Tumescent technique versus electrocautery mastectomy: A randomized controlled trial

BackgroundBreast cancer is the most common cancer in Danish women. In 2016 about 1450 (31%) Danish breast cancer patients had a mastectomy.The aim was to compare the frequency of postoperative complications in two methods of surgery, electrocautery dissection and tumescent technique, when performing a mastectomy.MethodsOpen randomized controlled trial of all consecutive primary breast cancer or DCIS female patients who underwent either a simple mastectomy or a modified radical mastectomy in Vejle Hospital, from January 2012 to October 2017.Primary outcomes were seroma production, bleeding, infection and necrosis.Secondary outcomes were duration of surgery and delay of adjuvant treatment caused by complications.Categorical outcome variables were compared between randomization groups using chi-square of Fisher exact test and continuous outcome variables by using Wilcoxon rank test. All analyses were performed at a 5% two-sided significance level.Results357 patients met the inclusion criteria. 14 had bilateral mastectomy, i.e. 371 breasts. The two randomization groups consisted of 105 patients/107 breasts operated by tumescent technique and 98 patients/102 breasts operated by electrocautery technique.Tumescent technique produced more seroma though not significant (p = 0.631) (mean 605 vs. 630 ml). Bleeding in the tumescent group was 10.3% vs. 5.9% in the electrocautery group (p = 0.245).Infection (5.9% vs. 7.5% p = 0.645) and necrosis (4.9% vs. 4.7% p = 0.938) was uncommon with no difference between the intervention groups.Infection was most common cause of delay of adjuvant treatment; 3.9% in the electrocautery technique group.No significant difference in duration of surgery (p = 0.392).ConclusionBoth techniques are equally safe for simple and modified radical mastectomy.     

Patient Satisfaction Following Level II Oncoplastic Breast Surgery: A Comparison with Mastectomy Utililizing the Breast-Q Questionnaire will be published in Surgical Oncology

IntroductionOncoplastic breast surgery (OBS) is increasingly used to decrease the deformity in breast conserving therapy (BCT) for breast cancer. We aimed to evaluate patient reported satisfaction following level II OBS and mastectomy utilizing the BREAST-Q questionnaire.MethodsPatients who underwent level II OBS BCT and those who underwent mastectomies were distributed the BREAST-Q post-reduction/mammoplasty module. Clinicopathological data were collected from review of patient charts. Results were scored using the standardized scoring system (Q-score). Results of the OBS group were compared to those in the mastectomy group.ResultsA total of 88 patients who underwent level II OBS and 101 patients who underwent mastectomy completed the questionnaire. Mann-Whitney odds estimator demonstrated higher satisfaction with breasts (1.51, 95% CI [1.04–2.25], p = 0.026) and higher psychosocial well-being (1.51, 95% CI [1.04–2.15], p = 0.022) in those who underwent OBS compared to mastectomy.ConclusionResults demonstrate a high satisfaction with breasts and improved psychosocial wellbeing in patients who underwent level II OBS compared to those undergoing mastectomy. These results demonstrate that OBS should be considered in patients where mastectomy otherwise would be necessary. Further larger multi-institutional studies are necessary to examine the effect of OBS on the quality of life of breast cancer patients.     

FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial

BackgroundPredictive markers of response to chemotherapy are lacking in breast cancer patients. Forkhead Box Protein 3 (FOXP3) is an anti-oncogene whose absence in cancer cells could confer resistance to DNA damaging agent. So we made the hypothesis that FOXP3 expression predicts the response to anthracyclines in breast cancer patients and that adjuvant chemotherapy adding taxanes to anthracyclines confers an overall survival (OS) benefit over anthracyclines alone, in patients with FOXP3-negative tumors.Patients and methodsExpression of FOXP3 in cancer cells was evaluated by immunohistochemistry in tumor samples from 1097 patients who participated in the PACS01 randomized trial that evaluated in adjuvant setting the adjunction of docetaxel (Taxotere) to anthracyclines in patients with localized breast cancer. Kaplan–Meier analysis and Cox regression model were used to assess OS according to the presence or absence of FOXP3 expression in tumor cells.ResultsFour hundred and five tumors were found to express FOXP3 (37%). FOXP3 expression in breast cancer cells was associated with better OS (P = 0.003). Uni- and multivariate survival analyses according to treatment arm revealed that FOXP3 expression in breast cancer cells is independently associated with improved OS in patients treated with anthracycline-based adjuvant chemotherapy, but not in patients treated with sequential anthracycline–taxane. Moreover, in vitro experiments showed that FOXP3 induction in breast cancer cell lines using histone deacetylase inhibitor enhances anthracyclines efficacy.ConclusionFOXP3 expression in tumor cells may be an accurate predictive biomarker of anthracycline efficacy in breast cancer.     

