificity of 72.7% compared with the low specificity of cyclins A2 and D1. CONCLUSIONS: Our study has identified for the first time that the expression of key cell cycle markers differs between benign and malignant papillary breast lesions and identified changes to the mitotic marker, cyclin B1, as particularly significant. However, given the low level and heterogeneous nature of expression of these markers, there remains a significant risk of undersampling in core biopsies and thus they are unlikely to be useful in routine clinical practice.

Preservation or division of the intercostobrachial nerve in axillary dissection for breast cancer: meta-analysis of randomised controlled trials.

PURPOSE: Management of the ICBN during axillary dissection is controversial and the division of ICBN is often trivialised. The effect of dividing the ICBN, and its association with sensory disturbance, is unclear. A systematic review and meta-analysis was performed to evaluate the effect of preserving the ICBN during axillary dissection. METHODS: A systematic literature review and meta-analysis is performed according to the PRISMA and Cochrane Collaboration guidelines. RESULTS: Three RCTs and four non-RCTs were reviewed. A meta-analysis demonstrated that the incidence of sensory disturbance was significantly lower with preservation of ICBN compared to division of the ICBN with Mantel-Haenzel combined odds ratio 0.31 (0.17-0.57, 95% CI). There was relatively low level of heterogeneity (I(2) = 19%, χ(2) = 2.48, df = 2). The sensory disturbance was more likely to be hyposensitivity when compared to hypersensitivity (p < 0.0001). No difference on number of lymph nodes dissected or operating time was noted. CONCLUSION: This meta-analysis demonstrates that division of the ICBN is associated with higher risk of sensory disturbance, and that the nature of this sensory disturbance is more likely to be hyposensitivity, attributable to reduced nerve function.

Recent insights into the molecular pathogenesis of mammary phyllodes tumours.

Phyllodes tumours (PTs) of the breast are true biphasic neoplasms within which interactions between the epithelium and stroma are critical for tumour development and progression. Despite numerous studies reporting the results of ancillary marker investigations in PTs, the current histological grading systems remain unreliable at predicting clinical outcome even when supplemented by these markers. As a consequence, there has been much interest in the prospect of using molecular/genetic techniques to develop a more robust "grading" system. This review focuses on recent cytogenetic and molecular studies investigating the pathogenesis of PTs and those correlating molecular findings with clinicopathological features of the tumours. Recent data highlight that intratumoural genetic heterogeneity is common in PTs and may account for the reported lack of correlation between histological grading and clinical behaviour. The entire spectrum of molecular aberrations in PTs are yet to be fully defined, however recent array-based studies using comparative genomic hybridisation have reported that copy number changes increase with the progression from benign PT to malignancy. Tumour recurrence and progression is likely to reflect the presence of under-recognised subclones. p(16INK4a) (CDKN2A) inactivation also appears to be important in PT pathogenesis. Further additional studies will be required to identify and validate new prognostic markers and therapeutic targets in order to improve the diagnosis, classification, prediction of outcome and management of patients with this rare neoplasm. Data generated from modern sequencing technologies are likely to provide new insights into the disease and assist in this endeavour.

Molecular alterations in metaplastic breast carcinoma.

Metaplastic carcinoma of the breast is a rare and heterogeneous subtype of breast carcinoma with a generally poor outcome, and few therapeutic options once disease recurs or progresses. Metaplastic carcinomas of the breast are usually of a larger size at diagnosis, with less frequent nodal metastasis compared with invasive ductal carcinoma no special type, and lack hormone and HER2 receptor expression. Recent research has revealed some potentially actionable genetic changes in a subset of these rare tumours. However, ongoing efforts to further characterise the genetic basis and the molecular alterations underlying the distinctive morphological and clinical characteristics of these tumours are needed in order to identify new targets for treatment. This review will describe the theories of pathogenesis of metaplastic breast carcinoma, and highlight genetic changes and potential therapeutic targets in this generally poor prognosis malignancy.

p16 and pRb immunohistochemical expression increases with increasing tumour grade in mammary phyllodes tumours.

AIMS: Control of cell cycling and proliferation is critical to the development of neoplasia and may play a role in the pathogenesis of phyllodes tumours (PTs). This study aimed to evaluate the immunohistochemical expression of certain proteins from the G(1)/S transition of the cell cycle in a cohort of PTs, to determine their role in tumour pathogenesis and to identify any associations with patient outcome. METHODS AND RESULTS: Sixty-five PTs (34 benign, 23 borderline and eight malignant) diagnosed at a single institution between 1990 and 2006 were analysed. Immunohistochemistry for p16, pRb, cyclin D1 and Ki67 was performed. Expression of the following markers increased significantly with tumour grade: stromal nuclear and cytoplasmic p16 (P = 0.01 and 0.002, respectively), stromal and epithelial pRb (P = 0.000,000,06 and 0.004, respectively), and stromal and epithelial Ki67 (P = 0.03 and 0.04, respectively). Epithelial pRb scores of 7 (range 0-7) were significantly associated with reduced disease-free survival (DFS) compared with scores of <7 (P = 0.0009). No relationship was found between cyclin D1 expression in either the epithelium or the stroma, and grade or DFS. CONCLUSIONS: The results suggest that alterations at the G(1)/S transition of the cell cycle play an important role in the progression of PTs.