Is the biology of breast cancer changing? A study of hormone receptor status 1984-1986 and 1996-1997

Using archived tumours, those from 1984-1986 and 1996-1997 underwent immunohistochemistry for hormone receptors and grade analysis. A significant shift towards more ER-positive and low-grade disease was found; this appears to reflect screening practices, but could still influence survival

The modified Glasgow prognostic score in prostate cancer: results from a retrospective clinical series of 744 patients

<p>Background: As the incidence of prostate cancer continues to rise steeply, there is an increasing need to identify more accurate prognostic markers for the disease. There is some evidence that a higher modified Glasgow Prognostic Score (mGPS) may be associated with poorer survival in patients with prostate cancer but it is not known whether this is independent of other established prognostic factors. Therefore the aim of this study was to describe the relationship between mGPS and survival in patients with prostate cancer after adjustment for other prognostic factors.</p> <p>Methods: Retrospective clinical series on patients in Glasgow, Scotland, for whom data from the Scottish Cancer Registry, including Gleason score, Prostate Specific Antigen (PSA), C-reactive protein (CRP) and albumin, six months prior to or following the diagnosis, were included in this study.</p> <p>The mGPS was constructed by combining CRP and albumin. Five-year and ten-year relative survival and relative excess risk of death were estimated by mGPS categories after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days.</p> <p>Results: Seven hundred and forty four prostate cancer patients were identified; of these, 497 (66.8%) died during a maximum follow up of 11.9 years. Patients with mGPS of 2 had poorest 5-year and 10-year relative survival, of 32.6% and 18.8%, respectively. Raised mGPS also had a significant association with excess risk of death at five years (mGPS 2: Relative Excess Risk = 3.57, 95% CI 2.31-5.52) and ten years (mGPS 2: Relative Excess Risk = 3.42, 95% CI 2.25-5.21) after adjusting for age, socioeconomic circumstances, Gleason score, PSA and previous in-patient bed days.</p> <p>Conclusions: The mGPS is an independent and objective prognostic indicator for survival of patients with prostate cancer. It may be useful in determining the clinical management of patients with prostate cancer in addition to established prognostic markers.</p&gt

Enhancing clinical decision support with genomic tools in breast cancer: a Scottish perspective

Introduction: The Oncotype DX Breast RS test has been adopted in Scotland and has been the subject of a large population-based study by a Scottish Consensus Group to assess the uptake of the recurrence score (RS), evaluate co-variates associated with the RS and to analyse the effect it may have had on clinical practice. Materials & Methods: Pan-Scotland study between August 2018–August 2021 evaluating 833 patients who had a RS test performed as part of their diagnostic pathway. Data was extracted retrospectively from electronic records and analysis conducted to describe change in chemotherapy administration (by direct comparison with conventional risk assessment tools), and univariate/multivariate analysis to assess relationship between covariates and the RS. Results: Chemotherapy treatment was strongly influenced by the RS (p < 0.001). Only 30 % of patients received chemotherapy treatment in the intermediate and high risk PREDICT groups, where chemotherapy is considered. Additionally, 55.5 % of patients with a high risk PREDICT had a low RS and did not receive chemotherapy. There were 17 % of patients with a low risk PREDICT but high RS who received chemotherapy. Multivariate regression analysis showed the progesterone receptor Allred score (PR score) to be a strong independent predictor of the RS, with a negative PR score being associated with high RS (OR 4.49, p < 0.001). Increasing grade was also associated with high RS (OR 3.81, p < 0.001). Classic lobular pathology was associated with a low RS in comparison to other tumour pathology (p < 0.01). Nodal disease was associated with a lower RS (p = 0.012) on univariate analysis, with menopausal status (p = 0.43) not influencing the RS on univariate or multivariate analysis. Conclusions: Genomic assays offer the potential for risk-stratified decision making regarding the use of chemotherapy. They can help reduce unnecessary chemotherapy treatment and identify a subgroup of patients with more adverse genomic tumour biology. A recent publication by Health Improvement Scotland (HIS) has updated guidance on use of the RS test for NHS Scotland [1].It suggests to limit its use to the intermediate risk PREDICT group. Our study shows the impact of the RS test in the low and high risk PREDICT groups. The implementation across Scotland has resulted in a notable shift in practice, leading to a significant reduction in chemotherapy administration in the setting of high risk PREDICT scores returning low risk RS. There has also been utility for the test in the low risk PREDICT group to detect a small subgroup with a high RS. We have found the PR score to have a strong independent association with high risk RS. This finding was not evaluated by the key RS test papers, and the potential prognostic information provided by the PR score as a surrogate biomarker is an outstanding question that requires more research to validate

Breast cancer patients' clinical outcome measures are associated with Src kinase family member expression

<p>BACKGROUND: This study determined mRNA expression levels for Src kinase family (SFK) members in breast tissue specimens and assessed protein expression levels of prominent SFK members in invasive breast cancer to establish associations with clinical outcome. Ki67 was investigated to determine association between SFK members and proliferation.</p> <p>METHODS: The mRNA expression levels were assessed for eight SFK members by quantitative real-time PCR. Immunohistochemistry was performed for c-Src, Lyn, Lck and Ki67.</p> <p>RESULTS: mRNA expression was quantified in all tissue samples. SRC and LYN were the most highly expressed in malignant tissue. LCK was more highly expressed in oestrogen receptor (ER)-negative, compared with ER-positive tumours. High cytoplasmic Src kinase protein expression was significantly associated with decreased disease-specific survival. Lyn was not associated with survival at any cellular location. High membrane Lck expression was significantly associated with improved survival. Ki67 expression correlated with tumour grade and nuclear c-Src, but was not associated with survival.</p> <p>CONCLUSIONS: All eight SFK members were expressed in different breast tissues. Src kinase was highest expressed in breast cancer and had a negative impact on disease-specific survival. Membrane expression of Lck was associated with improved clinical outcome. High expression of Src kinase correlated with high proliferation.</p&gt

Is Src a Viable Target for Treating Solid Tumours?