An evaluation of the clinical significance of FOXP3<Superscript>+</Superscript> infiltrating cells in human breast cancer

Studies in mice have shown that thymic-derived CD4+ CD25+ regulatory T cells (T reg; FOXP3⁺ lymphocytes) inhibit an antitumour immune response. Additional studies have also reported that the T reg population increases in peripheral blood and tumour tissues from patients with cancer. However, the relationship between the T reg population and the patient prognosis remains controversial. Our aim was to determine the prognostic value of T reg cell density in breast cancer using immunohistochemical assessment of FOXP3, which has been shown to be the optimal marker for T regs. Tissue microarrays were used, and the density of FOXP3⁺ cells was determined in a series of 1445 cases of well-characterised primary invasive breast carcinoma cases with long-term follow up. FOXP3⁺ cell numbers were counted in tumour nests, in tumour-adjacent stroma, and in distant stroma. The total number of FOXP3⁺ cells significantly correlated with higher tumour grade (r _s = 0.37, P < 0.001) and ER negativity (Mann–Whitney U test, P < 0.001). In addition, FOXP3 infiltration positively correlated with HER2 expression and basal phenotype subclass. On univariate analysis, FOXP3⁺ cells were associated with a worse prognosis (P = 0.012, log rank = 6.36). This association was found for intratumoural FOXP3⁺ and for tumour-adjacent stromal FOXP3⁺-cells (tumour-cell associated FOXP3, P = 0.001 and log rank 10.35). However, the number of FOXP3⁺ cells was not found to be an independent prognostic factor in multivariate analysis. We therefore conclude that FOXP3⁺ infiltrating cells do not have a dominant role in breast cancer prognosis and suggest that other inflammatory cell subsets may be more critical variables.     

Effect of standardised surgical assessment and shared decision-making on morbidity and patient satisfaction after breast conserving therapy: A cross-sectional study

BackgroundThe role of oncoplastic breast conserving therapy (OPBCT) on physical function, morbidity and patient satisfaction has yet to be defined. Additionally, technique selection should be individualised and incorporate patient preference. The study aim was to investigate differences between “standard” (sBCT) and oncoplastic breast conservation (OPBCT) in patient-reported outcomes (PROs) when patients have been assessed in a standardised manner and technique selection has been reached through shared decision-making (SDM).MethodsThis is a cross-sectional study of 215 women treated at a tertiary referral centre. Standardised surgical assessment included breast and lesion volumetry, definition of resection ratio, patient-related risk factors and patient preference. Postoperative morbidity and patient satisfaction were assessed by validated PROs tools (Diseases of the Arm, Shoulder and Hand-DASH and Breast-Q). Patient experience was assessed by semi-structured interviews.ResultsThere was no difference of the median values between OPBCT and sBCT in postoperative morbidity of the upper extremity (DASH 3.3 vs 5, p = 0.656) or the function of the chest wall (Breast-Q 82 vs 82, p = 0.758). Postoperative satisfaction with breasts did not differ either (Breast-Q 65 vs 61, p = 0.702). On the individual level, women that opted for OPBCT after SDM had improved satisfaction when compared to baseline (+3 vs ?1, p = 0.001). Shared decision-making changed patient attitude in 69.8% of patients, leading most often to de-escalation from mastectomy.ConclusionsThese findings support that a combination of standardised surgical assessment and SDM allows for tailored treatment and de-escalation of oncoplastic surgery without negatively affecting patient satisfaction and morbidity.     

