Nodal positivity in patients with clinically and radiologically node-negative breast cancer treated with neoadjuvant chemotherapy: multicentre collaborative study.

BACKGROUND: The necessity of performing a sentinel lymph node biopsy in patients with clinically and radiologically node-negative breast cancer after neoadjuvant chemotherapy has been questioned. The aim of this study was to determine the rate of nodal positivity in these patients and to identify clinicopathological features associated with lymph node metastasis after neoadjuvant chemotherapy (ypN+). METHODS: A retrospective multicentre study was performed. Patients with cT1-3 cN0 breast cancer who underwent sentinel lymph node biopsy after neoadjuvant chemotherapy between 2016 and 2021 were included. Negative nodal status was defined as the absence of palpable lymph nodes, and the absence of suspicious nodes on axillary ultrasonography, or the absence of tumour cells on axillary nodal fine needle aspiration or core biopsy. RESULTS: A total of 371 patients were analysed. Overall, 47 patients (12.7%) had a positive sentinel lymph node biopsy. Nodal positivity was identified in 22 patients (29.0%) with hormone receptor+/human epidermal growth factor receptor 2- tumours, 12 patients (13.8%) with hormone receptor+/human epidermal growth factor receptor 2+ tumours, 3 patients (5.6%) with hormone receptor-/human epidermal growth factor receptor 2+ tumours, and 10 patients (6.5%) with triple-negative breast cancer. Multivariable logistic regression analysis showed that multicentric disease was associated with a higher likelihood of ypN+ (OR 2.66, 95% c.i. 1.18 to 6.01; P = 0.018), whilst a radiological complete response in the breast was associated with a reduced likelihood of ypN+ (OR 0.10, 95% c.i. 0.02 to 0.42; P = 0.002), regardless of molecular subtype. Only 3% of patients who had a radiological complete response in the breast were ypN+. The majority of patients (85%) with a positive sentinel node proceeded to axillary lymph node dissection and 93% had N1 disease. CONCLUSION: The rate of sentinel lymph node positivity in patients who achieve a radiological complete response in the breast is exceptionally low for all molecular subtypes.

Upgrade rates and outcomes of screen-detected atypical intraductal epithelial proliferation (AIDEP) diagnosed on core needle biopsy.

INTRODUCTION: Atypical intraductal epithelial proliferation (AIDEP) is a breast lesion categorised as "indeterminate" if identified on core needle biopsy (CNB). The rate at which these lesions are upgraded following diagnostic excision varies in the literature. Women diagnosed with AIDEP are thought to be at increased risk of breast cancer. Our aim was to identify the rate of upgrade to invasive or in situ carcinoma in a group of patients diagnosed with AIDEP on screening mammography and to quantify their risk of subsequent breast cancer. METHODS: We conducted a retrospective review of a prospectively maintained database containing all patients diagnosed with AIDEP on CNB between 2005 and 2012 in an Irish breast screening centre. Basic demographic data was collected along with details of the original CNB result, rate of upgrade to carcinoma and details of any subsequent cancer diagnoses. RESULTS: In total 113 patients were diagnosed with AIDEP on CNB during the study period. The upgrade rate on diagnostic excision was 28.3% (n = 32). 6.2% (n = 7) were upgraded to invasive cancer and 22.1% (n = 25) to DCIS. 81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18-145.21). CONCLUSION: Our data showing an upgrade rate of 28% to carcinoma reflects recently published data and we believe it supports the continued practice of excising AIDEP to exclude co-existing carcinoma.

Management and outcomes of phyllodes tumours - 10 year experience.

