Pregnancy-associated plasma protein A regulates mitosis and is epigenetically silenced in breast cancer.

Aberrant mitosis is a common feature of cancer, yet little is known about the altered genes causing mitotic defects. We screened human tumours for cells with morphological signatures of highly specific mitotic defects previously assigned to candidate genes in a genome-wide RNA interference screen carried out in HeLa cells (www.mitocheck.org). We discovered a striking enrichment of early mitotic configurations indicative of prophase/prometaphase delay in breast cancer. Promoter methylation analysis of MitoCheck candidate genes assigned to the corresponding 'mitotic delay' class linked this defect to epigenetic silencing of the gene encoding pregnancy-associated plasma protein-A (PAPPA), a secreted protease. PAPPA silencing was highly prevalent in precursor lesions and invasive breast cancer. Experimental manipulation of PAPPA protein levels in human mammary epithelial cells and in breast cancer cell lines demonstrates that progression through early mitosis is dependent on PAPPA function, and that breast cancer cells become more invasive after down-regulation of this protease. PAPPA regulates mitotic progression through modulating the IGF-1 signalling pathway resulting in activation of the forkhead transcription factor FoxM1, which drives a transcriptional cluster of essential mitotic genes. Our results show that PAPPA has a critical function in normal cell division and is targeted early in breast cancer development.

Targeting DNA replication before it starts: Cdc7 as a therapeutic target in p53-mutant breast cancers.

Treatment options for triple-receptor negative (ER-/PR-/Her2-) and Her2-overexpressing (ER-/PR-/Her2+) breast cancers with acquired or de novo resistance are limited, and metastatic disease remains incurable. Targeting of growth signaling networks is often constrained by pathway redundancy or growth-independent cancer cell cycles. The cell-cycle protein Cdc7 regulates S phase by promoting DNA replication. This essential kinase acts as a convergence point for upstream growth signaling pathways and is therefore an attractive therapeutic target. We show that increased Cdc7 expression during mammary tumorigenesis is linked to Her2-overexpressing and triple-negative subtypes, accelerated cell cycle progression (P < 0.001), arrested tumor differentiation (P < 0.001), genomic instability (P = 0.019), increasing NPI score (P < 0.001), and reduced disease-free survival (HR = 1.98 [95% CI: 1.27-3.10]; P = 0.003), thus implicating its deregulation in the development of aggressive disease. Targeting Cdc7 with RNAi, we demonstrate that p53-mutant Her2-overexpressing and triple-negative breast cancer cell lines undergo an abortive S phase and apoptotic cell death due to loss of a p53-dependent Cdc7-inhibition checkpoint. In contrast, untransformed breast epithelial cells arrest in G1, remain viable, and are able to resume cell proliferation on recovery of Cdc7 kinase activity. Thus, Cdc7 appears to represent a potent and highly specific anticancer target in Her2-overexpressing and triple-negative breast cancers. Emerging Cdc7 kinase inhibitors may therefore significantly broaden the therapeutic armamentarium for treatment of the aggressive p53-mutant breast cancer subtypes identified in this study.

Have the organisms that cause breast abscess changed with time?--Implications for appropriate antibiotic usage in primary and secondary care.

Many patients with breast abscess are managed in primary care. Knowledge of current trends in the bacteriology is valuable in informing antibiotic choices. This study reviews bacterial cultures of a large series of breast abscesses to determine whether there has been a change in the causative organisms during the era of increasing methicillin-resistant Staphylococcus aureus (MRSA). Analysis was undertaken of all breast abscesses treated in a single unit over 2003 - 2006, including abscess type, bacterial culture, antibiotic sensitivity and resistance patterns. One hundred and ninety cultures were obtained (32.8% lactational abscess, 67.2% nonlactational). 83% yielded organisms. Staphylococcus aureus was the commonest organism isolated (51.3%). Of these, 8.6% were MRSA. Other common organisms included mixed anaerobes (13.7%), and anaerobic cocci (6.3%). Lactational abscesses were significantly more likely to be caused by S. aureus (p < 0.05). Methicillin-resistant Staphylococcus aureus rates were not statistically different between lactational and nonlactational abscess groups. Appropriate antibiotic choices are of great importance in the community management of breast abscess. Ideally, microbial cultures should be obtained to institute targeted therapy but we recommend the continued use of flucloxacillin with or without metronidazole (or amoxicillin-clavulanate as a single preparation) as initial empirical therapy.

Primitive Neuroectodermal Tumour (PNET) in subcutaneous abdominal wall: a case report.

