Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

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.

The accuracy of MRI in detecting pathological complete response following neoadjuvant chemotherapy in different breast cancer subtypes.

BACKGROUND: Pathological complete response (pCR) following neo-adjuvant chemotherapy (NACT) for breast cancer is associated with improved disease-free and overall survival in certain breast cancer subtypes. Magnetic Resonance Imaging (MRI) is increasingly used as standard to assess treatment response in patients receiving NACT. The aim of this study was to determine the clinical utility of MRI in accurately predicting pCR post-NACT. METHODS: A single-centre, retrospective study was conducted in breast cancer patients, who received NACT between 2013 and 2020. Patients who had an MRI before and after NACT were included. Pathological and MRI radiological response rates to NACT were analyzed and MRI accuracy assessed in detecting pCR according to breast cancer subtype. RESULTS: One hundred and sixty-seven patients were included in the study. Forty-one of the 167 patients achieved pCR (24.6 %), with the highest proportion in HR- HER2+ subgroup (58.3 %), followed by triple negative breast cancer (TNBC) (35 %). Only 22.2 % and 10.5 % of patients with HR + HER2+ and HR + HER2-respectively achieved pCR. The overall accuracy of MRI in predicting pCR after NACT was 77.3 %. The greatest accuracy was in TNBC (87.5 %) with a specificity and positive predictive value (PPV) of 100 % and the highest number of correctly diagnosed complete responses (14 of 40). MRI was less accurate in predicting response rates in HR + HER2- (PPV 91.2 %) and HR + HER2+ groups (PPV 90.5 %). MRI performed significantly better in predicting complete response in TNBC compared to HR + HER2-subtype (p = 0.0057). CONCLUSION: MRI is a clinically useful adjunct in assessing pCR following NACT and appears to predict pathological response more accurately in TNBC compared to HR + HER2-breast cancer subtypes. This has significant clinical implications in terms of surgical planning, adjuvant treatment options and prognosis.

Pregnancy-associated breast cancer: does timing of presentation affect outcome?

PURPOSE: Pregnancy-associated breast cancer (PABC) comprises breast cancer diagnosed during the gestational period or within 12 months postpartum. While the incidence of PABC appears to be increasing, data regarding prognosis remain limited. METHODS: Here we evaluate clinicopathologic features, treatments, and clinical outcomes among women with stage 0-III PABC diagnosed between 1992 and 2020. Comparisons were made between women who were diagnosed with PABC during gestation and those who were diagnosed within 12 months postpartum. RESULTS: A total of 341 women were identified, with a median age of 36 years (range 25-46). The pregnancy group comprised 119 (35%) women, while 222 (65%) women made up the postpartum group. Clinicopathologic features were similar between groups, with most patients being parous and presenting with stage I and II disease. Treatment delays were uncommon, with a median time from histologic diagnosis to treatment of 4 weeks for both groups. Recurrence-free survival was similar between groups: 67% at 10 years for both. While 10-year overall survival appeared higher in the postpartum group (83% versus 78%, p = 0.02), only the presence of nodal metastases was associated with an increased risk of death (hazard ratio 5.61, 95% CI 2.20-14.3, p < 0.001), whereas timing of diagnosis and receptor profile did not reach statistical significance. CONCLUSION: Clinicopathologic features of women with PABC are similar regardless of timing of diagnosis. While 10-year recurrence-free survival is similar between groups, 10-year overall survival is higher among women diagnosed postpartum; however, timing of diagnosis may not be the driving factor in determining survival outcomes.

A systematic review of oncological outcomes after nipple-sparing mastectomy for breast cancer.

Nipple-sparing mastectomy is an alternative to skin-sparing mastectomy in select patients. Increasing evidence supports its use in the setting of breast cancer, however concerns still exist regarding oncological safety. The aim of this systematic review was to evaluate long-term oncological outcomes of patients who underwent nipple-sparing mastectomy for breast cancer. A systematic review of the literature was performed to evaluate oncological outcomes in patients with breast cancer who underwent nipple-sparing mastectomy. Five major databases (PubMed, Embase, Scopus, Web of Science and Cochrane) were searched. The review included all original articles published in English reporting long-term oncological outcomes. 2334 studies were identified. After applying inclusion and exclusion criteria, 17 retrospective studies involving 7107 patients were included. The indication for nipple-sparing mastectomy was invasive carcinoma in 6069 patients (85.4%) and in situ disease in 1038 (14.6%). Median follow up was 48 months (range 25-94). The weighted mean rates of local recurrence and recurrence involving the nipple-areola complex were 5.4% (0.9-11.9) and 1.3% (0-4.9), respectively. The weighted mean distant failure rate was 4.8% (1.5-23.0). Therapeutic nipple-sparing mastectomy is oncologically safe in select patients with breast cancer.

