Search

Purpose: Targeted therapies (TTs), notably trastuzumab, have improved outcomes for breast cancer characterised by overexpression of human epidermal growth factor receptors including HER2. Compared with chemotherapy treatments, TTs are more specific in their targets and are delivered over longer periods of time, thus presenting different side-effect profiles. The objective of this paper is to systematically review and describe the side effects associated with TTs used in the adjuvant and metastatic settings for HER2+ breast cancer., Methods: The MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library databases were searched from January 2007 to March 2015 to identify clinical trials and prospective studies reporting toxicities associated with TTs (mainly trastuzumab and lapatinib) used without other therapies in the treatment of HER2-positive breast cancer. Two independent reviewers selected papers based on their titles and abstracts. All papers selected by either reviewer were included. A third reviewer extracted and tabulated the relevant data using a data extraction form., Results: We identified 5478 papers, of which 299 were reviewed and 18 trials identified involving 6980 patients. A total of 66 side effects were identified, including 46 "patient-based" symptoms and 20 "medically defined" outcomes. Side effects were more common for patients treated with therapies other than trastuzumab or with dual-HER2 regimens and for patients with metastatic disease. Diarrhoea and skin rash were the most prevalent symptoms, experienced by 29 % and 22 % of patients overall, respectively. There were 119 (2 %) cardiac events reported, and these were not exclusive to trastuzumab-treated patients. The majority of side effects (n = 52) were experienced by 1 % or less of patients and were predominantly of grade 1/2 toxicity., Conclusions: This systematic review provides a detailed analysis of side effects of HER2+ therapies in a large number of patients included in trials, enabling an accurate estimate of prevalence and a complete understanding of the patients' experience. This will help clinicians and patients in treatment planning.

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., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.

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.

Background: Breast cancer is a heterogeneous disease. Yet, many molecular players and mechanisms behind the complexity of its clinical behaviour remain unknown, and advances in biomedical research are expected to unravel novel molecular discoveries in breast and other cancers. Clinical proteomics is currently experiencing rapid advances in technology that promise new means to improve breast cancer early diagnosis, stratification, and treatment response., Methods: We reviewed recent literature adopting clinical proteomics in breast cancer research., Findings: This review highlights the principles, advantages, limitations, discoveries and future prospects of recent clinical proteomics discovery efforts in breast cancer research., Conclusion: Numerous proteomic studies of breast cancer have been accomplished aiming to aid the development of personalised therapies, increase understanding of post treatment relapse, and help improve prediction of patient prognosis. This has led to the possible identification of profiles refining breast cancer subtypes and the discovery of novel biomarkers pointing towards diagnostic and prognostic potential., (Copyright © 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

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., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Environmental factors influence breast cancer incidence and progression. High body mass index (BMI) is associated with increased risk of post-menopausal breast cancer and with poorer outcome in those with a history of breast cancer. High BMI is generally interpreted as excess adiposity (overweight or obesity) and the World Cancer Research Fund judged that the associations between BMI and incidence of breast cancer were due to body fatness. Although BMI is the most common measure used to characterise body composition, it cannot distinguish lean mass from fat mass, or characterise body fat distribution, and so individuals with the same BMI can have different body composition. In particular, the relation between BMI and lean or fat mass may differ between people with or without disease. The question therefore arises as to what aspect or aspects of body composition are causally linked to the poorer outcome of breast cancer patients with high BMI. This question is not addressed in the literature. Most studies have used BMI, without discussion of its shortcomings as a marker of body composition, leading to potentially important misinterpretation. In this article we review the different measurements used to characterise body composition in the literature, and how they relate to breast cancer risk and prognosis. Further research is required to better characterise the relation of body composition to breast cancer., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

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., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

Background: Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group., Methods: Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided., Results: Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years., Conclusions: These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