Comparison of Immediate Breast Reconstruction Outcomes in Patients With and Without Prior Cosmetic Breast Surgery

BackgroundSkin-sparing (SSM) and nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) have significantly increased. There is limited information on complications of IBR in patients with prior cosmetic breast surgery (CBS). We compare IBR outcomes in patients undergoing SSM and/or NSM with and without prior CBS.Materials and MethodsPatients undergoing mastectomy from January 1, 2017 to December 31, 2019 were selected. Patient characteristics, surgical approach, and complications were compared between mastectomy and IBR cases for breasts with and without prior CBS. Binary logistic regression analysis was performed to identify predictors of complications and reconstruction loss.Results956 mastectomies were performed in 697 patients, with IBR performed for 545 mastectomies in 356 patients. Median age was 51 (range 19-83), 45.8% of patients were age < 50, 62.6% of mastectomies were performed for breast cancer. 95 mastectomies (17.4%) were performed in breasts with prior CBS and 450 (82.6%) without. NSM was more frequently utilized for breasts with prior CBS (P < .001). Complications occurred in 80 mastectomies (14.7%); reconstruction loss in 30 (5.5%). On multivariable analysis, age ≥ 50 (OR 1.76, 95%CI 1.01-3.09, P = .047) and NSM (OR 2.11, 95%CI 1.17-3.79, P = .013) were associated with an increased risk of any complication. Prior CBS was not associated with an increased risk of complications (OR 1.11, 95%CI 0.58-2.14, P = .743) or reconstruction loss (OR 1.32, 95%CI 0.51-3.38, P = .567).ConclusionIn this analysis of mastectomy and IBR, prior CBS was not associated with an increased risk of complications or reconstruction loss. In patients with prior CBS undergoing mastectomy, IBR may be safely performed.     

Uni-vs. bilateral DIEP flap reconstruction – A multicenter outcome analysis

ObjectiveOver the past decade numbers of bilateral mastectomy have increased steadily. As a result, bilateral breast reconstruction is gaining popularity. The presented study compares complications and outcomes of unilateral and bilateral DIEP free-flap breast reconstructions using the largest database available in Europe.MethodsFemale breast cancer patients (n = 3926) receiving DIEP flap breast reconstructions (n = 4577 free flaps) at 22 different centers were included in this study. Free flaps were stratified into two groups: a unilateral- (UL) and a bilateral- (BL) breast reconstruction group. Groups were compared with regard to surgical complications and free flap outcome.ResultsMean operative time was significantly longer in the BL group (UL: 285.2 ± 107.7 vs. BL: 399.1 ± 136.8 min; p < 0.001). Mean ischemia time was comparable between groups (p = 0.741). There was no significant difference with regard to total (UL 1.8% vs. BL 2.6%, p = 0.081) or partial flap loss (UL 1.2% vs. BL 0.9%, p = 0.45) between both groups. Rates of venous or arterial thrombosis were comparable between both groups (venous: UL 2.9% vs. BL 2.2%, p = 0.189; arterial: UL 1.8% vs. BL 1.2%, p = 0.182). However, significantly higher rates of hematoma at the donor and recipient site were observed in the UL group (donor site: UL 1.1% vs. BL 0.1%, p = 0.001; recipient site UL 3.9% vs. BL 1.7%, p < 0.001).ConclusionsThe data underline the feasibility of bilateral DIEP flap reconstruction, when performed in a setting of specialized centers.     

BROWSE: A multicentre comparison of nine year outcomes in acellular dermal matrix based and complete submuscular implant-based immediate breast reconstruction-aesthetics,capsular contracture and patient reported outcomes

Approximately 60% of implant-based breast reconstructions (IBBR) are performed with an acellular dermal matrix (ADM), for which, reliable, good quality long-term outcome data is limited. In a retrospective multicentre cohort study, we aimed to determine long-term aesthetic and quality of life outcomes of IBBR with ADM (Strattice?) compared to a submuscular technique.MethodsCapsular contracture (Baker III/IV capsule) was determined by clinical examination by an independent researcher. Quality of life was assessed using BREAST-Q and aesthetic outcome by photographic assessment from a breast surgeon, breast care nurse and lay person, blinded to reconstruction type.ResultsWe recruited 117 (51 bilateral) patients with ADM reconstructions, median follow-up 62 months (range 29–113) and 49 patients (16 bilateral) with submuscular reconstructions, median follow-up 76 months (range 38–111). 17 (10.1%) ADM reconstructions were Baker 3/4 compared to six (9.2%) submuscular (p = 0.85). Of the Baker 1/2 reconstructions six (3.6%) ADM and eight (13.6%) submuscular had previously undergone revision surgery to correct capsular contracture (p = 0.01). Combining both findings gave an estimated rate of capsular contracture of 13.6% in the ADM group and 21.2% in the submuscular (p = 0.14). A higher mean score for satisfaction with breasts was demonstrated when comparing ADM to submuscular (62 and 55, respectively; p = 0.01) but no significant difference in other BREAST-Q domains. The mean ‘general satisfaction’ score was higher in the ADM group for all three photograph assessors.ConclusionThis study provides evidence of improved aesthetic outcome and reduction in capsular contracture with ADM reconstruction when compared to submuscular, consistent over long-term follow-up.     