Fertility treatment and breast-cancer incidence: meta-analysis.

BACKGROUND: The significance of exogenous hormone manipulation as part of fertility treatment and its relationship to the development of breast cancer remains uncertain. Several historical reviews have been performed with conflicting results. This study is an updated meta-analysis to determine whether there is a causal relationship between different fertility treatments and breast cancer. METHODS: The study report is based on the guidelines of PRISMA and Meta-Analysis of Observational Studies in Epidemiology. Studies published within the last 20 years were included to reflect up to date in vitro fertilization (IVF) practice. This study was prospectively registered on PROSPERO on 07/04/2021, registration identification CRD42021247706. The primary outcome of the study was to determine whether there is an increased incidence of breast cancer in women treated with hormonal fertility treatment. The secondary outcomes were to determine whether fertility treatments were individually associated with excess breast-cancer risk. RESULTS: Overall, 25 studies, including 617 479 participants, were eligible for inclusion. There was no significant breast-cancer risk association with fertility treatment (compared with general and subfertility reference groups). Summary odds ratio of all included studies was 0.97 (95 per cent c.i. 0.90 to 1.04). Women who received six or more IVF cycles did not have an increased risk of breast cancer. Similarly, there was no excess breast-cancer risk associated with clomiphene, human chorionic gonadotropin, gonadotropin analogues and progesterone when examined individually. Comparably, there was no significant association between fertility treatment and excess breast-cancer risk in patients with more than 10 years' follow-up. Summary odds ratio was 0.97 (95 per cent c.i. 0.85 to 1.12). CONCLUSION: This meta-analysis did not find a significant association between fertility treatments and excess breast-cancer risk. Women considering IVF should be informed that it does not appear to increase breast-cancer risk.

Optimal timing of surgery following breast cancer neoadjuvant chemotherapy: A systematic review and meta-analysis.

BACKGROUND: Administration of chemotherapy before breast surgery has the potential to reduce the risk of distant recurrence by targeting micrometastasis as well as allowing a more minimalistic approach to surgical intervention. We performed a systematic review to determine the optimum timing of surgery post breast cancer neoadjuvant chemotherapy (NACT). METHODS: The primary outcome was to determine whether the timing of surgery post NACT impacted overall survival (OS) and disease-free survival (DFS). We compared patient outcomes between those who had surgery within 8 weeks of completion of NACT to those that had surgery after 8 weeks. An outcome comparison between <4 weeks and 4-8 weeks was also performed. Secondary outcome included complete pathological response (pCR) post NACT. A meta-analysis was performed using the Mantel-Haenszel method. RESULTS: Five studies, including 8794 patients were eligible for inclusion. Patients that had surgery within 8 weeks of completion of NACT had a statistically significant improved OS(OR 0.47, 95% c. i 0.34-0.65) and DFS(OR 0.71 (95% c. i 0.52-0.98, P = 0.04). There were no survival advantages associated with having surgery less than 4 weeks post completion of NACT (OR 0.78, 95% c. i 0.46-1.33, P = 0.37). There was no difference in pCR rate between those that had surgery <4 weeks and 4-8 weeks (OR 1.01, 95% c. i 0.80-1.28, P = 0.93). CONCLUSION: This meta-analysis shows that the optimum timing of surgery post completion of NACT is 4-8 weeks as it is associated with increased OS and DFS.

The Impact of Postoperative Wound Complications on Oncological Outcomes Following Immediate Breast Reconstruction for Breast Cancer: A Meta-analysis.