Src was the first proto-oncogene to be discovered. Since then the role of Src has been extensively studied in vitro. Src is a key regulator of multiple signal transduction pathways and plays a significant part in cellular transformation. Dysfunction of Src, through overexpression or increased activation, has profound effects on basic cellular functions. Elevated Src expression and/or activation is evident across a wide range of solid tumour types, highlighting its place in carcinogenesis and making it an attractive therapeutic target. In this review, we discuss in vitro and in vivo data examining the role of Src in the different cellular processes involved in oncogenesis and metastasis, covering the association of Src with increased cell proliferation and survival, decreased cellular adhesion, increased cell motility and invasiveness, accelerated/advanced angiogenesis and pathogenic bone activity. We also review evidence gathered from human tumour tissue and translational research studies that further substantiates the role of Src in oncogenesis. A summary of Src inhibitors currently being developed and trialled as therapeutic agents is provided to underline Src as a potential molecular target for solid tumour therapy. Further clinical data are needed to conclusively demonstrate that Src inhibitors have clinical utility in the treatment of solid tumors

Shorter disease-specific survival of ER-positive breast cancer patients with high cytoplasmic Src kinase expression after tamoxifen treatment

<b>Background</b> <p>Src kinase, a non-receptor tyrosine kinase, is overexpressed and highly activated in a number of human cancers and appears to show a significant relationship with breast cancer progression. Recent in vitro studies have suggested that Src kinase may be involved in tamoxifen resistance.</p> <b>Methods</b> <p>Immunohistochemistry was performed on 392 resected breast cancers using an antibody to c-Src. Expression was assessed using the weighted histoscore method.</p> <b>Results</b> <p>Forty-five percentage of breast tumours exhibited nuclear, 46% cytoplasmic and 7% membrane expression. Lymph node positivity correlated with cytoplasmic c-Src tumour expression levels (P < 0.001). Nuclear c-Src correlated negatively with cytoplasmic and membrane c-Src expression (P < 0.001, P = 0.005). High expression levels of cytoplasmic c-Src was associated with worse disease-specific survival (P = 0.026) after completing 5 years of tamoxifen therapy. However, high expression of c-Src at any cellular location did not show any association with de novo relapse on tamoxifen (c-Src nuc P = 0.906, c-Src cyto P = 0.735 and c-Src memb P = 0.791)</p> <b>Conclusions</b> <p>No translational evidence was found in this study to support a role for Src kinase in developing de novo tamoxifen resistance. However, based on our findings on late clinical outcome, patients with high cytoplasmic c-Src may be selected for continuing endocrine therapy to prevent worsening prognosis.</p&gt

Activated c-Src (Y215) kinase expression predicts for early relapse on tamoxifen in human breast cancer

Abstract Abstract #3025 Recent studies have demonstrated activation of the non-receptor tyrosine kinase c-Src in tamoxifen resistant breast cancer cell lines, which when treated with Src inhibitors demonstrate a reduction in motility and invasiveness. However, there are little published translational studies confirming a role for c-Src in tamoxifen resistance in vivo. We aim to determine if activated c-Src expression correlates clinically with increased recurrence on tamoxifen.&amp;#x2028; Methods&amp;#x2028; Tissue microarrays were constructed from a patient cohort of 402 Tamoxifen treated ER positive patients. Immunohistochemistry was performed using commercially available antibodies to Total Src as well as to activated (phosphorylated) c-Src at 2 sites (Y416 and Y215) (pSrc416 and pSrc215 respectively). Expression was assessed by 2 independent scorers (weighted histoscore method). HER1-3 status and expression of membranous phosphorylated ER (sites serine 118 and 167) had previously been determined. All statistical calculations were performed using SPSS 15, including Kaplan-Meier life table analysis with log rank testing of differences in breast cancer related relapse whilst on tamoxifen.&amp;#x2028; Results&amp;#x2028; Membranous pSrc215 was observed in 20.3% of the cases but was more frequently observed in the cytoplasm (85.9%) and nucleus (90.5%). Overexpression of cytoplasmic pSrc215 was associated with an earlier time to recurrence (p = 0.037).&amp;#x2028; &amp;#x2028; Cox regression analysis confirmed this to be independent of grade, nodal and HER1-3 status (p=0.028, HR 3.17 (1.14–8.85)). Cytoplasmic pSrc215 was also strongly correlated with membranous phospho-ER, EGFR and HER3 status (Mann Whitney; p&amp;lt;0.001, p=0.026, p&amp;lt;0.001 respectively). Membranous and nuclear pSrc215 staining were not associated with time to relapse.&amp;#x2028; Over expression of Total Src and pSrc416 did not predict for relapse.&amp;#x2028; Discussion&amp;#x2028; Our findings provide support to in vitro studies linking c-Src with tamoxifen resistance. The phosphorylation site pSrc215 is a putative site of activation by HER2 and PGFR resulting in up to 50 fold activation of Src in vitro. The correlations demonstrated with HER status and membranous ER lead us to speculate that this interplay between non genomic ER and Src activation may provide a mechanism for the lack of response to tamoxifen in these patients.&amp;#x2028; Further studies are required to determine if activated pSrc215 represents activated c-Src alone or may also represent activation of other Src family members as the Y416 and Y215 sequences are highly conserved amongst the Src kinases with homologous activation sites. If confirmed, future use of novel combination therapies with Src inhibitors may have an important role in combating tamoxifen resistance. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3025.</jats:p