Factors which affect use of breast conservation and mastectomy in an underinsured Hispanic population

BackgroundDespite no difference in overall survival between breast conservation and mastectomy, significant variation exists between institutions and within populations. Less data exists about racial and ethnic minority populations. The current study was performed to evaluate variables that affect use of breast conservation and mastectomy in an underinsured Hispanic population.MethodsA retrospective review was performed of all patients who self-identified as of Hispanic ethnicity and underwent breast cancer operations from July 2001 to February 2011 at a safety net hospital. Sociodemographic, clinical, and treatment variables were evaluated. All patients with documented contraindications to breast conservation were excluded. Univariate analysis and multivariate analysis were performed to identify variables which were associated with type of operation.ResultsThe average age of the 219 patients included was 50 years. Most of the patients (93%) were insured with Medicaid or uninsured and 59% presented with clinical stage 2A/B cancers. Mastectomy was performed in 33% of patients and 67% had breast conservation. In adjusted multivariate analysis higher pathologic stage (p = 0.01) and English speakers (p = 0.03) were associated with mastectomy. By contrast, higher BMI (p = 0.03) and use of preoperative chemotherapy (p = 0.01) were associated with breast conservation.ConclusionsIn this underinsured Hispanic population, patients with higher pathologic stage and English speaking patients were more likely to undergo mastectomy. Patients who underwent preoperative chemotherapy and who had higher BMI were more likely to undergo breast conservation.     

Determinants of receiving immediate breast reconstruction: An analysis of patient characteristics at a tertiary care center in the US

BackgroundBreast reconstruction is an option for women undergoing mastectomy for breast cancer. Previous studies have reported underutilization of reconstructive surgery. This study aims to examine the role demographic, clinical and socio-economic factors may have on patients’ decisions to undergo breast reconstruction.MethodsWe analyzed data from our institutional database. Using multivariable and multinomial logistic regression, we compared breast cancer patients who had undergone mastectomy-only to those who had immediate breast reconstruction (overall and by type of reconstruction).ResultsWe analyzed data on 1459 women who underwent mastectomy during the period 2003–2015. Of these, 475 (32.6%) underwent mastectomy-only and 984 (67.4%) also underwent immediate breast reconstruction. After adjusting for potential confounders, older age (OR = 0.18, 95%CI:0.08–0.40), Asian race (OR = 0.29, 95%CI:0.19–0.45), bilateral mastectomy (OR = 0.71, 95%CI:0.56–0.90), and higher stage of disease (OR = 0.44, 95%CI:0.26–0.74) were independent risk factors for not receiving immediate breast reconstruction. Furthermore, patients with Medicare or Medicaid insurance were less likely than patients with private insurance to receive an autologous reconstruction. There was no evidence for changes over time in the way socio-demographic and clinical factors were related to receiving immediate breast reconstruction after mastectomy.ConclusionsClinical characteristics, sociodemographic factors like age, race and insurance coverage affect the decision for reconstructive surgery following mastectomy.     

Second invasive breast cancers in patients treated with breast-conserving therapy

