Primary Luminal Breast Cancer Research Articles

Психологические предикторы раннего обращения к врачу женщин с первичным люминальным раком молочной железы

Introduction. One of the most common localizations where there is a connection between early diagnosis, timely treatment and a successful outcome of a disease is breast cancer. The behavior of a woman is associated with whether she is seeking medical help earlier or later, this now is for the first time determined, among other things, by a number of psychological characteristics of her personality. These can be cognitive beliefs included in her picture of the world, locus of control, resilience, and life orientation. The aim of this study is to identify a set of psychological predictive markers that determine the moment of initial medical treatment (early or late stages of the disease) of women with primary luminal breast cancer. Materials and methods. Survey methods were used as research methods: World assumptions scale R. Janoff-Bulman (by M.A. Padun, A.V. Kotelnikova), locus of control scale J.B. Rotter (by E.F. Bazhin, E.A. Golynkina, L.M. Etkind), Life Orientation Test M.F. Scheier, C.S. Carver (by Tsiring D.A., Evnina K.Yu.), Hardiness Survey S. Maddi (by D. Leontiev), methods of mathematical statistics: methods of descriptive statistics, univariate analysis of variance, discriminant analysis. The study involved 138 women with breast cancer in the I-III stages of the disease, who for the first time sought professional medical help. Results. The study of the psychological characteristics of women with breast cancer who first consulted a doctor at various stages of the disease revealed a set of predictive markers that contribute to seeking medical help earlier or later. Women who were diagnosed with cancer at stage I of the disease (early treatment) were characterized by: in comparison with the others, low assessment of their own significance and value, low indicators of life orientation (dispositional pessimism). Whereas in women who applied at stage III of the disease (late treatment), to a lesser extent compared to others, their belief of control in general manifested, however, in situations of achievement and professional relations, the locus of control of these women is internal. Also, for women who applied at The study was funded by Russian Science Foundation, project number 19-18-00426. the third stage of the disease, the indicators of engagement and resilience are lower than for women who applied at the early stages. Analysis of the psychological variables that differentiate women according to the stages of primary treatment showed that resilience, internality in the field of their achievement and life orientation affect the behavior of women associated with the initial visit to the doctor.

Integrated Analysis of Key Differentially Expressed Genes Identifies DBN1 as a Predictive Marker of Response to Endocrine Therapy in Luminal Breast Cancer.

Endocrine therapy is the mainstay of adjuvant treatment for patients with luminal breast cancer. Despite ongoing advances in endocrine therapy to date, a proportion of patients ultimately develop endocrine resistance, resulting in failure of therapy and poor prognosis. Therefore, as part of the growing concept of personalised medicine, the need for identification of predictive markers of endocrine therapy response at an early stage, is recognised. The METABRIC series was used to identify differentially expressed genes (DEGs) in term of response to adjuvant endocrine therapy. Drebrin 1 (DBN1) was identified as a key DEG associated with response to hormone treatment. Next, large, well-characterised cohorts of primary luminal breast cancer with long-term follow-up were assessed at the mRNA and protein levels for the value of DBN1 as a prognostic marker in luminal breast cancer, as well as its potential for predicting the benefit of endocrine therapy. DBN1 positivity was associated with aggressive clinicopathological variables and poor patient outcomes. Importantly, high DBN1 expression predicted relapse patients who were subject to adjuvant endocrine treatment. Our results further demonstrate that DBN1 is an independent prognostic marker in luminal breast cancer. Its association with the response to endocrine therapy and outcome provides evidence for DBN1 as a potential biomarker in luminal breast cancer, particularly for the benefit of endocrine treatment. Further functional investigations into the mechanisms underlying sensitivity to endocrine therapy is required.

PPFIA1 expression associates with poor response to endocrine treatment in luminal breast cancer

BackgroundPPFIA1 is an important regulator of cell migration and invasion, regulating focal adhesion signalling and disassembly. PPFIA1 is frequently amplified in breast cancer, and recent functional studies indicate that PPFIA1 is an important promoter of migration and invasion in breast cancer. This study aims to evaluate the utility of PPFIA1 expression in the luminal breast cancer as a prognostic marker to predict the response to endocrine therapy.MethodsLarge, well-characterised cohorts of primary luminal breast cancer patients with long-term follow-up was assessed for the clinical impact of PPFIA1 expression at the transcriptomic and proteomic levels. Prognostic significance of PPFIA1 and its relationship with clinical outcome and benefit of endocrine therapy were analysed. In addition, its association with other related-genes was analysed.ResultsThere was significant association between PPFIA1 expression and a member of the liprin family that involves in cell invasion (PPFIBPI), and the cell cycle regulator (CCND1), whereas a negative association was observed with the tumour suppressor gene (CD82). Patients with high PPFIA1 expression were associated with high risk of recurrence, distant metastasis and death from breast cancer (P < 0.05). Importantly, high PPFIA1 expression predicted relapse in a subset of patients who were subject to endocrine treatment alone, and was an independent prognostic marker of unfavourable outcome in these patients (P < 0.05).ConclusionsThese findings support the proposed role for PPFIA1 as a regulator of cell migration in breast cancer and provides definitive evidence for the clinical utility of PPFIA1 expression in patients with luminal breast cancer. Most importantly, our data suggests that PPFIA1 might be a potential predictive marker for poor benefit from endocrine therapy.

