Ronan W. Glynn

Younger age as a prognostic indicator in breast cancer: A cohort study

BackgroundThe debate continues as to whether younger women who present with breast cancer have a more aggressive form of disease and a worse prognosis. The objectives of this study were to determine the incidence of breast cancer in women under 40 years old and to analyse the clinicopathological characteristics and outcome compared to an older patient cohort.MethodsData was acquired from a review of charts and the prospectively reviewed GUH Department of Surgery database. Included in the study were 276 women diagnosed with breast cancer under the age of forty and 2869 women over forty. For survival analysis each women less than 40 was matched with two women over forty for both disease stage and grade.ResultsThe proportion of women diagnosed with breast cancer under the age of forty in our cohort was 8.8%. In comparison to their older counterparts, those under forty had a higher tumour grade (p = 0.044) and stage (p = 0.046), a lower incidence of lobular tumours (p < 0.001), higher estrogen receptor negativity (p < 0.001) and higher HER2 over-expression (p = 0.002); there was no statistical difference as regards tumour size (p = 0.477). There was no significant difference in overall survival (OS) for both groups; and factors like tumour size (p = 0.026), invasion (p = 0.026) and histological type (p = 0.027), PR (p = 0.031) and HER2 (p = 0.002) status and treatment received were independent predictors of OSConclusionBreast cancer in younger women has distinct histopathological characteristics; however, this does not result in a reduced survival in this population.

Representation of Cancer in the Medical Literature - A Bibliometric Analysis

Background There exists a lack of knowledge regarding the quantity and quality of scientific yield in relation to individual cancer types. We aimed to measure the proportion, quality and relevance of oncology-related articles, and to relate this output to their associated disease burden. By incorporating the impact factor(IF) and Eigenfactor™(EF) into our analysis we also assessed the relationship between these indices and the output under study. Methods All publications in 2007 were retrieved for the 26 most common cancers. The top 20 journals ranked by IF and EF in general medicine and oncology, and the presence of each malignancy within these titles was analysed. Journals publishing most prolifically on each cancer were identified and their impact assessed. Principal Findings 63260 (PubMed) and 126845 (WoS) entries were generated, respectively. 26 neoplasms accounted for 25% of total output from the top medical publications. 5 cancers dominated the first quartile of output in the top oncology journals; breast, prostate, lung, and intestinal cancer, and leukaemia. Journals associated with these cancers were associated with much higher IFs and EFs than those journals associated with the other cancer types under study, although these measures were not equivalent across all sub-specialties. In addition, yield on each cancer was related to its disease burden as measured by its incidence and prevalence. Conclusions Oncology enjoys disproportionate representation in the more prestigious medical journals. 5 cancers dominate yield, although this attention is justified given their associated disease burden. The commonly used IF and the recently introduced EF do not correlate in the assessment of the preeminent oncology journals, nor at the level of individual malignancies; there is a need to delineate between proxy measures of quality and the relevance of output when assessing its merit. These results raise significant questions regarding the best method of assessment of research and scientific output in the field of oncology.

17q12-21 - The pursuit of targeted therapy in breast cancer

PURPOSE Identification of HER2/neu, and the subsequent development of targeted therapy for patients who over-express it, has revolutionized their management. Research has since focused on the area of chromosome 17 in which HER2/neu is located in order to identify other genes in the vicinity. The aims of this review are, firstly, to discuss current thinking in relation to the role of these genes in the pathogenesis of breast cancer and, secondly, to examine how this evidence may be assimilated such that new forms of targeted therapy can be developed. EXPERIMENTAL DESIGN This review discusses the evidence in relation to 4 genes located at the HER2/neu amplicon, namely TOP2A, GRB7, STARD3 and RARA. RESULTS TOP2A has aroused particular interest as over-expression of its protein has been shown to correlate, both with amplification of HER2/neu, and with response to anthracycline-based chemotherapeutic agents in breast cancer. GRB7 is included on Oncotype DXtm, and has recently been implicated in gastric and oesophageal cancer. STARD3 and RARA also hold clinical relevance, the former having been shown to function in steroidogenesis and therefore implicated in hormone-receptor-positive breast cancer. Finally, RARA may be the key to unlocking the problem of resistance to all-trans retinoic acid (ATRA) in breast cancer sufferers; this treatment has previously been demonstrated to induce remission in over 80% of patients with acute promyelocytic leukaemia (APML). CONCLUSION These genes hold potential as therapeutic targets, and warrant further investigation as we move towards our goal of individually tailored therapeutic strategies in breast cancer.