ObjectiveSecond breast cancers after breast-conserving therapy (BCT) include ipsilateral breast tumor recurrence (IBTR) and metachronous contralateral breast cancer (CBC). Each IBTR is further classified as true recurrence (TR) or new primary tumor (NP). We aim to compare survival outcomes of TR, NP and CBC, and explore the optimal treatments.Methods168,427 patients with primary breast cancer who underwent BCT between 1990 and 2005 were identified in the SEER database. The risks of IBTR and CBC were estimated by annual hazard rate. The breast cancer-specific survival (BCSS) were assessed using multivariable Cox regression analysis.ResultsWith median follow-up of 13 years after BCT, 5413 patients developed an IBTR and 4050 patients had a CBC. The risk of IBTR peaked between 10 and 15 years after BCT, while the risk of CBC distributed evenly. 45.9% of IBTRs were classified as a TR and 54.1% as an NP. The time interval from primary breast cancer to NP was longer than to TR and CBC (P < 0.001). Patients with TR had a poorer BCSS than NP (P = 0.003) and CBC (P = 0.002). There was no difference in BCSS between mastectomy and repeat BCT for treating TR (P = 0.584) or NP (P = 0.243). The BCSS of CBCs treated with BCT was better than mastectomy (P = 0.010). Chemotherapy didn't improve the survival of patients with TR (P = 0.058). However, TRs with grade III or negative hormone receptors benefited from chemotherapy significantly.ConclusionPatients with TR had a poorer BCSS than NP and CBC. Classifying IBTR may provide clinical significance for treatments.     

Multifocality in ipsilateral breast tumor recurrence - A study in ablative specimens

BackgroundThe incidence and clinical significance of multifocality in ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) are unclear. With growing interest in repeat BCT, this information has become of importance. This study aimed to gain insight in the incidence of multifocality in IBTR, to identify patient- and tumor-related predicting factors and to investigate the prognostic significance of multifocality.MethodsTwo hundred and fifteen patients were included in this analysis. All had an IBTR after BCT and were treated by salvage mastectomy and appropriate adjuvant therapy. Predictive tumor- and patient-related factors for multifocality in IBTR were identified using X2 test and univariate logistic regression analyses. Prognostic outcomes were calculated using Kaplan Meier analysis and compared using the log rank test.ResultsMultifocality was present in 50 (22.9%) of IBTR mastectomy specimens. Axillary positivity in IBTR was significantly associated with multifocality in IBTR. Chest wall re-recurrences occurred more often after multifocal IBTR (14% versus 7% after unifocal IBTR, p = 0.120). Regional re-recurrences did not differ significantly between unifocal and multifocal IBTR (8% vs. 6%, p = 0.773). Distant metastasis after salvage surgery occurred more frequently after multifocal IBTR (15% vs. 24%, p = 0.122). Overall survival was 132 months after unifocal IBTR and 112 months after multifocal IBTR (p = 0.197).ConclusionThe prevalence of multifocality in IBTR is higher than in primary breast cancer. Axillary positivity in IBTR was associated with a multifocal IBTR. Chest wall re-recurrences and distant metastasis were, although not statistically significant, more prevalent after multifocal IBTR.     

Psychosocial well-being at time of diagnosis of breast cancer affects the decision whether or not to undergo breast reconstruction

ObjectivesNumerous studies have shown that breast reconstruction after mastectomy improves QoL in breast cancer survivors. However, still about half of the patients does not opt for reconstruction. In order to accommodate suitable counseling, we should elucidate the factors that play a role in the decision-making process. This study aimed to evaluate the influence of QoL, among women diagnosed with breast cancer before the start of any treatment, on their decision whether or not to undergo breast reconstruction.Materials and methodsBREAST-Q surveys were provided to breast cancer patients at the specialized breast care outpatient clinic after their first consultation with a surgical oncologist, between June 2017 and March 2019. The Q-scores of the subdomains physical well-being, psychosocial well-being, sexual well-being, and satisfaction with breasts of patients that underwent mastectomy were statistically analyzed.ResultsSixty-seven patients, undergoing mastectomy, completed the questionnaire. Fifty-four percent received reconstructive surgery. Mean age of patients seeking breast reconstruction was significantly lower than patients who did not opt for a reconstruction (53.5 vs. 63.7). Mean follow-up after mastectomy was 18.1 months. Except for satisfaction with breasts, mean Q-scores were higher in the group of patients who did not choose for reconstructive surgery. Psychosocial well-being was significantly higher in the non-reconstruction group (p = 0.012).ConclusionsPsychosocial well-being at time of diagnosis of breast cancer was significantly higher in patients refraining from breast reconstructive surgery after mastectomy. Psychosocial characteristics might be essential for the decision-making process as well. Further prospective research should evaluate this.     

