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Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant. PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum samples were collected pre-treatment (pre-trt; n = 122), at day 15 of cycle 1 (D15; n = 108), during the one week-off palbociclib before initiating cycle 2 (D28; n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa. Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15. STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. CLINICALTRIALS. NCT02536742; EudraCT 2014-005387-15.

PurposeCyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.Experimental designParental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.ResultsParental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.ConclusionsAberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involv

Background: Thymidine kinase 1 (TK1) plays a critical role in DNA synthesis and cell proliferation. Recent studies have shown potential for serum TK1 activity (sTKa) as a prognostic marker and indicator of early response to endocrine therapy in advanced breast cancer. The aim of this study is to assess the correlation between sTKa and patient outcome. Patients and methods: The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was a double-blind, double-dummy, randomised trial of fulvestrant versus exemestane after progression on non-steroidal aromatase inhibitor therapy, in postmenopausal women with advanced breast cancer. Retrospective analyses of serum archived from EFECT were conducted. sTKa was assessed using the DiviTum® assay on samples collected at baseline, after three and six months of endocrine therapy, and at disease progression. Results: The median time to progression (mTTP) for patients with low baseline sTKa levels was 5.03 months (95% confidence interval [CI]: 3.91–5.89) versus 2.57 months (95% CI: 2.04–3.52) in patients with high sTKa baseline levels (P < 0.0001). On treatment, patients whose sTKa increased from baseline had a significantly shorter mTTP (3.39 months, 95% CI: 2.14–4.11) than those without an sTKa increase (5.39 months, 95% CI: 4.01–6.68) (P = 0.0045). Similar results were observed in the separate EFECT treatment arms. After adjusting for major prognostic factors, sTKa remained an independent marker. Conclusion: sTKa is a potential circulating prognostic marker in patients with advanced breast cancer treated with endocrine therapy. It may also represent a tool for upfront identification of endocrine therapy resistance and early positive response to therapy. Independent validation of these results is warranted., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Background: Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial. Methods: We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported p values resulted from Fisher’s exact test. Results: Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+ n = 129; HR− n = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% versus 18% respectively; p = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52–0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients versus 28% in HR+/RBsig High. Conclusions: These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment., SCOPUS: ar.j, info:eu-repo/semantics/published

UnlabelledThe transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program.ImplicationsAP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.

Background: The estrogen receptor (ER) signaling pathway is the dominant driver of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, endocrine treatment, such as the anti-estrogen tamoxifen, represents the most effective and widely used therapy for ER positive breast cancer patients. Unfortunately not all patients respond to endocrine treatment and a wide proportion of patients ultimately develop resistance and die. Selecting patients with an increased risk of recurrence and identifying those that might benefit from a particular therapy is of great value in order to personalize breast cancer therapies. A minority of breast cancers does not express ER and displays features of aggressiveness and poor prognosis. Prognostic markers are urgently needed for this subset of patients as well. The p160 family of ER co-activator is composed of three different members: SRC1, SRC2 and AIB1. SRC1 and AIB1 are frequently overexpressed in breast cancer and appear to be linked to hormone resistance, particularly in HER2 positive breast cancer. SMRT is an ER co-repressor that has been implicated in tamoxifen resistance. Data on p160 family members and SMRT expression in human breast cancer samples and its prognostic and predictive significance in endocrine treated patients are controversial or lacking altogether. Moreover, the role of these co-regulators in ER negative disease is poorly understood. Methods: SRC1, SRC2, AIB1 and SMRT expression was determined by immunohistochemistry on tissue microarrays derived from two fully documented cohorts of 1812 and 1424 patients. Results: HER2 and AIB1 dual-positive tumors were associated with markedly worse outcome compared to tumors overexpressing either HER2 or AIB1 alone, irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. Additionally, we found that co-expression of two or more SRCs were significantly associated with worse outcome in ER posi

Background: The estrogen receptor (ER) signaling pathway is the dominant driver of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, endocrine treatment, such as the anti-estrogen tamoxifen, represents the most effective and widely used therapy for ER positive breast cancer patients. Unfortunately not all patients respond to endocrine treatment and a wide proportion of patients ultimately develop resistance and die. Selecting patients with an increased risk of recurrence and identifying those that might benefit from a particular therapy is of great value in order to personalize breast cancer therapies. A minority of breast cancers does not express ER and displays features of aggressiveness and poor prognosis. Prognostic markers are urgently needed for this subset of patients as well. The p160 family of ER co-activator is composed of three different members: SRC1, SRC2 and AIB1. SRC1 and AIB1 are frequently overexpressed in breast cancer and appear to be linked to hormone resistance, particularly in HER2 positive breast cancer. SMRT is an ER co-repressor that has been implicated in tamoxifen resistance. Data on p160 family members and SMRT expression in human breast cancer samples and its prognostic and predictive significance in endocrine treated patients are controversial or lacking altogether. Moreover, the role of these co-regulators in ER negative disease is poorly understood. Methods: SRC1, SRC2, AIB1 and SMRT expression was determined by immunohistochemistry on tissue microarrays derived from two fully documented cohorts of 1812 and 1424 patients. Results: HER2 and AIB1 dual-positive tumors were associated with markedly worse outcome compared to tumors overexpressing either HER2 or AIB1 alone, irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. Additionally, we found that co-expression of two or more SRCs were significantly associated with worse outcome in ER posi

Background: The estrogen receptor (ER) signaling pathway is the dominant driver of cell proliferation and survival in the majority of human breast cancers. Not surprisingly, endocrine treatment, such as the anti-estrogen tamoxifen, represents the most effective and widely used therapy for ER positive breast cancer patients. Unfortunately not all patients respond to endocrine treatment and a wide proportion of patients ultimately develop resistance and die. Selecting patients with an increased risk of recurrence and identifying those that might benefit from a particular therapy is of great value in order to personalize breast cancer therapies. A minority of breast cancers does not express ER and displays features of aggressiveness and poor prognosis. Prognostic markers are urgently needed for this subset of patients as well. The p160 family of ER co-activator is composed of three different members: SRC1, SRC2 and AIB1. SRC1 and AIB1 are frequently overexpressed in breast cancer and appear to be linked to hormone resistance, particularly in HER2 positive breast cancer. SMRT is an ER co-repressor that has been implicated in tamoxifen resistance. Data on p160 family members and SMRT expression in human breast cancer samples and its prognostic and predictive significance in endocrine treated patients are controversial or lacking altogether. Moreover, the role of these co-regulators in ER negative disease is poorly understood. Methods: SRC1, SRC2, AIB1 and SMRT expression was determined by immunohistochemistry on tissue microarrays derived from two fully documented cohorts of 1812 and 1424 patients. Results: HER2 and AIB1 dual-positive tumors were associated with markedly worse outcome compared to tumors overexpressing either HER2 or AIB1 alone, irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. Additionally, we found that co-expression of two or more SRCs were significantly associated with worse outcome in ER posi