Primitive neuroectodermal tumour (PNET) is a rare tumour mainly found in children under ten years old. It may be broadly categorised into those occurring from the central or peripheral nervous system of which the majority arise centrally. We report a 61 year-old lady who had previous lobular breast cancer presenting with a rapidly expanding lesion in her anterior right upper abdominal wall. Clinically it appeared to be benign, however, histopathology of the excised lesion revealed a localised PNET. This case is an unusual case of a PNET in an adult that is peripheral in nature arising from subcutaneous tissue in the abdominal wall.

Effect of aspirin and warfarin on early survival after intracerebral haemorrhage.

BACKGROUND: To determine whether taking aspirin or warfarin at the time of an intracerebral haemorrhage (ICH) has an independent effect on early survival. METHODS: All people with ICH presenting in Christchurch, New Zealand over a three-year period were identified. Independent predictors of mortality at 7, 14 and 28 days were calculated using binary logistic regression. RESULTS: Two hundred and fifty three cases were identified. Unadjusted 28-day mortality was 43% overall, but 53 % for warfarin associated ICH and 43% for patients taking aspirin. Haemorrhage volume, haemorrhage location, intraventricular spread and the use of warfarin were all independently and significantly associated with mortality at all three time intervals (7, 14 and 28 days). The effect of warfarin was apparent despite similar volumes of bleed in each group. Aspirin was not associated with increased early mortality. Increasing age was also an independent predictor associated with death at 28 days. INTERPRETATION: Use of warfarin (but not aspirin) immediately prior to ICH was independently associated with increased mortality, after controlling for comorbidities. Thus therapeutic efforts to rapidly reverse the warfarin induced coagulopathy may be justified to lower mortality.

Promise of multiphoton detection in discovery and diagnostic proteomics.

Proteomics has lacked adequate methods for handling the complexity (hundreds of thousands of different proteins) and range of protein concentrations (> or =10(6)) of eukaryotic proteomes. New multiphoton-detection methods for ultrasensitive detection of proteins produce 10,000-fold gains in sensitivity and allow highly quantitative, linear detection of 50 zmol (30,000 molecules) to 500 fmol of proteins in complex samples. The potential of multiphoton detection in top-down proteomics analyses is illustrated with applications in monitoring proteomes in very small numbers of cells, in identifying and monitoring complex functional isoforms of cancer-related proteins, and in super-sensitive immunoassays of serum proteins for high-performance detection of cancer.

Radiotherapy waiting times for women with breast cancer: a population-based cohort study.

BACKGROUND: Waiting times for cancer patients are a national priority in the UK. Previous studies have shown variation between cancer networks in the time between diagnosis and start of radiotherapy for all cancer patients. Studies of the relationship between delay in receiving treatment and survival of breast cancer patients have been inconsistent. This study aimed to examine factors associated with waiting times for radiotherapy for breast cancer patients. METHODS: 35,354 women resident in South East England and diagnosed with breast cancer between 1992 and 2001 who received radiotherapy within six months of diagnosis were identified from the Thames Cancer Registry. Time to radiotherapy was measured from either the date of diagnosis or the start of the previous treatment, whichever was shorter. Unadjusted and adjusted logistic regression models were fitted to examine whether patients received radiotherapy within 60 days of their diagnosis or previous treatment. RESULTS: The adjusted proportions of patients receiving radiotherapy within 60 days varied significantly between different cancer networks (range: 43% to 81%), and decreased from 68% in 1992 to 33% in 2001. After adjustment there was no association between deprivation of area of residence, age or stage and radiotherapy wait. Median time waited to radiotherapy increased over the study period whether measured from the start of chemotherapy, hormone therapy, surgery or the date of diagnosis. CONCLUSION: This study covered a period of time before the investment following the Cancer Plan of 2000. Results are consistent with other findings suggesting variation between cancer networks and increasing waits over time. Further studies should examine different methods of measuring waiting time, the causes and consequences of waits for radiotherapy and the effect of current initiatives and investments.

Improved immediate breast reconstruction as a result of oncoplastic multidisciplinary meeting.

