Modelling pulmonary microthrombosis coupled to metastasis: distinct effects of thrombogenesis on tumorigenesis

Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection. We found that controlled induction of a specific number of these microthrombotic insults in the lungs caused an increase in expression of the hypoxia-inducible transcription factors (HIFs), a pro-angiogenic and pro-tumorigenic environment, as well as an increase in myeloid cell infiltration. Induction of pulmonary microthrombosis prior to introduction of tumour cells to the lungs had no effect on tumorigenic success, but thrombosis at the time of tumour cell seeding increased number and size of tumours in the lung, and this effect was strikingly more pronounced when the micro-occlusion occurred on the day following introduction of tumour cells. The tumorigenic effect of microbead treatment was seen even when thrombosis was induced five days after tumour cell injection. We also found positive correlations between thrombotic factors and expression of HIF2$\alpha$ in human tumours. The model system described here demonstrates the importance of thrombotic insult in metastatic success and can be used to improve understanding of thrombosis-associated tumorigenesis and its treatment.Research was supported through a Wellcome Trust Principal Research Fellowship to R.S.J. (RG59596). C.B. is supported through a Scientific Fellowship from Breast Cancer Now (2014MaySF275). C.E.E. received a Pump-Priming Grant from the University of Cambridge British Heart Foundation Centre of Research Excellence (RG68639)

Nomograms for preoperative prediction of axillary nodal status in breast cancer

Background: Axillary staging in patients with breast cancer and clinically node-negative disease is performed by sentinel node biopsy (SLNB). The aim of this study was to integrate feasible preoperative variables into nomograms to guide clinicians in stratifying treatment options into no axillary staging for patients with non-metastatic disease (N0), SLNB for those with one or two metastases, and axillary lymph node dissection (ALND) for patients with three or more metastases. Methods: Patients presenting to Skåne University Hospital, Lund, with breast cancer were included in a prospectively maintained registry between January 2009 and December 2012. Those with a preoperative diagnosis of nodal metastases were excluded. Patients with data on hormone receptor status, human epidermal growth factor receptor 2 and Ki-67 expression were included to allow grouping into surrogate molecular subtypes. Based on logistic regression analyses, nomograms summarizing the strength of the associations between the predictors and each nodal status endpoint were developed. Predictive performance was assessed using the area under the receiver operating characteristic (ROC) curve. Bootstrap resampling was performed for internal validation. Results: Of the 692 patients eligible for analysis, 248 were diagnosed with node-positive disease. Molecular subtype, age, mode of detection, tumour size, multifocality and vascular invasion were identified as predictors of any nodal disease. Nomograms that included these predictors demonstrated good predictive abilities, and comparable performances in the internal validation; the area under the ROC curve was 0·74 for N0 versus any lymph node metastasis, 0·70 for one or two involved nodes versus N0, and 0·81 for at least three nodes versus two or fewer metastatic nodes. Conclusion: The nomograms presented facilitate preoperative decision-making regarding the extent of axillary surgery

Cosmetic Outcomes and Symmetry Comparison in Patients Undergoing Bilateral Therapeutic Mammoplasty for Breast Cancer

Background: Breast-reduction techniques are increasingly used in oncoplastic breast surgery. Bilateral therapeutic mammoplasty has the benefit of decreasing breast volume, enabling resection of larger tumors, and the potential to assure good postoperative symmetry. The aims of this study were to objectively asses the cosmetic outcomes of therapeutic mammoplasty in patients with breast cancer, using the breast cancer conservative treatment cosmetic results (BCCT.core) software, to compare this score with the surgeon’s score and the patient’s assessment, and to evaluate if other defined parameters have an impact on cosmetic outcomes. The secondary aim was to compare breast symmetry pre- and postoperatively. Materials and Methods: We enrolled 146 consecutive patients with primary breast cancer who underwent therapeutic mammoplasty between 2011 and 2018 in Kristianstad Central Hospital, Sweden. We retrospectively collected data from patients’ records. We analyzed the BCCT.core score using postoperative photographs to objectively evaluate cosmetic outcomes on a four-grade scale and compared with preoperative photographs to evaluate symmetry. Cosmetic outcomes were also assessed subjectively by patients and surgeons, using a 10-point Likert scale. Results: The majority of patients (89%) had good or excellent BCCT.core scores, which correlated with surgeons’ scores, rs = − 0.22 (p < 0.001). Overall, patients were more satisfied with the cosmetic outcomes than the surgeons (p < 0.001). Evidence supporting an association between the defined clinicopathological variables, for example, tumor size, and cosmetic outcomes, was weak. Conclusion: Therapeutic mammoplasty yields a very good cosmetic outcome, evaluated both by subjective and objective measurements. Importantly, symmetry can be improved in patients with asymmetry