The association between immediate breast reconstruction (IBR)-related wound complications and breast cancer recurrence (BCR) remains uncertain. This study aimed to investigate the oncological outcomes in patients with wound complications following mastectomy and IBR. A comprehensive search was undertaken for all studies describing complications in patients with breast cancer following IBR. Studies were included if they reported on complications and investigated their relationship with BCR. A meta-analysis was performed using a random-effects model, with data presented as odds ratios and 95% confidence intervals. A total of 1418 patients from five studies were included in the final analysis. The mean age of patients included was 47.2 years. A total of 382 (26.9%) patients had postoperative complications following a majority of implant-based IBR (929/1418). A total of 158 (11.1%) recurrences, which included 63 locoregional and 106 distant recurrences, was noted at a mean follow-up of 66 months. Although there was an increase in recurrence rates in the complication group (n = 66/382; 17.3% vs. n = 92/1036; 8.9%), there was no significant association between complications and BCR (17.3% vs. 8.9%; P = .18) or mortality (3.6% vs. 2.3%; P = .15). Time to adjuvant therapy was significantly increased in patients with complications (mean difference, 8.69 days; range, 1.18-16.21 days; P = .02; I2 = 0.02). This meta-analysis demonstrated a higher incidence of wound complications following IBR and a statistically significant increased time to adjuvant therapy. However, this did not translate into adverse oncological outcomes in patients with breast cancer undergoing IBR.

Fibromatosis of the breast: a 10-year multi-institutional experience and review of the literature.

BACKGROUND: Breast fibromatosis is a rare clinical entity, but poses significant diagnostic and therapeutic challenges. In light of recent changes in management practices, the aim was to review our institutional experience of breast fibromatosis and provide a review of current available literature on such management. METHODS: A search of pathological databases within two tertiary institutions for all patients diagnosed with fibromatosis of the breast over a 10-year period (2007-2016) was performed. Clinicopathological characteristics and modes of treatment were recorded for each patient. Concurrently a comprehensive literature search was performed and studies relating to breast fibromatosis and its management were identified and reviewed. RESULTS: Sixteen patients were identified. Median age at diagnosis was 42 (range 21-70) and all patients were diagnosed with core biopsy. The most useful imaging modality in diagnosis was ultrasonography and magnetic resonance imaging. 13/16 were treated surgically whilst 3/16 were treated using a watch-and-wait approach. 6/13 (46%) required re-excision of margins and 2/13 (15%) had recurrence after surgery. On review of the literature, there is no dedicated guideline in place for the management of breast fibromatosis. Currently a 'watch and wait' approach is favoured over surgical intervention due to high levels of recurrence and associated surgical morbidity. All cases should be discussed at a sarcoma multidisciplinary team meeting and tyrosine kinase inhibitors should be considered in advanced cases. CONCLUSIONS: Breast fibromatosis is rare but affects young patients. Active surveillance is now favoured over surgical resection due to high recurrence rates and extensive morbidity. Dedicated guidelines are required to ensure best outcomes.

False-negative rate of ultrasound-guided fine-needle aspiration cytology for identifying axillary lymph node metastasis in breast cancer patients.

Axillary nodal status remains an important determinant of prognosis and of the therapeutic strategy in patients with a newly diagnosed breast cancer. The aim of this study was to assess the false-negative rate of ultrasound (US)-guided fine-needle aspiration cytology (FNAC) in axillary node staging at breast cancer diagnosis. All patients with a newly diagnosed breast cancer who had an indeterminate or suspicious axillary node sampled with an FNAC between 2007 and 2014 were included in the study. FNAC results were compared to the final histopathological results of surgically removed axillary lymph nodes. Patient demographics, tumor, and nodal characteristics were analyzed. Diagnostic accuracy tests were performed using IBM SPSS, version 22. A total of 3515 patients with breast cancer were identified, 675 of whom had ultrasound-guided FNAC of ipsilateral axillary lymph nodes (mean age: 55 years; Range: 26-84). A benign (C2) result was observed in 52% (n = 351) and a malignant (C5) result in 35% (n = 238). C1 was obtained in 11% (n = 76), C3 in 0.6% (n = 4), and C4 in 0.9% (n = 6). Of the 238 patients with a malignant (C5) FNAC, 99.6% had confirmed axillary lymph node metastatic disease on histopathology. Of the 351 patients with benign FNAC (C2), 31% (n = 108) of patients had a positive lymph node on histology. The false-negative rate of preoperative FNAC remains too high (31%) to omit definitive surgical staging of the axilla. The high diagnostic accuracy when a positive FNAC is obtained allows appropriate tailored decisions regarding definitive therapy.