INTRODUCTION: The National Institute for Health and Clinical Excellence guidelines recommend that breast reconstruction should be available to all women undergoing mastectomy and discussed at the initial surgical consultation (2002, and updated 2009). The National Mastectomy and Breast Reconstruction Audit (2009) showed that 21% of mastectomy patients underwent immediate breast reconstruction (IBR) and 11% had delayed breast reconstruction (DBR). Breast reconstruction has been shown to have a positive effect on quality of life postmastectomy. This retrospective study investigated the impact of the introduction of a dedicated oncoplastic multidisciplinary meeting (OP MDM) on our unit's breast reconstruction rate. PATIENTS AND METHODS: A retrospective analysis of 229 women who underwent mastectomy, of whom 81 (35%) underwent breast reconstruction between April 2014 and March 2016. Data were analyzed before and after introduction of OP MDM in April 2015. Data on patient age, type of surgery (mastectomy only, mastectomy and reconstruction), timing of reconstruction (IBR, DBR), and type of reconstruction (implant, autologous) were collected. RESULTS: Between April 2015 and March 2016, following establishment of OP multidisciplinary team in April 2015, of the 120 patients who had mastectomy, 50 (42%) underwent breast reconstruction with 78% (39/50) choosing IBR (56% implant reconstruction and 22% autologous). Compared to the period between April 2014 and March 2015 preceding the OP MDM, of 109 patients who underwent mastectomy, only 31 (28%) had breast reconstruction with 64% (20/31) choosing IBR (45% implant reconstruction and 19% autologous). The rate of DBR was lower, 22% (11/50), following OP MDM compared to 35% (11/31) before OP MDM. CONCLUSION: There has been an increased uptake of breast reconstruction surgery from 28% to 42%. The biggest impact was on those opting for the immediate type reconstruction option (78%). The OP MDM has significantly contributed to this increased rate of reconstruction.

Breast cancer: multidisciplinary care and clinical outcomes.

A multidisciplinary approach to the management of breast cancer is the standard of care in developed health systems. We performed a systematic review to assess the extent and quality of evidence on whether multidisciplinary care (MDC), or related aspects of care contribute to clinical outcomes in breast cancer, and in particular whether these influence survival. Only two primary studies have looked at MDC and neither of these studies considered long-term outcomes. The studies of MDC (case series) provide weak evidence that MDC may alter treatment patterns. Several population-based cohort studies showed that related aspects of team work, specialist (surgeon) and hospital workload and specialisation, are associated with improved survival. This group of studies used better quality design with more clearly defined outcome measures, and most of the studies have allowed for possible confounding variables. Evidence of a survival benefit was most consistent for specialist (surgeon) effect. However, the reasons behind the improved survival reported in these studies are unclear, and it is unlikely that this is entirely attributable to treatment patterns. We conclude that although intrinsically multidisciplinary care should be associated with better survival, there remains a paucity of evidence to support this. Studies of the long-term clinical effects of MDC in breast cancer should be a priority for future evaluation.

Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost.

PURPOSE: Patients undergoing breast-conserving surgery were offered boost radiotherapy with targeted intraoperative radiotherapy (TARGIT) using the Intrabeam system to test the feasibility, safety, and efficacy of the new approach. METHODS AND MATERIALS: We treated 302 cancers in 301 unselected patients. This was not a low-risk group. One-third of patients (98/301) were younger than 51 years of age. More than half of the tumors (172, 57%) were between 1 cm and 2 cm, and one-fifth (62, 21%) were >2 cm; 29% (86) had a Grade 3 tumor and, in 29% (87), axillary lymph nodes contained metastasis. After primary surgery, 20 Gy was delivered intraoperatively to the surface of the tumor bed, followed by external-beam radiotherapy (EBRT), but excluding the usual boost. RESULTS: The treatment was well tolerated. The follow-up ranged from 3 to 80 months (164 and 90 patients completed 2 and 3 years follow-up, respectively). Four patients (1.3%) had local recurrence. The Kaplan-Meier estimate of local recurrence is 2.6% (SE = 1.7) at 5 years. This compares favorably with the 4.3% recurrence rate in boosted patients from the EORTC boost study, in which only 8.1% patients were node-positive, as opposed to 29% in our series. CONCLUSION: Targeted intraoperative radiotherapy combined with EBRT results in a low local recurrence rate. This could be attributed to both accurate targeting and timeliness of the treatment. These data support the need for a randomized trial to test whether the TARGIT boost is superior to conventional external boost, especially in high-risk women.

Ovarian ablation as a treatment for breast cancer.

Ovarian ablation is an effective treatment for premenopausal women with hormone receptor positive breast cancer. It can be achieved permanently by surgery or radiotherapy and reversibly by LhRH agonists. This paper discusses the evidence that it is an effective adjuvant therapy and defines the place of oophorectomy in the management of such patients. The achievement of an amenhorreic state is important and chemotherapy may well exert some of its effects by causing ovarian suppression. The use of LhRH agonists in managing such patients is discussed.