INTRODUCTION: Phyllodes tumours represent 0.3-1% of breast tumours, typically presenting in women aged 35-55 years. They are classified into benign, borderline and malignant grades and exhibit a spectrum of features. There is significant debate surrounding the optimal management of phyllodes tumour, particularly regarding appropriate margins. METHODS: This is a retrospective review of a prospectively maintained database of patients who underwent surgical management for phyllodes tumours in a single tertiary referral centre from 2007-2017. Patient demographics, tumour characteristics, surgical treatment and follow-up data were analysed. Tumour margins were classified as positive (0 mm), close (≤2 mm) and clear (>2 mm). RESULTS: A total of 57 patients underwent surgical excision of a phyllodes tumour. The Mean age was 37.7 years (range: ages 14-91) with mean follow-up of 38.5 months (range: 0.5-133 months). There were 44 (77%) benign, 4 (7%) borderline and 9 (16%) malignant phyllodes cases. 54 patients had breast conserving surgery (BCS) and 3 underwent mastectomy. 30 (53%) patients underwent re-excision of margins. The final margin status was clear in 32 (56%), close in 13 (23%) and positive in 12 (21%). During follow-up, 4 patients were diagnosed with local recurrence (2 malignant, 1 borderline and 1 benign pathology on recurrence samples). CONCLUSION: There are no clear guidelines for the surgical management and follow-up of phyllodes tumours. This study suggests that patients with malignant phyllodes and positive margins are more likely to develop local recurrence. There is a need for large prospective studies to guide the development of future guidelines.

Lobular intraepithelial neoplasia: Outcomes and optimal management.

INTRODUCTION: Lobular neoplasia is a term encompassing both atypical lobular hyperplasia and lobular carcinoma in situ. These pathological findings are of uncertain malignant potential and predispose to a higher lifetime risk of breast cancer. Debate surrounds the management of such lesions, with the rationale for diagnostic excision based on the possibility of upgrading to malignancy. In this study, we report the upgrade rate of these lesions and risk of subsequent development of breast cancer. METHODS: This is a retrospective review of a prospectively maintained data base of all biopsies of breast screening-detected abnormalities in a single Irish breast-screening unit. We included all patients with lobular neoplasia on core needle biopsy who underwent diagnostic excision from 2005 to 2012. We excluded those who had concurrent high-risk lesions on biopsy. End points included upgrade rate and subsequent diagnosis of malignancy on follow-up. RESULTS: During the study period, 66 patients met criteria for inclusion, with a mean age of 53.74 years. Upgrade rate following excision was 13.64% (n = 9/66). Of those not upgraded, 7.02% (n = 4/57) were subsequently diagnosed with malignancy. Median time to diagnosis was 59.61 months (range = 10.5-124.4). CONCLUSION: There is a significant rate of upgrade following diagnostic excision of lobular neoplasia, supporting the practice of diagnostic excision. There is an increased lifetime risk of breast cancer for women with a diagnosis of lobular neoplasia, with many of these cancers occurring outside the standard five-year monitoring period, suggesting a potential benefit in extending surveillance.

Benign breast papilloma: Is surgical excision necessary?

In many centers internationally, current standard of care is to excise all papillomas of the breast, despite recently reported low rates of upgrade to malignancy on final excision. The objective of this study was to determine the upgrade rate to malignancy in patients with papilloma without atypia. A retrospective review of a prospectively maintained database of all cases of benign intraductal papilloma in a tertiary referral symptomatic breast unit between July 2008 and July 2018 was performed. Patients with evidence of malignancy or atypia on core biopsy and those with a history of breast cancer or genetic mutations predisposing to breast cancer were excluded. One hundred and seventy-three cases of benign papilloma diagnosed on core biopsy were identified. Following exclusions, the final cohort comprised of 138 patients. Mean age at presentation was 51. Mean follow-up time was 9.6 months. The most common symptom was a lump (40%). Of the 124 patients who underwent excision, three had ductal carcinoma in situ and there were no cases of invasive disease, giving an upgrade rate to malignancy of 2.4%. Upgrade to other high-risk lesions (atypical lobular and ductal hyperplasia and lobular carcinoma in situ) was demonstrated in 15 cases (12.1%). Benign papilloma was confirmed in 100 cases (81.5%), and 6 (4.8%) had no residual papilloma found on final excision. Twelve patients (8.7%) were managed conservatively. Of those, one later went on to develop malignancy. Patients with a diagnosis of benign papilloma without atypia on core biopsy have a low risk of upgrade to malignancy on final pathology, suggesting that observation may be a safe alternative to surgical excision. Further research is warranted to determine which patients can be safely managed conservatively.

Locoregional Recurrence Following Breast Cancer Surgery in the Trastuzumab Era: A Systematic Review by Subtype.

