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.

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.

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.

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.

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.

Nipple discharge and the efficacy of duct cytology in evaluating breast cancer risk.

BACKGROUND: Nipple discharge accounts for up to 5% of referrals to breast surgical services. With the vast majority of breast carcinomas originating in the ductal system, symptomatic dysfunction of this system often raises disproportionate clinical concern. The aim of this study is firstly, to evaluate the clinical importance of nipple discharge as an indicator of underlying malignancy and secondly, to assess the diagnostic application of duct cytology in patients presenting with nipple discharge. STUDY DESIGN: We performed a retrospective analysis of all patients presenting with nipple discharge as their primary symptom to the symptomatic breast unit at a tertiary referral center over a 30-month period (n = 313). The Hospital Inpatient Enquiry (HIPE) System and BreastHealth database were used to identify our study cohort. Parameters evaluated included patient demographics, clinical presentation, clinical evaluation, radiological assessment and histological/cytological analysis. RESULTS: Three-hundred and thirteen patients presented with nipple discharge as their primary complaint. Invasive breast carcinoma was diagnosed by Triple Assessment in 5% of patients. 24% of patients presenting with nipple discharge underwent nipple aspiration and cytological analysis. Duct cytology was diagnostic of the underlying breast carcinoma in 50% of triple assessment diagnosed carcinoma. Four risk factors were identified as having a significant association with breast carcinoma, these included (a) age >50 years (p < 0.0001), (b) bloody nipple discharge (p < 0.008), (c) presence of a breast lump (p < 0.0001) and (d) single duct discharge (p < 0.006). CONCLUSIONS: Nipple discharge is a poor indicator of an underlying malignancy. Use of nipple aspiration and duct cytology for the assessment of nipple discharge is of limited diagnostic benefit. However, by utilizing the systematic, gold standard approach of Triple Assessment (clinical, radiological and cytological evaluation), the risk of underlying carcinoma can be accurately defined.

Outcome of axillary staging in early breast cancer: a meta-analysis.

Axillary lymph node dissection (ALND) is associated with significant morbidity, whilst sentinel node biopsy (SNB) has the potential to minimize complications in the management of breast cancer. The aim of this study was to systematically appraise the outcome of SNB when compared to ALND. A comprehensive search for published trials examining outcomes after SNB for breast cancer was performed using medline and cross-referencing available data. Each study was reviewed and data extracted. Primary outcomes were nodal positivity and surgery-related morbidity. A total of 9,608 patients were identified from trials comparing ALND and SNB. The overall rate of axillary lymph node positivity for those with no clinically palpable nodes was 28.8% for ALND and 27.6% for SNB (OR = 1.00, 95% CI = 0.86-1.17, P = 0.956), though there was a trend for superior detection of metastatic disease with SNB when this was compared with ALND alone (OR = 1.22, 95% CI = 0.95-1.57, P = 0.122). Patients who undergo SNB are significantly less likely to suffer post-operative morbidity relative to ALND: risk of infection (OR = 0.58, 95% CI = 0.42-0.80, P = 0.0011), seroma (OR = 0.40, 95% CI = 0.31-0.51, P = 0.0071), arm swelling (OR = 0.30, 95% CI = 0.14-0.66, P = 0.0028) and numbness (OR = 0.25, 95% CI = 0.1-0.59, P = 0.0018). SNB is at least equivalent to ALND in detecting metastatic disease in the axilla. SNB is the optimum approach in terms of morbidity for the assessment of axillary metastasis in clinically node negative breast cancer.

Enhancing the adjuvant treatment of hormone receptor positive breast cancer.

Aromatase inhibitors (AIs) are now regarded as the optimum hormonal therapy for postmenopausal women with hormone receptor positive breast cancer. However, it is unclear which of the currently available AIs offers patients the most effective and the best-tolerated treatment strategy. We performed a systematic review and meta-analysis of randomized-controlled trials that compared AIs (as first-line agents) with standard hormonal treatment in patients with breast cancer. The results suggest that letrozole offers a more favorable side-effect profile particularly in terms of musculoskeletal adverse events. However, the available data suggests a small survival benefit from the use of anastrozole although patients treated with anastrozole appear to have a more favorable disease profile at study entry. Examination of survival data on adjuvant tamoxifen therapy from these trials supports this observation.

Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ.

PURPOSE: There is no consensus on what constitutes an adequate surgical margin in patients receiving breast-conserving surgery (BCS) and postoperative radiation therapy (RT) for ductal carcinoma in situ (DCIS). Inadequate margins may result in high local recurrence, and excessively large resections may lead to poor cosmetic outcome without oncologic benefit. METHODS: A comprehensive search for published trials that examined outcomes after adjuvant RT after BCS for DCIS was performed using MEDLINE and cross referencing available data. Reviews of each study were conducted, and data were extracted. Primary outcome was ipsilateral breast tumor recurrence (IBTR) related to surgical margins. RESULTS: A total of 4,660 patients were identified from trials examining BCS and RT for DCIS. Patients with negative margins were significantly less likely to experience recurrence than patients with positive margins after RT (odds ratio [OR] = 0.36; 95% CI, 0.27 to 0.47). A negative margin significantly reduced the risk of IBTR when compared with a close (OR = 0.59; 95% CI, 0.42 to 0.83) or unknown margin (OR = 0.56; 95% CI, 0.36 to 0.87). When specific margin thresholds were examined, a 2-mm margin was superior to a margin less than 2 mm (OR = 0.53; 95% CI, 0.26 to 0.96); however, we saw no significant difference in the rate of IBTR with margins between 2 mm and more than 5 mm (OR = 1.51; 95% CI, 0.51 to 5.0; P > .05). CONCLUSION: Surgical margins negative for DCIS should be obtained after BCS for DCIS. A margin threshold of 2 mm seems to be as good as a larger margin when BCS for DCIS is combined with RT.