Missense, nonsense, and translationally silent mutations can inactivate genes by altering the inclusion of mutant exons in mRNA, but their overall frequency among disease-causing exonic substitutions is unknown. Here, we have tested missense and silent mutations deposited in the BRCA1 mutation databases of unclassified variants for their effects on exon inclusion. Analysis of 21 BRCA1 variants using minigene assays revealed a single exon-skipping mutation c.231G>T. Comprehensive mutagenesis of an adjacent 12-nt segment showed that this silent mutation resulted in a higher level of exon skipping than the 35 other single-nucleotide substitutions. Exon inclusion levels of mutant constructs correlated significantly with predicted splicing enhancers/silencers, prompting the development of two online utilities freely available at http://www.dbass.org.uk. EX-SKIP quickly estimates which allele is more susceptible to exon skipping, whereas HOT-SKIP examines all possible mutations at each exon position and identifies candidate exon-skipping positions/substitutions. We demonstrate that the distribution of exon-skipping and disease-associated substitutions previously identified in coding regions was biased toward top-ranking HOT-SKIP mutations. Finally, we show that proteins 9G8, SC35, SF2/ASF, Tra2, and hnRNP A1 were associated with significant alterations of BRCA1 exon 6 inclusion in the mRNA. Together, these results facilitate prediction of exonic substitutions that reduce exon inclusion in mature transcripts., (© 2011 Wiley-Liss, Inc.)

p53 is activated genetically by a set of kinases that are components of the calcium calmodulin kinase superfamily, including CHK2, AMP kinase, and DAPK-1. In dissecting the mechanism of DAPK-1 control, a novel mutation (N1347S) was identified in the death domain of DAPK-1. The N1347S mutation prevented the death domain module binding stably to ERK in vitro and in vivo. Gel filtration demonstrated that the N1347S mutation disrupted the higher order oligomeric nature of the purified recombinant death domain miniprotein. Accordingly, the N1347S death domain module is defective in vivo in the formation of high molecular weight oligomeric intermediates after cross-linking with ethylene glycol bis(succinimidylsuccinate). Full-length DAPK-1 protein harboring a N1347S mutation in the death domain was also defective in binding to ERK in cells and was defective in formation of an ethylene glycol bis(succinimidylsuccinate)-cross-linked intermediate in vivo. Full-length DAPK-1 encoding the N1347S mutation was attenuated in tumor necrosis factor receptor-induced apoptosis. However, the N1347S mutation strikingly prevented ERK:DAPK-1-dependent apoptosis as defined by poly(ADP-ribose) polymerase cleavage, Annexin V staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling imaging. Significant penetrance of the N1347S allele was identified in normal genomic DNA indicating the mutation is germ line, not tumor derived. The frequency observed in genomic DNA was from 37 to 45% for homozygous wild-type, 41 to 47% for heterozygotes, and 12 to 15% for homozygous mutant. These data highlight a naturally occurring DAPK-1 mutation that alters the oligomeric structure of the death domain, de-stabilizes DAPK-1 binding to ERK, and prevents ERK:DAPK-1-dependent apoptosis.

Objective: To review the clinical course and outcome of patients with germ cell cancer and liver metastases treated at one centre, as the presence of hepatic metastases, although rare, is a poor prognostic feature in germ cell cancer., Patients and Methods: The case records of all patients with germ cell cancer and liver metastases at presentation, and treated with chemotherapy at a medical oncology unit between 1984 and 2001, were reviewed. The treatment regimens, tumour responses and patient outcome were recorded., Results: Twenty-seven patients with germ cell cancer metastatic to the liver were identified. Complete biochemical and radiological responses were achieved in eight patients after initial chemotherapy and surgery for non-hepatic residual disease. Seven patients had only residual radiological hepatic abnormalities with normal tumour markers at the completion of initial treatment. There were no immediate hepatic resections and no further therapy was given. Serial computed tomography (CT) confirmed a progressive reduction in the size of hepatic lesions in six of seven patients. The persistence of residual hepatic abnormalities was not predictive of relapse, and overall survival of these patients (median survival 49 months, range 15-120) compared well with recent reports of such patients who have undergone hepatic resection., Conclusions: Conservative management with regular assessment by CT is an acceptable alternative to immediate hepatic resection for patients with isolated residual radiological hepatic abnormalities on completing first-line therapy for metastatic germ cell cancer, and does not adversely affect their survival.

