BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses.

BACKGROUND: The co-chaperone protein Bcl-2-associated athanogene-1 (BAG-1) is overexpressed in breast cancer and has been incorporated in the oncotype DX and PAM50 breast cancer prognostic assays. Bcl-2-associated athanogene-1 exists as multiple protein isoforms that interact with diverse partners, including chaperones Hsc70/Hsp70, Ser/Thr kinase Raf-1 and Bcl-2, to promote cancer cell survival. The BAG-1L isoform specifically binds to and increases the transcriptional activity of oestrogen receptor in cells, and in some, but not all studies, BAG-1 expression is predictive of clinical outcome in breast cancer. METHODS: A systematic review of published studies reporting BAG-1 (mRNA and/or protein) expression and clinical outcome in early breast cancer. The REporting Recommendations for Tumour MARKer and Prognostic Studies (REMARK) criteria were used as a template against which data were assessed. Meta-analyses were performed for studies that provided a hazard ratio and 95% confidence intervals for clinical outcomes including disease-free survival or breast cancer-specific survival from univariate analysis. RESULTS: Eighteen studies used differing methodologies and reported on differing outcomes. Meta-analyses were only possible on results from a subset of reported studies. Meta-analyses suggested improved outcome with high BAG-1 mRNA and high BAG-1 nuclear expression by immunohistochemisty. CONCLUSIONS: Increased levels of BAG-1 are associated with better breast cancer outcomes.

Genetic testing in a cohort of young patients with HER2-amplified breast cancer.

BACKGROUND: Young age at diagnosis for breast cancer raises the question of genetic susceptibility. We explored breast cancer susceptibility genes testing on ≤40-year-old patients with HER2-amplified invasive breast cancer. PATIENTS AND METHODS: Patients were selected from a large UK cohort study. The inclusion criterion was age ≤40 at diagnosis with confirmed HER2-amplified breast cancer. The probability of finding a BRCA gene mutation was calculated based on family history. Genetic testing used was either clinical testing for BRCA1 and BRCA2, with a subset also tested for TP53 mutations, or research-based testing using a typical panel comprising 17 breast cancer susceptibility genes (CSGs) including BRCA1, BRCA2 and TP53. RESULTS: Of the 591 eligible patients, clinical testing results were available for 133 cases and an additional 263 cases had panel testing results. BRCA testing across 396 cases found 8 BRCA2 (2%) and 6 BRCA1 (2%) pathogenic mutations. Of the 304 patients tested for TP53 mutations, overall 9 (3%) had deleterious TP53 mutations. Of the 396 patients, 101 (26%) met clinical criteria for BRCA testing (≥10% probability), among whom 11% had pathogenic BRCA mutations (6 BRCA2, 5 BRCA1). Where the probability was calculated to be <10%, only 4 of 295 (1%) patients had BRCA mutations. Among the 59 patients who had TP53 testing meeting the 10% threshold, 7 had mutations (12%). Likely functionally deleterious mutations in 14 lower penetrance CSGs were present in 12 of 263 (5%) panel-tested patients. CONCLUSION: Patients aged <41 at diagnosis with HER2+ breast cancer and no family history of breast cancer can be reassured that they have a low chance of being a high-risk gene carrier. If there is a strong family history, not only BRCA but also TP53 gene testing should be considered. The clinical utility of testing lower penetrance CSGs remains unclear.

An evaluation of the prognostic model PREDICT using the POSH cohort of women aged ⩽40 years at breast cancer diagnosis.