Validated prediction model for positive resection margins in breast-conserving surgery based exclusively on preoperative data

BACKGROUND: Positive margins after breast-conserving surgery (BCS) and subsequent second surgery are associated with increased costs and patient discomfort. The aim of this study was to develop a prediction model for positive margins based on risk factors available before surgery. METHODS: Patients undergoing BCS for in situ or invasive cancer between 2015 and 2016 at site A formed a development cohort; those operated during 2017 in site A and B formed two validation cohorts. MRI was not used routinely. Preoperative radiographic and tumour characteristics and method of operation were collected from patient charts. Multivariable logistic regression was used to develop a prediction model for positive margins including variables with discriminatory capacity identified in a univariable model. The discrimination and calibration of the prediction model was assessed in the validation cohorts, and a nomogram developed. RESULTS: There were 432 patients in the development cohort, and 190 and 157 in site A and B validation cohorts respectively. Positive margins were identified in 77 patients (17.8 per cent) in the development cohort. A non-linear transformation of mammographic tumour size and six variables (visible on mammography, ductal carcinoma in situ, lobular invasive cancer, distance from nipple-areola complex, calcification, and type of surgery) were included in the final prediction model, which had an area under the curve of 0.80 (95 per cent c.i. 0.75 to 0.85). The discrimination and calibration of the prediction model was assessed in the validation cohorts, and a nomogram developed. CONCLUSION: The prediction model showed good ability to predict positive margins after BCS and might, after further validation, be used before surgery in centres without the routine use of preoperative MRI.Presented in part to the San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, December 2018 and the Swedish Surgical Society Annual Meeting, Helsingborg, Sweden, August 2018

St Gallen 2019 guidelines understage the axilla in lobular breast cancer : a population-based study

BACKGROUND: The St Gallen 2019 guidelines for primary therapy of early breast cancer recommend omission of completion axillary lymph node dissection (cALND), regardless of histological type, in patients with one or two sentinel lymph node (SLN) metastases. Concurrently, adjuvant chemotherapy is endorsed for luminal A-like disease with four or more axillary lymph node (ALN) metastases. The aim of this study was to estimate the proportion of patients with invasive lobular cancer (ILC) versus invasive ductal cancer of no special type (NST) with one or two SLN metastases for whom cALND would have led to a recommendation for adjuvant chemotherapy. METHODS: Patients with ILC and NST who had surgery between 2014 and 2017 were identified in the National Breast Cancer Register of Sweden. After exclusion of patients with incongruent or missing data, those who fulfilled the St Gallen 2019 criteria for cALND omission were included in the population-based study cohort. RESULTS: Some 1886 patients in total were included in the study, 329 with ILC and 1507 with NST. Patients with ILC had a higher metastatic nodal burden and were more likely to have a luminal A-like subtype than those with NST. The prevalence of at least four ALN metastases was higher in ILC (31.0 per cent) than NST (14.9 per cent), corresponding to an adjusted odds ratio of 2.26 (95 per cent c.i. 1.59 to 3.21). Luminal A-like breast cancers with four or more ALN metastases were over-represented in ILC compared with NST, 52 of 281 (18.5 per cent) versus 43 of 1299 (3.3 per cent) (P < 0.001). CONCLUSION: Patients with ILC more often have luminal A-like breast cancer with at least four nodal metastases. Omission of cALND in patients with luminal A-like invasive lobular cancer and one or two SLN metastases warrants future attention as there is a risk of nodal understaging and undertreatment in one-fifth of patients