The development of endocrine therapy for women with breast cancer.

The development of endocrine therapies has transformed the treatment of patients with breast cancer. The shift from ablative surgery and aggressive chemotherapies to more targeted, better tolerated therapy has improved both mortality and quality of life for patients with hormone-responsive disease. During the 1970s, the selective oestrogen-receptor modulator, tamoxifen, emerged as a new treatment for women with advanced breast cancer. The subsequent development of numerous and diverse selective endocrine therapies such as luteinising hormone-releasing hormone agonists, aromatase inhibitors and oestrogen-receptor antagonists have added further treatment options. Furthermore, with well-tolerated and effective endocrine therapy, adjuvant treatment became an option for patients with early breast cancer. Tamoxifen emerged as the gold standard adjuvant therapy in the 1980s; however, later trials in postmenopausal women showed the aromatase inhibitors offer advantages over tamoxifen. In addition to AIs being indicated as adjuvant therapy, some are also being evaluated for use as a preventative measure in high-risk women. This chronological account outlines key milestones in the evolution of endocrine therapies over the last 40 years, highlighting each class of agent and the key trials that have led to changes in clinical practice. The advances in endocrine therapies outlined here, coupled with advances in breast cancer management and diagnostics, will likely lead to more patient-tailored therapy, resulting in greater clinical benefits and more cost-effective treatment strategies.

Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.

PURPOSE: The Cancer Research UK "Over 50s" trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years. PATIENTS AND METHODS: Between 1987 and 1997, 3,449 patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were randomly assigned to either stop or continue for an additional 3 years, if they were alive and recurrence free. Data on recurrences, new tumors, deaths, and cardiovascular events were obtained (April 2010). RESULTS: There were 1,103 recurrences, 755 deaths as a result of breast cancer, 621 cardiovascular (CV) events, and 236 deaths as a result of CV events. Fifteen years after starting treatment, for every 100 women who received tamoxifen for 5 years, 5.8 fewer experienced recurrence, compared with those who received tamoxifen for 2 years. The risk of contralateral breast cancer was significantly reduced (hazard ratio, 0.70; 95% CI, 0.48 to 1.00). Among women age 50 to 59 years, there was a 35% reduction in CV events (P = .005) and 59% reduction in death as a result of a CV event (P = .02); in older women, the effect was much smaller and not statistically significant. CONCLUSION: Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment. It also lowers the risk of CV disease and death as a result of a CV event, particularly among those age 50 to 59 years. Women should therefore be encouraged to complete the full course. Although aromatase inhibitors improve disease-free survival, tamoxifen remains a cheap and highly effective alternative, particularly in developing countries.

Long-term effectiveness of adjuvant goserelin in premenopausal women with early breast cancer.

BACKGROUND: Systematic reviews have found that luteinizing hormone-releasing hormone (LHRH) agonists are effective in treating premenopausal women with early breast cancer. METHODS: We conducted long-term follow-up (median 12 years) of 2706 women in the Zoladex In Premenopausal Patients (ZIPP), which evaluated the LHRH agonist goserelin (3.6 mg injection every 4 weeks) and tamoxifen (20 or 40 mg daily), given for 2 years. Women were randomly assigned to receive each therapy alone, both, or neither, after primary therapy (surgery with or without radiotherapy/chemotherapy). Hazard ratios and absolute risk differences were used to assess the effect of goserelin treatment on event-free survival (breast cancer recurrence, new tumor or death), overall survival, risk of recurrence of breast cancer, and risk of dying from breast cancer, in the presence or absence of tamoxifen. RESULTS: Fifteen years after the initiation of treatment, for every 100 women not given tamoxifen, there were 13.9 (95% confidence interval [CI] = 17.5 to 19.4) fewer events among those who were treated with goserelin compared with those who were not treated with goserelin. However, among women who did take tamoxifen, there were 2.8 fewer events (95% CI = 7.7 fewer to 2.0 more) per 100 women treated with goserelin compared with those not treated with goserelin. The risk of dying from breast cancer was also reduced at 15 years: For every 100 women given goserelin, the number of breast cancer deaths was lower by 2.6 (95% CI = 6.6 fewer to 2.1 more) and 8.5 (95% CI = 2.2 to 13.7) in those who did and did not take tamoxifen, respectively, although in the former group the difference was not statistically significant. CONCLUSIONS: Two years of goserelin treatment was as effective as 2 years of tamoxifen treatment 15 years after starting therapy. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added.