Predictive markers of endocrine response in breast cancer

Ongoing clinical and research efforts seek to optimise the use of endocrine therapy in the treatment of breast cancer. Accurate biomarkers are needed that predict response for individual patients. The presence of the estrogen receptor(ER) as the direct(for tamoxifen and fulvestrant) or indirect(for aromatase inhibitors) target molecule for endocrine therapy remains the foremost biomarker and determinant of response. However, ER expression only poorly predicts outcome and further indicators of response or resistance are required. The development and application of molecular signature assays such as Oncotype Dx, Prosigna, Mammaprint and Endopredict have provided valuable information on prognosis and these are being used to support clinical decision making on whether endocrine therapy alone alongside surgery is sufficient for ER-positive early stage breast cancers or whether combination of endocrine with chemotherapy are also warranted. Ki67, the proliferation marker, has been widely used in the neo-adjuvant(pre-operative) setting to help predict response and long term outcome. Gene expression studies within the same setting have allowed monitoring of changes of potential predictive markers. These have identified frequent changes in estrogenregulated and proliferation genes. Specific molecules such as mutant ER may also prove helpful biomarkers in predicting outcome and monitoring response to treatment.

c-MET immunohistochemical expression in sporadic and inflammatory bowel disease associated lesions

BACKGROUND Post-colonoscopy colorectal cancer(CRC)rates for patients with inflammatory bowel disease(IBD)are unacceptably high.During colonoscopy,an intravenous fluorescent anti-c-MET probe may improve endoscopic detection of lesions.However,c-MET expression in IBD lesions is poorly defined,limiting translational studies.AIM To comprehensively define c-MET expression in sporadic and IBD-associated colorectal carcinogenesis.METHODS c-MET expression was immunohistochemically assessed in 319 formalin-fixed paraffin-embedded tissue specimens,colonoscopically or surgically retrieved between 1994-2017.Tissue included:30 normal colorectal biopsies,30 hyperplastic polyps(HP),31 sessile serrated lesions(SSL),55 tubular/tubulovillous adenomas with low(TA-LGD,n=32)or high grade dysplasia(TA-HGD,n=23),26 sporadic(s)-CRCs,16 quiescent IBD biopsies,11 active/inflamed IBD biopsies,18 IBDassociated dysplastic lesions(IBD-dys),and 102 IBD-CRCs.Expression was scored by two independent observers as:0=absent,1=weak,2=moderate or 3=strong.Mann-Whitney U and Kruskal-Wallis tests were used to assess significance.RESULTS Positive epithelial cytoplasmic and membranous c-MET expression was observed in all tissues,indicating there is ubiquitous expression in the colorectum.c-MET expression was weak in normal colonic epithelium compared with each of the sporadic colonic lesions,including TA-LGD(P<0.001),TA-HGD(P=0.004),HP(P<0.001),SSL(P<0.001),and s-CRC(P<0.001).Specifically,in sporadic(non-IBD)lesions,expression was stronger in TA-LGD compared with normal mucosa(P<0.001),and stronger in s-CRC compared with TA-HGD(P=0.004).However,there was no significant difference between TA-LGD and TA-HGD(P=0.852).Further,there was no difference in c-MET expression between HP and SSL(P=0.065).In IBD,expression was weaker in quiescent colonic mucosa compared with inflamed colonic mucosa(P<0.001).There was no difference between inflamed colonic mucosa and IBD-dys(P=0.512)or IBD-CRC(P=0.296).However,expression was stronger in IBD-dys(P<0.001)and IBD-CRC(P<0.001)compared with quiescent IBD colonic mucosa.CONCLUSION The characterisation of c-MET expression suggest that an intravenous probe may improve the endoscopic detection of lesions in both non-IBD patients and IBD patients with quiescent disease.

Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

Nuclear factor E2-related factor 2(NRF2),a transcription factor,is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis.NRF2 function is well studied in in vitro,animal and general physiology models.However,emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer,autism,anxiety disorders and diabetes.A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes.The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species(ROS)neutralizing and cytoprotective drug-metabolizing enzymes(phase I,II,III and 0).Further,NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance.Interestingly,we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome.This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes,which extends beyond its described classical role as a ROS regulator.This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner.This places NRF2 as a key determinant of action,effectiveness and resistance to anticancer therapy.