BACKGROUND: Breast cancer is the most common cancer in younger women (aged ⩽40 years) in the United Kingdom. PREDICT (http://www.predict.nhs.uk) is an online prognostic tool developed to help determine the best available treatment and outcome for early breast cancer. This study was conducted to establish how well PREDICT performs in estimating survival in a large cohort of younger women recruited to the UK POSH study. METHODS: The POSH cohort includes data from 3000 women aged ⩽40 years at breast cancer diagnosis. Study end points were overall and breast cancer-specific survival at 5, 8, and 10 years. Evaluation of PREDICT included model discrimination and comparison of the number of predicted versus observed events. RESULTS: PREDICT provided accurate long-term (8- and 10-year) survival estimates for younger women. Five-year estimates were less accurate, with the tool overestimating survival by 25% overall, and by 56% for patients with oestrogen receptor (ER)-positive tumours. PREDICT underestimated survival at 5 years among patients with ER-negative tumours. CONCLUSIONS: PREDICT is a useful tool for providing reliable long-term (10-year) survival estimates for younger patients. However, for more accurate short-term estimates, the model requires further calibration using more data from young onset cases. Short-term prediction may be most relevant for the increasing number of women considering risk-reducing bilateral mastectomy.

Obesity and the outcome of young breast cancer patients in the UK: the POSH study.

BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI <25 kg/m(2)), 784 (27.6%) were overweight (ov, BMI ≥25 to <30), and 533 (18.7%) were obese (ob, BMI ≥30). The median tumour size was significantly higher in obese and overweight patients than U/H patients (Ob 26 mm versus U/H 20 mm, P < 0.001; Ov 24 mm versus U/H 20 mm, P < 0.001). Obese and overweight patients had significantly more grade 3 tumours (63.9% versus 59.0%, P = 0.048; Ov 63.6% versus U/H 59.0% P = 0.034) and node-positive tumours (Ob 54.6% versus U/H 49.0%, P = 0.027; Ov 54.2% versus U/H 49%, P = 0.019) than U/H patients. Obese patients had more ER/PR/HER2-negative tumours than healthy-weight patients (25.0% versus 18.3%, P = 0.001). Eight-year overall survival (OS) and distant disease-free interval (DDFI) were significantly lower in obese patients than healthy-weight patients [OS: hazard ratio (HR) 1.65, P < 0.001; DDFI: HR 1.44, P < 0.001]. Multivariable analyses adjusting for tumour grade, size, nodal, and HER2 status indicated that obesity was a significant independent predictor of OS and DDFI in patients with ER-positive disease. CONCLUSIONS: Young obese breast cancer patients present with adverse tumour characteristics. Despite adjustment for this, obesity still independently predicts DDFI and OS.

Family history and outcome of young patients with breast cancer in the UK (POSH study).

BACKGROUND: Young patients presenting to surgical clinics with breast cancer are usually aware of their family history and frequently believe that a positive family history may adversely affect their prognosis. Tumour pathology and outcomes were compared in young British patients with breast cancer with and without a family history of breast cancer. METHODS: Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) is a large prospective cohort study of women aged less than 41 years with breast cancer diagnosed and treated in the UK using modern oncological management. Personal characteristics, tumour pathology, treatment and family history of breast/ovarian cancer were recorded. Follow-up data were collected annually. RESULTS: Family history data were available for 2850 patients. No family history was reported by 65·9 per cent, and 34·1 per cent reported breast/ovarian cancer in at least one first- or second-degree relative. Patients with a family history were more likely to have grade 3 tumours (63·3 versus 58·9 per cent) and less likely to have human epidermal growth factor receptor 2-positive tumours (24·7 versus 28·8 per cent) than those with no family history. In multivariable analyses, there were no significant differences in distant disease-free intervals for patients with versus those without a family history, either for the whole cohort (hazard ratio (HR) 0·89, 95 per cent c.i. 0·76 to 1·03; P = 0·120) or when stratified by oestrogen receptor (ER) status (ER-negative: HR 0·80, 0·62 to 1·04, P = 0·101; ER-positive: HR 0·95, 0·78 to 1·15, P = 0·589). CONCLUSION: Young British patients presenting to breast surgical clinics with a positive family history can be reassured that this is not a significant independent risk factor for breast cancer outcome.

Understanding of BRCA VUS genetic results by breast cancer specialists.