Breast screening in symptomatic women over 35 years of age: improvements in service efficiency.

INTRODUCTION: The rationalization of cancer services in Ireland saw all women with symptomatic breast problems referred to one of the eight regional cancer centers. A pilot triaging system was introduced in St Vincent's University Hospital to streamline these services. Women over 35 years who do not meet urgent referral criteria are referred for a mammogram prior to a clinic appointment ("image first"). The aim of this study was to retrospectively determine the recall rates, biopsy rates, and rate of breast cancer identification within this cohort of patients. This was compared to a screening population of patients. METHODS: Patients triaged into the "image first" group within a one-year period were identified. Results of the initial mammogram, further imaging and subsequent biopsies were recorded. Data relating to number of recalls, number of patients biopsied and number of cancers identified within the Merrion Unit of the National Breastcheck Screening Program was obtained for comparison. RESULTS: One thousand six hundred eighty-eight referrals were triaged as "image first" over this period. 185 (11%) of patients required a biopsy of an identified lesion. Breast cancer was diagnosed in 65 patients (3.9%). During the same study period, of the 42,099 women who were screened for breast cancer, 496 (1.8%) underwent biopsy and 267 (0.63%) were diagnosed with breast cancer. CONCLUSION: Image first patients, who represent a cohort of "symptomatic" non-urgent women, have a greater rate of breast cancer detection than an asymptomatic screening population. This may have an impact on the appropriate triaging of symptomatic women in a national cancer center.

Oncologic Outcomes After Treatment for MRI Occult Breast Cancer (pT0N+).

BACKGROUND: Studies assessing outcomes in occult breast cancer have often included women treated before the routine use of magnetic resonance imaging (MRI). This study examined outcomes for patients presenting with axillary adenopathy and no primary breast tumor detectable by MRI or other imaging methods. METHODS: All patients with axillary nodal metastases consistent with breast carcinoma and no breast primary tumor detectable by physical exam, mammography, or MRI treated between 1 January 1996 and 30 June 2011 were identified from an institutional database. Data were collected on local, regional, and distant recurrences. RESULTS: For the study, 38 patients were identified. Modified radical mastectomy (MRM) was performed for 13 of the patients, whereas 25 of the patients underwent axillary dissection (ALND) and whole-breast radiotherapy (WBRT). Most of the women had pathologic N1 disease [median number of positive nodes, 2 (MRM cohort) and 3 (ALND + WBRT cohort); p = 0.38]. All the patients received chemotherapy, and 30 (79%) of the 38 patients received an anthracycline and taxane. Regional nodal radiation was used for 60% of those with ALND + WBRT and for all 46% of the MRM patients who received chest wall radiotherapy. During a median follow-up period of 7 years, there were no nodal recurrences. Two patients treated with ALND + WBRT had in-breast recurrences, whereas none in the MRM group experienced a local recurrence. The proportion that experienced distant disease was similar between the MRM cohort (1 of 13) and the ALND + WBRT cohort (2 of 25). CONCLUSION: Breast cancer presenting as axillary adenopathy with no detectable primary tumor is rare. Breast conservation with WBRT is a viable option for patients with a diagnosis of occult breast cancer and a negative preoperative MRI.

Current Management of the Axilla.

Despite advances in estimating prognosis and predicting response to adjuvant systemic therapy, the status of the axillary lymph nodes remains a critical component in initial surgical planning and in determining therapeutic strategies for patients with breast cancer. Buoyed by evidence from multi-institutional randomized clinical trials, the last 2 decades have witnessed remarkable and practice-changing advances in our approach to the axilla. This review concentrates on the current best practice in axillary management for both node-negative and node-positive patients, with particular focus on the evolving management of the axilla in the era of neoadjuvant systemic therapy.

Impact of Body Mass Index on Clinical Axillary Nodal Assessment in Breast Cancer Patients.