Trends and timing of risk-reducing mastectomy uptake in unaffected BRCA1 and BRCA2 carriers in Slovenia

ObjectivesRisk-reducing mastectomy (RRM) is one of key prevention strategies in female carriers of germline BRCA pathogenic/likely pathogenic variants (PV/LPV). We retrospectively investigated the rate, timing and longitudinal trends of bilateral RRM uptake and the incidence and types of cancers among unaffected BRCA carriers who underwent genetic counseling at the Institute of Oncology Ljubljana in Slovenia.Materials and methodsFemale BRCA carriers without personal history of cancer were included in the study. Clinical data on PV/LPV type, date of RRM, type of reconstructive procedure, occult carcinoma and histopathology results was collected and analyzed.ResultsOf the 346 unaffected BRCA carriers (median age 43 years, 70% BRCA1, 30% BRCA2, median follow-up 46 months) who underwent genetic testing between October 1999 and December 2019, 25.1% had a RRM (range 35–50 years, median age at surgery 38 years). A significant difference in time to prophylactic surgery between women undergoing RRM only vs. women undergoing RRM combined with risk-reducing salpingo-oophorectomy was observed (22.6 vs 8.7 months, p = 0.0009). We observed an upward trend in the annual uptake in line with the previously observed Angelina Jolie effect. In 5.7% of cases, occult breast cancer was detected. No women developed breast cancer after RRM. Women who did not opt for surgical prevention developed BRCA1/2-related cancers (9.3%).ConclusionThe uptake of RRM among unaffected BRCA carriers is 25.1% and is similar to our neighboring countries. No women developed breast cancer after RRM while women who did not opt for surgical prevention developed BRCA1/2 related cancers in 9.3% of cases. The reported data may provide meaningful aid for carriers when deciding on an optimal prevention strategy.     

Surgical management of BRCA-mutation carriers: A single institution experience

IntroductionThe optimal surgical management of BRCA-mutation carriers remains a subject of debate. To evaluate the appropriateness of breast cancer (BC) treatment, the oncological outcomes of BRCA-mutation carriers treated either with breast-conserving therapy (BCT) or mastectomy were compared. Additionally, the role of bilateral salpingo-oophorectomy (BSO) and potential independent predictive factors for BC treatment were analyzed.Materials and methodsWe retrospectively reviewed all the consecutive patients with a pathogenic germline mutation in the BRCA1/2 genes tested at our Institution between July 2008 and October 2018. Primary end-points were disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS).ResultsThe characteristics and outcomes of 124 BRCA-associated BC patients were analyzed. Overall, 69 (55.7%) and 55 (44.3%) patients underwent BCT and mastectomy, respectively; 72 (58.1%) patients underwent BSO. After a median interval of 13.3 months, 24 patients underwent mastectomy after primary BCT. There was no significant difference in terms of DFS, DDFS, and OS between patients treated with BCT or mastectomy (p = 0.39,p = 0.27,p = 0.265, respectively). Patients treated with BSO had significantly better DDFS and OS compared to ovarian conservation (p = 0.033,p = 0.040, respectively). Three independent predictive factors for BCT were identified: age ≤41 years, genetic testing performed post-operatively, and breast tumors ≤21 mm.ConclusionsOur data suggest that BRCA-mutation carriers treated with BCT present similar oncological outcomes compared to mastectomy. Ovarian preservation decreases survival. Young BRCA-mutated patients with small BCs may not need up-front mastectomy, and BSO might be performed when ovarian cancer risk epidemiologically rises and potential reproductive desire is fulfilled.     

FOXP3-positive regulatory T lymphocytes and epithelial FOXP3 expression in synchronous normal, ductal carcinoma in situ, and invasive cancer of the breast

