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

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

Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study

Purpose: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. Methods: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb–July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. Results: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32–81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7–8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months’ treatment duration; median of 4 mm [IQR − 20, 4]. In a small subset of patients ( n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month’s duration of BrET. Discussion: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials

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

Abstract P6-08-10: Disease Specific Survival of Breast Cancer Patients Is Not Associated with Expression of Inactive or Even Partially Activated Src Kinase

Abstract Background: c-Src is implicated as a regulator of cell proliferation and survival (1). Recent work has demonstrated that c-Src and fully activated Y419Src expression in breast cancer specimens was associated with poor clinical outcome of breast cancer patients (2). c-Src is activated by a number of pathways. Known as the classical activation pathway, dephosphorylation of Y530 is needed to initiate a configuration change of the protein allowing full activation by autophosphorylation of tyrosine site 419. Phosphorylation of the tyrosine residual 530 on the c-terminal tail by Csk tyrosine kinase acts as a negative regulatory protein binding site, keeping Src kinase in a closed confirmation (3). The aim of this translational study was to assess associations between inactivate and partially activated Src expression to clinic-pathological features of the cohort and if different stages of c-Src activation equally influences breast cancer patients’ disease specific survival. Methods: Tissue microarray technology was used to analyse tissue taken from 165 breast cancer patients taken at time of surgical resection. Immunohistochemistry was performed using anti-Clone 28 and Clone 28 antibody. To investigate those different stages of Src kinase activation, Clone 28 antibody was employed to recognise the semi-active form of Src. To evaluate protein expression of inactive Src kinase, anti-Src family negative regulatory [pY] site (anti-Clone 28= AC28) antibody was utilised for detecting phosphorylated tyrosine site 530. Expression was assessed using the weighted histoscore method by two independent scorers. Results: Using those antibodies, 50% of AC28 and Clone28 expression was observed in the nucleus and 44% AC28 and 46% Clone28 expression in the cytoplasm. Only 3.6% of AC28 was detected in the membrane, compared to Clone28 with 53% in the membrane and 55 % perinuclear. Nuclear expression of AC28 correlated negatively with ER status (chi square P&amp;lt;0.001), whereas cytoplasmic AC28 and Clone28 correlated negatively with membrane c-Src expression (chi square p=0.008, chi square P&amp;lt;0.001). On univariate and multivariate analysis there was no significant association noticed between AC28 and Clone28 expression and disease specific survival at any cellular location. Conclusions: ER negative breast cancers patients were more likely to express inactive Src in the nucleus. Breast cancer patients with higher cytoplasmic expression of inactive or partially activated Src were more likely not to express c-Src at the membrane (site of activation). Inactive and partially activated Src are not associated with patients’ survival. References: 1) Frame MC. Biochim Biophys Acta 2002; 1602: 114-130. 2) Elsberger B, et. al: Am J Path (2009);175(4):1389-97. 3) Roskoski R Jr. Biochem Biophys Res Commun. 2005 May 27;331(1):1- 14. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-08-10.</jats:p

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

&lt;b&gt;Background&lt;/b&gt; &lt;p&gt;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.&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; &lt;p&gt;Immunohistochemistry was performed on 392 resected breast cancers using an antibody to c-Src. Expression was assessed using the weighted histoscore method.&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; &lt;p&gt;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 &#60; 0.001). Nuclear c-Src correlated negatively with cytoplasmic and membrane c-Src expression (P &#60; 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)&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; &lt;p&gt;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.&lt;/p&gt