BACKGROUND: More than one-third of American adults are obese, and an elevated body mass index (BMI) is postulated to reduce the sensitivity of the clinical evaluation of the axilla. Clinical nodal examination is important in allocating breast cancer patients to appropriate axillary management. This study sought to determine whether BMI influences the rate of nodal positivity in women designated clinically as node-negative (cN0) by physical examination. METHODS: Breast cancer patients deemed cN0 who underwent sentinel lymph node biopsy (SLNB) from February 2006 to December 2011 were identified from a prospectively maintained database. Clinicopathologic features including BMI and axillary surgery results were recorded and compared among pathologically node-negative and node-positive patients. RESULTS: Overall, 5142 cN0 patients underwent 5262 SLNB procedures during the study period. Nearly one-third of the patients (28 %) were obese (BMI, >30 kg/m(2)). A positive SLN was identified in 25 % of the patients, and 84 % proceeded to axillary lymph node dissection. Predictors of SLN positivity included younger age, larger tumor size, high nuclear grade, multifocality, and lymphovascular invasion. An increased BMI did not correlate with a higher likelihood of SLN positivity (p = 0.6). The likelihood of cN0 patients having a high burden of axillary metastases (>3 positive nodes) was 4 % overall and, similarly, did not differ according to BMI (p = 0.4). CONCLUSION: Elevated BMI was not associated with a higher likelihood of SLN positivity or heavy nodal disease burden among women staged as cN0 by physical exam. These findings indicate that physical examination is appropriate and sufficient for preoperative axillary evaluation of women undergoing initial surgery regardless of patient BMI.

Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer.

INTRODUCTION: HOX genes play vital roles in growth and development, however, atypical redeployment of these genes is often associated with steroidal adaptability in endocrine cancers. We previously identified HOXC11 to be an indicator of poor response to hormonal therapy in breast cancer. In this study we aimed to elucidate genes regulated by HOXC11 in the endocrine resistant setting. METHODS: RNA-sequencing paired with transcription factor motif-mapping was utilised to identify putative HOXC11 target genes in endocrine resistant breast cancer. Validation and functional evaluation of the target gene, prosaposin (PSAP), was performed in a panel of endocrine sensitive and resistant breast cancer cell lines. The clinical significance of this finding was explored in clinical cohorts at both mRNA and protein level. RESULTS: PSAP was shown to be regulated by HOXC11 in both tamoxifen and aromatase inhibitor (AI) resistant cell lines. Transcript levels of HOXC11 and PSAP correlated strongly in samples of primary breast tumours (r = 0.7692, n = 51). PSAP has previously been reported to activate androgen receptor (AR) in prostate cancer cells. In a panel of breast cancer cell lines it was shown that endocrine resistant cells exhibit innately elevated levels of AR compared to their endocrine sensitive counterparts. Here, we demonstrate that stimulation with PSAP can drive AR recruitment to a hormone response element (HRE) in AI resistant breast cancer cells. Functionally, PSAP promotes cell migration and invasion only in AI resistant cells and not in their endocrine sensitive counterparts. In a cohort of breast cancer patients (n = 34), elevated serum levels of PSAP were found to associate significantly with poor response to endocrine treatment (p = 0.04). Meta-analysis of combined PSAP and AR mRNA are indicative of poor disease-free survival in endocrine treated breast cancer patients (hazard ratio (HR): 2.2, P = 0.0003, n = 661). CONCLUSION: The HOXC11 target gene, PSAP, is an AR activator which facilitates adaptation to a more invasive phenotype in vitro. These findings have particular relevance to the development of resistance to AI therapy which is an emerging clinical issue. PSAP is a secreted biomarker which has potential in identifying patients failing to exhibit sustained response to hormonal treatment.

Transcriptomic Profiling of Sequential Tumors from Breast Cancer Patients Provides a Global View of Metastatic Expression Changes Following Endocrine Therapy.