Herceptin (trastuzamab, Genentech, San Francisco, CA, USA) prolongs survival in metastatic breast cancer patients whose tumours overexpress the HER2/neu protein. Compared with chemotherapy alone, patients receiving chemotherapy and Herceptin have a significantly longer time to progression, a higher response rate and a longer duration of response. These effects are most marked in first-line treatment of metastatic disease. The addition of Herceptin is associated with few additional side-effects, apart from cardiac toxicity in patients concurrently receiving anthracyclines. As such, it seems reasonable for Herceptin to become considered as one of the routine treatment options in metastatic breast cancer. It would therefore be appropriate for HER2 status testing to be incorporated into the assessment of all patients with metastatic disease. The use of this medication will be limited by its cost. Furthermore, data are lacking on appropriate treatments durations in responders., (Copyright 2000 Harcourt Publishers Ltd.)

Aim: To investigate whether monocytes and neutrophils from patients with primary proliferative polycythaemia (PPP) exhibit increased expression of markers of cell activation and, if so, whether they are associated with the phagocytic activity of these cells and concentrations of circulating cytokines., Methods: Expression of CD11b, CD14, CD18, and CD64 on monocytes and neutrophils was assessed by flow cytometry. Phagocytosis was analysed using immunoglobulin opsonised Escherichia coli. Serum concentrations of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF) and macrophage CSF (M-CSF) were determined by bioassays, and interferon-gamma (IFN-gamma) by enzyme linked immunosorbent assay (ELISA)., Results: Patients with PPP (n = 18), when compared with normal subjects (n = 10), had increased percentages of CD64+ monocytes (52% v 36%) and neutrophils (42% v 11%) and of CD14+ neutrophils (36% v 18%). Monocytes from patients with PPP exhibited increased expression of CD64 (47 v 26) and of CD11b (65 v 36). These abnormalities were not found in patients with secondary (n = 8) or apparent (n = 13) polycythaemia. The percentage of neutrophils undergoing phagocytosis was higher in patients with PPP (mean 64%; n = 6) than in normal subjects (mean 42%; n = 5). G-CSF, GM-CSF and IFN-gamma concentrations in patients' serum samples were comparable with normal; M-CSF was not detected in any of the samples. There was no correlation between cytokine concentrations and the expression of CD11b, CD14, CD18, and CD64 on patients' phagocytes., Conclusions: Increased expression of CD11b and CD64 by monocytes, increased percentages of CD14+ and CD64+ neutrophils and the high phagocytic activity of neutrophils suggests that these cells are activated in vivo in patients with PPP. The phenotypic changes of PPP phagocytes were not associated with increased concentrations of circulating cytokines and probably reflect intrinsic abnormalities within the neoplastic PPP clone.

Patients with B-cell chronic lymphocytic leukaemia (BCLL) have low levels of serum IgG. In order to determine if this is a pan IgG deficiency or a selective suppression of one or more IgG subclasses, levels of IgG 1, 2, 3 and 4 in nine BCLL patients were determined and compared to those of nine age and sex matched controls. No significant differences were found in the levels of IgG1 and IgG2, but the patients were found to have significantly lower levels of IgG3 (p < 0.05) and IgG4 (p < 0.05). Selective deficiencies of these isotypes may explain the particular pattern of infection seen in BCLL patients.

Patients with B-cell chronic lymphocytic leukaemia (B-CLL) have an increased susceptibility to infection. Quantitative abnormalities of T-cells have been previously reported in B-CLL, although the relationship between such abnormalities and the incidence of infection still remains to be established. We therefore enumerated lymphocyte subpopulations in 22 patients with B-CLL grouped according to the number of infective episodes in the previous three years. No significant differences were found between the patient groups and the mean number of T-cells subsets (helper, suppressor, suppressor-inducer and suppressor effector) or NK cells, but patients with frequent infections were found to have significantly higher CD5+ B-cell counts. Thus, we confirm that T-cell subpopulations are numerically altered in patients with B-CLL, but found that such changes are not predictive of susceptibility to infection. Our results however suggest that the malignant B-cells may exhibit immunosuppressive activity.