INTRODUCTION: Increasing evidence suggests that molecular subtype influences locoregional recurrence (LRR) of breast cancer. Previous systematic reviews that evaluated the quantitative influence of subtype on LRR predated the use of Trastuzumab. This study assessed the impact of subtype on LRR in a contemporary treatment era. METHODS: A comprehensive search for all published studies assessing LRR according to breast cancer subtype was performed. Only studies with patients treated with Trastuzumab were included. Relevant data were extracted from each study for systematic review. Primary outcome was LRR related to breast cancer subtype. RESULTS: In total, 11,219 patients were identified from seven studies. Overall LRR rate was 3.44%. The lowest LRR rates were in luminal A (1.7%), and the highest rates were in triple-negative (7.4%) subtypes. There were significantly lower risks of LRR in patients with luminal A subtype compared with luminal B [odds ratio (OR) 0.54, 95% confidence interval (CI) 0.38-0.76; p < 0.0004], HER2/neu-overexpressing (OR 0.32, 95% CI 0.24-0.45; p < 0.0001) and triple-negative breast cancers (OR 0.25, 95% CI 0.19-0.32; p < 0.0001). There were significant differences in LRR between the luminal B and HER2/neu-overexpressing breast cancers (OR 0.61, 95% CI 0.41-0.89; p = 0.0145). The reduced risk in HER2/neu overexpressing compared with triple-negative breast cancers approached statistical significance (OR 0.75, 95% CI 0.55-1.03; p = 0.0933). CONCLUSIONS: Significant variations in LRR occur across breast cancer subtypes, with lowest rates in luminal cancers and highest rates in triple-negative breast cancers. Low levels of LRR highlight advances in breast cancer management in the contemporary era.

Minimally invasive, maximal outcomes in breast surgery.

The contemporary treatment of breast cancer has evolved in response to numerous randomised control trials which have aided in the development of guidelines for effective treatment. Breast cancer surgery has progressed thanks in part to the advances made in chemotherapy, radiation therapy and early detection. As these advances continue the field of surgery needs to progress in tandem to maximise survival outcomes but to also minimise morbidity.

The fate of chemoresistance in triple negative breast cancer (TNBC).

BACKGROUND: Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. SCOPE OF REVIEW: How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. MAJOR CONCLUSIONS: Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. GENERAL SIGNIFICANCE: Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy.

An overview of triple negative breast cancer for surgical oncologists.

Triple negative breast cancers (TNBCs) represent a distinct subgroup of breast cancers with an immunohistochemical phenotype that is negative for oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). The aim of this article is to provide a broad overview of recent developments in the diagnosis and management of TNBC for surgical oncologists. This overview discusses the subtypes of TNBC and the relationship between this type of breast cancer and the BRCA1 gene. In addition, the article explores recent advances in the treatment of TNBC from a surgical, radiation, and medical oncology point of view. Lastly, evolving therapeutic strategies that have potential to enhance outcomes for patients with TNBC are also discussed.

Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells.

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High-grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR-433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR-433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p-Rb), and an increase in ß-galactosidase activity. Furthermore, in silico analysis identified four possible miR-433 target genes associated with cellular senescence: cyclin-dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p-Rb is attributable to a miR-433-dependent downregulation of CDK6, establishing it as a novel miR-433 associated gene. Interestingly, we show that high miR-433 expressing cells release miR-433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR-433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR-433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence.

Breast cancer: from Halsted to Harney.

The management of breast cancer has evolved in the last 40 years to now encompass not only treating the cancer in the most effective way, but also to detect and treat cancers before they can pose a risk to patients. This evolution in therapy and diagnostics has moved away from treating patients with the maximum amount of therapy they can tolerate towards a new paradigm where patents receive the minimum treatment to be most efficacious.

Meta-analysis to determine if surgical resection of the primary tumour in the setting of stage IV breast cancer impacts on survival.