BACKGROUND: Mainstreaming genetic medicine, increased media coverage and clinical trials for BRCA mutation carriers are leading oncologists into more patient discussions about BRCA genetic testing. BRCA variants of uncertain significance (VUS) occur in 10-20% of tests. VUS detection introduces additional uncertainty for patient and potentially clinician. We aimed to explore the ability of breast cancer specialists (BCS) in the UK to correctly respond to a VUS report. METHODS: A survey sent to 800 UK BCS collected demographics data, VUS general knowledge and interpretation and communication based on two genetics reports. A separate survey of UK clinical geneticists collected demographics data, laboratory reporting practice and methods used to clarify VUS pathogenicity including classification systems. RESULTS: Of the 155 BCS (22.5%) who completed the survey, 12% reported no genetics training. Ninety five percent referred patients for BRCA genetic tests, 71% felt unsure about the clinical implications of the test reports presented here. A VUS report from a patient with a positive family history was interpreted and theoretically communicated correctly by 94% but when presented with a different VUS report with no management guidance and negative family history, 39% did not know how to communicate this result to the patient. Geneticists reported multiple VUS classification systems; the most commonly used was word-based in 32%. CONCLUSIONS: A consistent and standardised format to report particularly VUS results across all diagnostic laboratories plus additional training of UK BCS will be necessary for effective mainstreaming of BRCA testing to the oncology clinic.

Ethnicity and outcome of young breast cancer patients in the United Kingdom: the POSH study.

BACKGROUND: Black ethnic groups have a higher breast cancer mortality than Whites. American studies have identified variations in tumour biology and unequal health-care access as causative factors. We compared tumour pathology, treatment and outcomes in three ethnic groups in young breast cancer patients treated in the United Kingdom. METHODS: Women aged ≤ 40 years at breast cancer diagnosis were recruited to the POSH national cohort study (MREC: 00/06/69). Personal characteristics, tumour pathology and treatment data were collected at diagnosis. Follow-up data were collected annually. Overall survival (OS) and distant relapse-free survival (DRFS) were assessed using Kaplan-Meier curves, and multivariate analyses were performed using Cox regression. RESULTS: Ethnicity data were available for 2915 patients including 2690 (91.0%) Whites, 118 (4.0%) Blacks and 87 (2.9%) Asians. Median tumour diameter at presentation was greater in Blacks than Whites (26.0 mm vs 22.0 mm, P=0.0103), and multifocal tumours were more frequent in both Blacks (43.4%) and Asians (37.0%) than Whites (28.9%). ER/PR/HER2-negative tumours were significantly more frequent in Blacks (26.1%) than Whites (18.6%, P=0.043). Use of chemotherapy was similarly high in all ethnic groups (89% B vs 88.6% W vs 89.7% A). A 5-year DRFS was significantly lower in Blacks than Asians (62.8% B vs 77.0% A, P=0.0473) or Whites (62.8 B% vs 77.0% W, P=0.0053) and a 5-year OS for Black patients, 71.1% (95% CI: 61.0-79.1%), was significantly lower than that of Whites (82.4%, 95% CI: 80.8-83.9%, W vs B: P=0.0160). In multivariate analysis, Black ethnicity had an effect on DRFS in oestrogen receptor (ER)-positive patients that is independent of body mass index, tumour size, grade or nodal status, HR: 1.60 (95% CI: 1.03-2.47, P=0.035). CONCLUSION: Despite equal access to health care, young Black women in the United Kingdom have a significantly poorer outcome than White patients. Black ethnicity is an independent risk factor for reduced DRFS particularly in ER-positive patients.

A Phase II Study of Biodegradable Stents Plus Palliative Radiotherapy in Oesophageal Cancer.