Authorship trends in the surgical literature

Authorship is increasingly influential in career progression and academic promotion. This study aimed to examine authorship trends in surgical titles between 1998 and 2008, and to compare these trends with those in general medicine publications.

TOP2A Amplification in the Absence of That of HER-2/neu: Toward Individualization of Chemotherapeutic Practice in Breast Cancer

PRIMARY OBJECTIVE To investigate the relationship between human epidermal growth factor receptor (HER)-2/neu and the gene encoding topoisomerase IIα (TOP2A) in breast cancer, while elucidating their association with clinicopathological variables. METHODS Real-time quantitative polymerase chain reaction (RQ-PCR) was performed on a 96-patient study group to assess gene amplification, and levels were determined using the comparative cycle threshold approach and Taqman assays. An immunohistochemistry (IHC) microarray (n = 76) was then employed to check for correlation between gene amplification and protein expression levels. RESULTS Amplification levels of TOP2A did not differ significantly according to HER-2/neu status by either RQ-PCR or IHC microarray. Of the HER-2/neu(-) patients, 29.1% demonstrated levels of TOP2A above the third quartile, whereas 22.9% of the HER-2/neu(+) patients had values in the first quartile (log TOP2A <0.62), thereby indicating low-level amplification. Of the 60 patients characterized as HER-2/neu(-) using IHC and fluorescence in situ hybridization (FISH), 22.9% were classified as TOP2A(+) on the IHC microarray. Of the 14 patients deemed HER-2/neu(+) using IHC and FISH, meanwhile, the majority (n = 10) were classified as TOP2A(+). CONCLUSIONS Our results indicate that amplification of TOP2A in breast cancer is not confined to those who are concomitantly HER-2/neu(+), and suggest that a significant proportion of HER-2/neu(-) patients exhibit high levels of TOP2A.

Topoisomerase 2 Alpha and the Case for Individualized Breast Cancer Therapy

BackgroundMany patients with breast cancer receive no benefit from their treatment. This has led to a search for novel therapeutic targets whose identification may facilitate a more tailored approach, thereby avoiding unnecessary toxicity. Of these, topoisomerase 2 alpha (TOP2A), located at the HER2/neu amplicon on chromosome 17, has generated particular interest because its expression has been shown to correlate with response to anthracycline-based therapies.MethodsWe evaluated the relationship between TOP2A and its collocated gene, HER2/neu, and summarized the evidence for and against confining anthracycline-based therapies to those patients who demonstrate increased expression or amplification of these targets.ResultsThe emerging consensus supports the restriction of anthracyclines to those patients who are HER2/neu positive, with the evidence suggesting that alterations in the status of TOP2A are almost completely restricted to this group of patients.ConclusionsIt seems increasingly likely that response to anthracyclines is predicated on these alterations.

Expression levels of HER2/neu and those of collocated genes at 17q12-21, in breast cancer

HER2/neu is associated with poorer clinical outcome in breast cancer. Expression patterns of co-localised cancer-associated genes at 17q12-21 were examined using RT-PCR. The study group consisted of a 96-patient cohort. Relative quantity of mRNA expression was calculated using the comparative cycle threshold method and Qbase software. Results were analysed to detect expression patterns among the genes, and to identify associations between expression levels and clinical data. Levels of HER2/neu correlated with those of GRB7 (r=0.551, p<0.001), RARA (r=0.391, p<0.001), RPL19 (r=0.549, p<0.001) and LASP1 (r=0.399, p<0.001). GRB7 was significantly inversely associated with improved DFS at 60 months (p=0.036). RARA levels were greater in HER2/neu-positive as opposed to HER2/neu-negative patients (p=0.021); levels were significantly higher in ER-positive patients, relative to those who were ER-negative (p=0.003). Levels of RPL19 were significantly higher in the HER2/neu-overexpressing (p=0.010) and luminal B subtypes (p=0.007). LASP1 levels were higher in those patients who had been classified clinically as HER2/neu-positive (p=0.004). This study reaffirms the correlation between HER2/neu and the co-localised LASP1 and GRB7; the latter target may hold additional significance in addition to being a surrogate marker for HER2/neu expression. The relationship identified between RARA and ER-positivity may herald an avenue for targeted therapy of these tumours.