INTRODUCTION: The role of primary tumor excision in patients with stage IV breast cancer is unclear. Therefore, a meta-analysis of relevant studies was performed to determine whether surgical excision of the primary tumor enhances oncological outcome in the setting of stage IV breast cancer. METHODS: A comprehensive search for relevant published trials that evaluated outcomes following excision of the primary tumor in stage IV breast cancer was performed using MEDLINE and available data were cross-referenced. Data were extracted following review of appropriate studies by authors. The primary outcome was overall survival following surgical removal of the primary tumor. RESULTS: Data from ten studies included 28,693 patients with stage IV disease of whom 52.8% underwent excision of the primary carcinoma. Surgical excision of the primary tumor in the setting of stage IV breast cancer was associated with a superior survival at 3 years (40% (surgery) versus 22% (no surgery) (odds ratio 2.32, 95% confidence interval 2.08-2.6, p<0.01). Subgroup analyses for selection of patients for surgery or not, favored smaller primary tumors, less competing medical comorbidities and lower metastatic burden (p<0.01). There was no statistical difference between the two groups regarding location of metastatic disease, grade of tumor, or receptor status. CONCLUSIONS: Patients with stage IV disease undergoing surgical excision of the primary tumor achieve a superior survival rate then their nonsurgical counterparts. In the absence of robust evidence, this meta-analysis provides evidence base for primary resection in the setting of stage IV breast cancer for appropriately selected patients.

Systematic antibody generation and validation via tissue microarray technology leading to identification of a novel protein prognostic panel in breast cancer.

BACKGROUND: Although omic-based discovery approaches can provide powerful tools for biomarker identification, several reservations have been raised regarding the clinical applicability of gene expression studies, such as their prohibitive cost. However, the limited availability of antibodies is a key barrier to the development of a lower cost alternative, namely a discrete collection of immunohistochemistry (IHC)-based biomarkers. The aim of this study was to use a systematic approach to generate and screen affinity-purified, mono-specific antibodies targeting progression-related biomarkers, with a view towards developing a clinically applicable IHC-based prognostic biomarker panel for breast cancer. METHODS: We examined both in-house and publicly available breast cancer DNA microarray datasets relating to invasion and metastasis, thus identifying a cohort of candidate progression-associated biomarkers. Of these, 18 antibodies were released for extended analysis. Validated antibodies were screened against a tissue microarray (TMA) constructed from a cohort of consecutive breast cancer cases (n = 512) to test the immunohistochemical surrogate signature. RESULTS: Antibody screening revealed 3 candidate prognostic markers: the cell cycle regulator, Anillin (ANLN); the mitogen-activated protein kinase, PDZ-Binding Kinase (PBK); and the estrogen response gene, PDZ-Domain Containing 1 (PDZK1). Increased expression of ANLN and PBK was associated with poor prognosis, whilst increased expression of PDZK1 was associated with good prognosis. A 3-marker signature comprised of high PBK, high ANLN and low PDZK1 expression was associated with decreased recurrence-free survival (p < 0.001) and breast cancer-specific survival (BCSS) (p < 0.001). This novel signature was associated with high tumour grade (p < 0.001), positive nodal status (p = 0.029), ER-negativity (p = 0.006), Her2-positivity (p = 0.036) and high Ki67 status (p < 0.001). However, multivariate Cox regression demonstrated that the signature was not a significant predictor of BCSS (HR = 6.38; 95% CI = 0.79-51.26, p = 0.082). CONCLUSIONS: We have developed a comprehensive biomarker pathway that extends from discovery through to validation on a TMA platform. This proof-of-concept study has resulted in the identification of a novel 3-protein prognostic panel. Additional biochemical markers, interrogated using this high-throughput platform, may further augment the prognostic accuracy of this panel to a point that may allow implementation into routine clinical practice.

Meta-analysis of the effect of central neuraxial regional anesthesia compared with general anesthesia on postoperative natural killer T lymphocyte function.

STUDY OBJECTIVE: To compare the effect of central neuraxial (spinal or epidural) anesthesia with general anesthesia on postoperative natural killer (NK) T lymphocyte function. DESIGN: Meta-analysis. SETTING: University-affiliated hospital. MEASUREMENTS: A systematic search of the medical literature from 1966 to 2009 yielded 5 eligible studies with a total of 184 patients who received neuraxial blockade. Natural killer T lymphocyte function was studied. MAIN RESULTS: There was significant heterogeneity between the studies [I(2) = 94.4% (95% CI= 90.3-96.2%)]. Overall fixed-effect odds ratio was 0.86 (0.66-1.14, P = 0.25). The random-effect odds ratio was 1.13 (0.26-4.92, P = 0.79). CONCLUSION: Anesthetic technique does not appear to significantly affect postoperative NK T lymphocyte function. Given the heterogeneity observed, further clinical studies in cancer patients of the effect of anesthetic technique on immune function in general, and NK T lymphocyte function in particular, are needed.