AIMS: Self-expanding metal stents provide rapid improvement of dysphagia in oesophageal cancer but are associated with complications. The aim of the present study was to test the effectiveness of an alternative treatment of combining biodegradable stents with radiotherapy. MATERIALS AND METHODS: A Simon two-stage single-arm prospective phase II trial design was used to determine the efficacy of biodegradable stents plus radiotherapy in patients with dysphagia caused by oesophagus cancer who were unsuitable for radical treatment. Fourteen patients were recruited and data from 12 were included in the final analyses. RESULTS: Five of 12 patients met the primary end point: one stent-related patient death; four further interventions for dysphagia within 16 weeks of stenting (41.7%, 95% confidence interval 15.2-72.3%). The median time to a 10-point deterioration of quality of life was 2.7 weeks. Nine patients died within 52 weeks of registration. The median time to death from any cause was 15.0 weeks (95% confidence interval 9.6-not reached). CONCLUSION: The high re-intervention observed, which met the pre-defined early stopping criteria, meant that the suggested alternative treatment was not sufficiently effective to be considered for a larger scale trial design. Further work is needed to define the place of biodegradable stents in the management of malignant oesophageal strictures.

Uva-ursi extract and ibuprofen as alternative treatments for uncomplicated urinary tract infection in women (ATAFUTI): a factorial randomized trial.

OBJECTIVES: The aim was to investigate if offering symptomatic therapy (Uva-ursi or ibuprofen) alongside a delayed prescription would relieve symptoms and reduce the consumption of antibiotics for adult women presenting with acute uncomplicated urinary tract infection (UTI). METHODS: A 2 × 2 factorial placebo controlled randomized trial in primary care. The participants were 382 women aged 18-70 years with symptoms of dysuria, urgency, or frequency of urination and suspected by a clinician to have a lower UTI. The interventions were Uva-ursi extract and/or ibuprofen advice. All women were provided with a delayed or 'back-up' prescription for antibiotics. Missing data were imputed using multiple imputation methods (ISRCTN registry: ISRCTN43397016). RESULTS: An ITT analysis of mean score for frequency symptoms assessed on Days 2-4 found no evidence of a difference between Uva-ursi vs. placebo -0.06 (95% CI -0.33 to 0.21; p 0.661), nor ibuprofen vs. no ibuprofen advice -0.01 (95% CI -0.27 to 0.26; p 0.951). There was no evidence of a reduction in antibiotic consumption with Uva-ursi (39.9% vs. placebo 47.4%; logistic regression odds ratio (OR) 0.59 (95% CI 0.22-1.58; p 0.293) but there was a significant reduction for ibuprofen advice (34.9% vs. no advice 51.0%; OR 0.27 (95% CI 0.10 to 0.72; p 0.009). There were no safety concerns and no episodes of upper tract infection were recorded. CONCLUSIONS: We found no evidence of an effect of either intervention on the severity of frequency symptoms. There is evidence that advice to take ibuprofen will reduce antibiotic consumption without increasing complications. For every seven women given this advice, one less will use antibiotics.

The presentation, management and outcome of inflammatory breast cancer cases in the UK: Data from a multi-centre retrospective review.

OBJECTIVES: Inflammatory Breast cancer (IBC) is a rare but aggressive form of breast cancer. Its incidence and behaviour in the UK is poorly characterised. We collected retrospective data from hospitals in the UK and Ireland to describe the presentation, pathology, treatment and clinical course of IBC in the UK. MATERIALS AND METHODS: Patients with IBC diagnosed between 1997-2014 at fourteen UK and Irish hospitals were identified from local breast unit databases. Patient characteristics, tumour pathology and stage, and details of surgical, systemic and radiotherapy treatment and follow-up data were collected from electronic patient records and medical notes. RESULT: This retrospective review identified 445 patients with IBC accounting for 0.4-1.8% of invasive breast cancer cases. Median follow-up was 4.2 years. 53.2% of tumours were grade 3, 56.2% were oestrogen receptor positive, 31.3% were HER2 positive and 25.1% were triple negative. 20.7% of patients had distant metastases at presentation. Despite trimodality treatment in 86.4%, 40.1% of stage III patients developed distant metastases. Five-year overall survival (OS) was 61.0% for stage III and 21.4% for stage IV patients. CONCLUSIONS: This is the largest series of UK IBC patients reported to date. It indicates a lower incidence than in American series, but confirms that IBC has a high risk of recurrence with poor survival despite contemporary multi-modality therapy. A national strategy is required to facilitate translational research into this aggressive disease.