Laryngeal cancer: Quantitative and qualitative assessment of research output, 1945–2010

To provide an in‐depth evaluation of research yield in laryngeal cancer from 1945 to 2010, using large‐scale data analysis, employment of bibliometric indicators of production and quality, and density equalizing mapping.

The Relationship between Breast Cancer and Research; a Bibliometric Study.

Background: Thousands of articles are published every year in the medical literature relating to the diagnosis and treatment of cancer patients. An area of contention of late has been the amount of research time and money being devoted to breast cancer, to what some believe is to the detriment of research into other forms of malignancy. The aims of this study were to further investigate the relationship between malignancy and research, in order to better quantify the degree to which breast cancer is being over- or under-represented in the research world.Methods: Bibliometrics is the science of studying written communication by systematic measurement and analysis of research publications. In this study, we examined research output over a one-year period for the 26 most commonly diagnosed cancers in the UK. Our strategy was based on that employed by a group in Edinburgh in 2001, and involved correlating research output with incidence and mortality statistics. In addition, we sought to elucidate changes in research output over time and then to correlate these changes with improvements in survival. The survival data used was that published by Coleman et al in 2004, and represents changes in survival over 5 year periods between 1986 and 1999 in England and Wales.Results: A total of 73,798 publications were included in this study. Breast cancer received more research attention than any other malignancy in the time period of this study. Proportional to its incidence and associated mortality, however, breast cancer was markedly underrepresented. This relationship was consistent across publication and study types, and in the higher impact journals. There was a strong positive correlation between improvement in 5-year survival and research output (p = 0.003). Those malignancies enjoying the greatest increases in output included those involving the prostate, non-hodgkins lymphoma, breast and vaginal cancer.Conclusions: This study was intended to provide a snapshot-in-time of research output in malignancy. It has shown that, on the basis of both incidence and mortality, breast cancer is not receiving disproportionate attention by the research community, contrary to popular opinion. Whilst the absolute figures clearly reflect the success of the breast cancer advocacy community in raising and maintaining the profile of the disease, the evidence suggests that, if anything, breast cancer is not receiving the interest it deserves, based on its burden to society. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1080.

O-81 The impact of caseload on practice patterns in breast cancer: Evidence from the UK Breast Screening Programme

Studies examining the relationship between caseload and surgical practice in breast cancer have generally involved a small number of units or patients, and have been based on outdated practice patterns. We aimed to examine the caseload volume of screening units and individual breast cancer surgeons, and to investigate the relationship between these volumes and practice patterns in the contemporary setting. The non-operative and operative history of screen-detected breast cancers, diagnosed in women who were screened between 2000 and 2008 within the UK Breast Screening Programme, was extracted from national databases. This information was then correlated with unitand individual surgeon caseload. There were 14,008,192 screening events and 110,912 cancers detected over the study period. No differences were seen between practice patterns in the lowversus high-volume units. The percentage of surgeons seeing P30 cases of breast cancer per year rose from 35.4% to 51.6%, whilst the number of surgeons responsible for <10 cases annually decreased from 32.9% to 23.5%, over the study period. There was a positive correlation between the number of cancers seen by individual surgeons and the rate at which they employed SNB (p < 0.001), and performed immediate breast reconstruction (p < 0.001).The number of mastectomies performed was approximately 4% lower in surgeons with high caseload versus those with a low caseload (p = 0.035). Whilst many surgeons are still practicing out-with ABS at BASO guidelines, significant improvements have been made. The important variable in terms of practice patterns is the number of cancers each individual surgeon deals with; the caseload of individual units is less important.