Locoregional recurrence after breast cancer surgery: a systematic review by receptor phenotype.

Molecular subtyping confirms that breast cancer comprises at least four genetically distinct entities based on the expression of specific genes including estrogen receptor (ER), progesterone receptor (PR), and HER2/neu receptor. The quantitative influence of subtype on ipsilateral locoregional recurrence (LRR) is unknown. The aim of this study was to systematically appraise the influence of breast cancer subtype on LRR following breast conserving therapy (BCT) and mastectomy. A comprehensive search for studies examining outcomes after BCT and/or mastectomy according to breast cancer subtype was performed using Medline and cross-referencing available data. Reviews of each study were conducted and data extracted to perform meta-analysis. Primary outcome was LRR related to breast cancer subtype. A total of 12,592 breast cancer patients who underwent either BCT (n = 7,174) or mastectomy (n = 5,418) were identified from 15 studies. Patients with luminal subtype tumors (ER/PR +ve) had a lower risk of LRR than both triple-negative (RR 0.38; 95% CI 0.23-0.61); and HER2/neu-overexpressing (RR 0.34; 95% CI 0.26-0.45) tumors following BCT. Luminal tumors were also less likely to develop LRR than HER2/neu-overexpressing (OR 0.69; 95% CI 0.54-0.89) or triple-negative tumors (OR 0.61; 95% CI 0.46-0.79) after mastectomy. HER2/neu-overexpressing tumors have increased risk of LRR compared to triple-negative tumors (RR 1.44; 95% CI 1.06-1.95) following BCT but there was no difference in LRR between HER2/neu-overexpressing and triple-negative tumors following mastectomy (RR 0.91; 95% CI 0.68-1.22). Luminal tumors exhibit the lowest rates of LRR. Patients with triple-negative and HER2/neu-overexpressing breast tumors are at increased risk of developing LRR following BCT or mastectomy. Breast cancer subtype should be taken into account when considering local control and identifies those at increased risk of LRR, who may benefit from more aggressive local treatment.

FDG-PET/CT in the staging of local/regional metastases in breast cancer.

Breast cancer is the commonest female malignancy in the Western world and the most reliable predictor for survival is axillary lymph node metastases. Conventional staging techniques employed in breast cancer include mammography, ultrasonography, isotope bone scanning, sentinel lymph node biopsy, axillary lymph node dissection and magnetic resonance imaging. More recently FDG-PET and FDG-PET/CT have been used to complement the above methods. This review assesses the role of FDG-PET/CT in axillary staging in patients with primary breast cancer. A PubMed search was conducted and all articles containing relevant or new information were included. Relevant studies examined identified that FDG-PET/CT has a sensitivity of 60% and a specificity of 97% in detecting lymphatic metastasis. Although positive axillary FDG-PET/CT is a good predictor of axillary disease and correlates well with SLNB, the relatively poor sensitivity (60%) must be considered for treatment planning.

Minimally invasive parathyroidectomy using surgical sonography.

Minimally invasive parathyroidectomy is the procedure of choice for primary hyperparathyroidism due to parathyroid adenoma. Localization of the offending adenoma in minimally invasive parathyroidectomy (MIP) has been described in the literature aided by isotope, telescope or ultrasound guidance. We present a prospective study of two techniques based on surgeon experience. Thirty patients diagnosed with primary hyperparathyroidism at the Mater hospital in Dublin, Ireland were randomized to have a minimally invasive parathyroidectomy using surgical sonography (MIPUSS) or the conventional unilateral open procedure (OP) over a two year period. The age, sex and serum calcium/parathormone were comparable in both groups. There was no significant difference in complications between the two groups with temporary hypocalcemia occurring in 3 patients undergoing unilateral neck exploration and in 2 MIPUSS patients. There was one transient episode of recurrent laryngeal neuropraxia occurring in the OP group which resolved at 30 day follow-up. The incision size, operating time, hospital stay, and required post-operative analgesia were all markedly reduced in the MIPUSS group. In conclusion, MIPUSS is safe, effective and has advantages in terms of operating time, incision size and early discharge.

An imbalance in progenitor cell populations reflects tumour progression in breast cancer primary culture models.

BACKGROUND: Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. METHODS: Primary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively. RESULTS: Significant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumorigenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells. CONCLUSIONS: Our results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.