FOXP3-expressing T regulatory lymphocytes (Tregs) have been described as putative mediators of immune tolerance, and thus facilitators of tumor growth. When found in association with various malignancies, Tregs are generally markers of poor clinical outcome. However, it is unknown whether they are also associated with cancer progression. We evaluated quantitative FOXP3 expression in lymphocytes as well as in epithelial cells in a set of thirty-two breast tumors with synchronous normal epithelium, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) components. Tumors were stained for FOXP3 and CD3 expression and Tregs quantified by determining the ratio of colocalized FOXP3 and CD3 relative to 1) total CD3-expressing lymphocytes and 2) to FOXP3-expressing epithelial cells. The median proportion of FOXP3-expressing CD3 cells significantly increased with malignant progression from normal to DCIS to IDC components (0.005, 0.019 and 0.030, respectively; p ≤ 0.0001 for normal vs. IDC and p = 0.004 for DCIS vs. IDC). The median intensity of epithelial FOXP3 expression was also increased with invasive progression and most markedly augmented between normal and DCIS components (0.130 vs. 0.175, p ≤ 0.0001). Both Treg infiltration and epithelial FOXP3 expression were higher in grade 3 vs. grade 1 tumors (p = 0.014 for Tregs, p = 0.038 for epithelial FOXP3), but did not vary significantly with hormone receptor status, size of invasive tumor, lymph node status, or disease stage. Notably, Treg infiltration significantly correlated with epithelial up-regulation of FOXP3 expression (p = 0.013 for normal, p = 0.001 for IDC). These findings implicate both Treg infiltration and up-regulated epithelial FOXP3 expression in breast cancer progression.     

Surgery following neoadjuvant chemotherapy for HER2-positive locally advanced breast cancer. Time to reconsider the standard attitude

BackgroundWhile the addition of targeted therapy to neoadjuvant chemotherapy (NACT) dramatically increases the rate of pathological complete response in HER2-positive breast cancer, no reduction in the rate of mastectomy has been observed in randomised studies.MethodsA retrospective single centre analysis of all patients treated with anti HER2-based NACT for T2–4 breast cancer, focusing on patients treated with mastectomy.ResultsAmong 165 patients treated between June 2005 and July 2012, surgery was performed immediately post-NACT in 152 cases (92%). Breast-conserving surgery could be performed for 108 of the patients (71%), with a 4-year local relapse-free survival of 97%. A mastectomy was performed in two cases following patients’ wishes and in 37 cases based on pre-NACT findings (n = 18) or post-NACT outcomes (n = 19). For 21 out of the 37 cases, a good pathological response was observed, and multidisciplinary reanalysis suggests that breast-conserving surgery outright may have been sufficient for 12 patients. Finally, a salvage mastectomy based on post-lumpectomy pathological results was decided in five cases (11%). The 4-year metastasis-free survival was 84% for all patients operated on after NACT (n = 152).ConclusionsGiven the good efficacy of anti HER2-based NACT, breast-conserving surgery should be standard practice for most patients. Total mastectomy on the other hand should be restricted to a few patients, mainly those with positive margins on the lumpectomy specimen.     

Correlation between severe infection and breast cancer metastases in the EORTC 10994/BIG 1-00 trial: Investigating innate immunity as a tumour suppressor in breast cancer

BackgroundBreast cancer cells which express an innate immune signature regulated by interferon regulatory factor 7 (IRF7) have reduced metastatic potential. Infections can induce interferon signalling and may activate an anti-tumour immune response. We investigated whether ‘severe infection’ can be a clinical surrogate of this phenomenon and/or the presence of high levels of the IRF7 signature at diagnosis before neo-adjuvant chemotherapy (NACT) is associated with a reduced distant relapse risk, specifically in bones.MethodsClinical data of the European Organisation for Research and Treatment of Cancer 10994/BIG 1-00 phase III trial which randomised 1856 patients treated with NACT between 2001 and 2006, were used. Severe infection was febrile neutropenia or any other grade III–IV infective adverse event during NACT. The IRF7 signature was calculated from gene expression data available for 160 patients on a pre-NACT biopsy. Cox models for distant relapse-free interval (DRFI) investigated the effect of the severe infection and IRF7. Fine and Gray models studied the occurrence of bone metastases as first distant relapse.ResultsMedian follow-up was 4.8 years. No association between severe infection and DFRI was observed in the entire population (n = 1615 eligible patients) hazard ratio [(HR] = 0.99, 90% CI, confidence interval [CI] = 0.81–1.20). For IRF7 (N = 160), a trend towards an association with DRFI was observed (HR = 0.89 for a 50 unit increase, 90% CI = 0.78–1.02, p = 0.081). Higher levels of the IRF7 signature were significantly associated with a decreased bone metastases risk: (HR = 0.76 for a 50 unit increase, 95% CI, 0.62–0.94, p = 0.012).ConclusionsIn this study it was shown that severe infection during NACT was not associated with decreased DRFI while high expression of the IRF7 gene signature was significantly associated with reduced bone relapse. This result may be useful for future adjuvant bisphosphonate/denosumab use.