PURPOSE: Disease recurrence is a common problem in breast cancer and yet the mechanisms enabling tumor cells to evade therapy and colonize distant organs remain unclear. We sought to characterize global expression changes occurring with metastatic disease progression in the endocrine-resistant setting. EXPERIMENTAL DESIGN: Here, for the first time, RNAsequencing has been performed on matched primary, nodal, and liver metastatic tumors from tamoxifen-treated patients following disease progression. Expression of genes commonly elevated in the metastases of sequenced patients was subsequently examined in an extended matched patient cohort with metastatic disease from multiple sites. The impact of tamoxifen treatment on endocrine-resistant tumors in vivo was investigated in a xenograft model. RESULTS: The extent of patient heterogeneity at the gene level was striking. Less than 3% of the genes differentially expressed between sequential tumors were common to all patients. Larger divergence was observed between primary and liver tumors than between primary and nodal tumors, reflecting both the latency to disease progression and the genetic impact of intervening therapy. Furthermore, an endocrine-resistant in vivo mouse model demonstrated that tamoxifen treatment has the potential to drive disease progression and establish distant metastatic disease. Common functional pathways altered during metastatic, endocrine-resistant progression included extracellular matrix receptor interactions and focal adhesions. CONCLUSIONS: This novel global analysis highlights the influence of primary tumor biology in determining the transcriptomic profile of metastatic tumors, as well as the need for adaptations in cell-cell communications to facilitate successful tumor cell colonization of distant host organs.

Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies.

Several "moderate-risk breast cancer susceptibility genes" have been conclusively identified. Pathogenic mutations in these genes are thought to cause a two to fivefold increased risk of breast cancer. In light of the current development and use of multigene panel testing, the authors wanted to systematically obtain robust estimates of the cancer risk associated with loss-of-function mutations within these genes. An electronic search was conducted to identify studies that sequenced the full coding regions of ATM, CHEK2, BRIP1, PALB2, NBS1, and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that sequenced the germline DNA in both high-risk cases and geographically matched controls. A meta-analysis was then performed on protein-truncating variants (PTVs) identified in the studies for an association with breast cancer risk. A total of 10,209 publications were identified, of which 64 studies comprising a total of 25,418 cases and 52,322 controls in the 6 interrogated genes were eligible under our selection criteria. The pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally, mutations in these genes have shown geographic and ethnic variation. This comprehensive study emphasizes the fact that caution should be taken when identifying certain genes as moderate susceptibility with the lack of sufficient data, especially with regard to the NBS1, RAD50, and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies, are warranted.

Preconditioning Shields Against Vascular Events in Surgery (SAVES), a multicentre feasibility trial of preconditioning against adverse events in major vascular surgery: study protocol for a randomised control trial.

BACKGROUND: Patients undergoing vascular surgery procedures constitute a 'high-risk' group. Fatal and disabling perioperative complications are common. Complications arise via multiple aetiological pathways. This mechanistic redundancy limits techniques to reduce complications that target individual mechanisms, for example, anti-platelet agents. Remote ischaemic preconditioning (RIPC) induces a protective phenotype in at-risk tissue, conferring protection against ischaemia-reperfusion injury regardless of the trigger. RIPC is induced by repeated periods of upper limb ischaemia-reperfusion produced using a blood pressure cuff. RIPC confers some protection against cardiac and renal injury during major vascular surgery in proof-of-concept trials. Similar trials suggest benefit during cardiac surgery. Several uncertainties remain in advance of a full-scale trial to evaluate clinical efficacy. We propose a feasibility trial to fully evaluate arm-induced RIPC's ability to confer protection in major vascular surgery, assess the incidence of a proposed composite primary efficacy endpoint and evaluate the intervention's acceptability to patients and staff. METHODS/DESIGN: Four hundred major vascular surgery patients in five Irish vascular centres will be randomised (stratified for centre and procedure) to undergo RIPC or not immediately before surgery. RIPC will be induced using a blood pressure cuff with four cycles of 5 minutes of ischaemia followed by 5 minutes of reperfusion immediately before the start of operations. There is no sham intervention. Participants will undergo serum troponin measurements pre-operatively and 1, 2, and 3 days post-operatively. Participants will undergo 12-lead electrocardiograms pre-operatively and on the second post-operative day. Predefined complications within one year of surgery will be recorded. Patient and staff experiences will be explored using qualitative techniques. The primary outcome measure is the proportion of patients who develop elevated serum troponin levels in the first 3 days post-operatively. Secondary outcome measures include length of hospital and critical care stay, unplanned critical care admissions, death, myocardial infarction, stroke, mesenteric ischaemia and need for renal replacement therapy (within 30 days of surgery). DISCUSSION: RIPC is novel intervention with the potential to significantly improve perioperative outcomes. This trial will provide the first evaluation of RIPC's ability to reduce adverse clinical events following major vascular surgery. TRIAL REGISTRATION: www.clinicaltrials.gov NCT02097186 Date Registered: 24 March 2014.