Genetic Counseling in the Follow-up of Breast Cancer patients; Conversion of a Luminal Tumor to TNBC

Background: Triple-negative subtype does not have any of the receptors that are commonly found in breast cancer. Patients suffering from Triple-negative breast cancer are at risk of early metastasis and BRCA mutation. The conversion of the receptors during the metastatic progression or local recurrence of breast cancer is a well-known topic that affects the therapeutic measures and outcome. Confirmation of immunohistochemistry is essential in these conditions, but genetic evaluation is controversial. Case presentation: A woman suffering from primary luminal breast cancer presented with femoral bone metastasis in the follow-up after two years. Bone metastasis was compatible with the triple-negative subtype. This case was discussed at the weekly breast multidisciplinary team session of the Department of Breast Surgery, Tehran University of Medical Sciences.Question: Does the patient need genetics counseling in a conversion setting? And does the new specimen need CISH/FISH techniques to confirm TNBC tumors?Conclusion: There are no strong guidelines to recommend genetic counseling and BRCA testing for patients with breast cancer biomarkers conversion. Re-assessing the specimen for ER, PR, and HER-2 is necessary for this setting.

Prognostic significance of amplifications of stemness genes in primary luminal breast cancer depending on the response to neoadjuvant chemotherapy.

e14655 Background: Neoadjuvant chemotherapy (NAС) is one of the treatment options for breast cancer (BC). However, chemotherapy is known can cause intratumoral changes that increase the risk of metastasis. We have previously found that the appearance of new amplifications in the chromosomal regions harboring stemness genes (3q, 5p, 6p, 7q, 8q, 9p, 9q, 10p, 10q21.1, 13q, 16p, 18Chr, 19p) is associated with the development of hematogenous metastases in 100% of cases. In our study, we evaluated the prognostic significance of amplifications stemness genes in primary BC depending on the NAC response. Methods: The study included 104 patients with stage II-III luminal B (Her2Neu -) breast cancer. All patients received 4-8 courses of NAС followed by surgery and hormone therapy. The follow-up period was 4-10 years. Amplifications in primary tumor DNA were determined using Affymetrix high density microarrays. Metastasis-free survival was estimated using the Kaplan-Meier method. Results: Zero or only 1 amplification was identified in tumor tissue of 42 patients (41%) (group 1). Two or more amplifications were identified in tumor tissue of 60 patients (59%) (group 2). We evaluated metastasis-free survival separately in each group, depending on the NAС response. It was found that in group 1, the median survival time was 122 months in cases with partial or complete regression (PR + pCR, and 63 months in cases with stable disease or disease progression (S + P), p &gt; 0.05. In group 2, the median survival of patients with PR + pCR was not reached, and it was 63 months in patients with S + P, p = 0.025. Conclusions: Achievement of partial or complete regression in breast cancer patients, whose primary tumors displayed 2 or more amplifications of stemness genes, was associated with the increased rates of metastasis-free survival and can be considered as a positive prognostic criterion. However, the response to NAC did not impact survival of patients with 0-1 amplification of stemness genes.

Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific

The functions and transcriptional profiles of dendritic cells (DCs) result from the interplay between ontogeny and tissue imprinting. How tumors shape human DCs is unknown. Here we used RNA-based next-generation sequencing to systematically analyze the transcriptomes of plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 conventional DCs (cDC1s), type 2 conventional DCs (cDC2s), CD14+ DCs and monocytes-macrophages from human primary luminal breast cancer (LBC) and triple-negative breast cancer (TNBC). By comparing tumor tissue with non-invaded tissue from the same patient, we found that 85% of the genes upregulated in DCs in LBC were specific to each DC subset. However, all DC subsets in TNBC commonly showed enrichment for the interferon pathway, but those in LBC did not. Finally, we defined transcriptional signatures specific for tumor DC subsets with a prognostic effect on their respective breast-cancer subtype. We conclude that the adjustment of DCs to the tumor microenvironment is subset specific and can be used to predict disease outcome. Our work also provides a resource for the identification of potential targets and biomarkers that might improve antitumor therapies.

RELATIONS OF PROTEASOMAL SYSTEM WITH TUMOR STAGE IN LUMINAL BREAST CANCER

The aim of this study was to investigate characteristics of the proteasomal system in luminal breast cancer. There were included 124 patients with primary luminal breast cancer in stage Т13N0-2M0 who had not received neoadjuvant treatment. The process of lymphogenous metastasis was associated with a significant change in caspase-like activity (CL) and subunit composition of proteasomes. CL activity of proteasomes was increased in luminal A breast cancer with extensive lymphogenic metastasis (N2), while it was decreased in the luminal B subtype of cancer. It was accompanied by an increase in the composition of the proteasomal total pool subunits, regulatory and immune subunits. Decrease in CL activity of proteasomes can be poor prognostic sign which is associated with the lymphogenous invasion of the tumor process in luminal B breast cancer.

GATA3 frameshift mutation promotes tumor growth in human luminal breast cancer cells and induces transcriptional changes seen in primary GATA3 mutant breast cancers.

The GATA3 transcription factor is one of the most frequently mutated genes in breast cancer. Heterozygous mutations, mostly frameshifts, are seen in 15% of estrogen receptor positive breast cancers, the subtype in which these mutations are almost exclusively found. Mouse studies have shown that Gata3 is critical for breast development and that GATA3 gene dosage affects breast tumor progression. Human patient data have shown that high Gata3 expression, a feature of luminal subtype breast cancers, is associated with a better prognosis. Although the frequency of GATA3 mutation suggests an important role in breast cancer development or progression, there is little understanding of how mutations in GATA3 affect its function in luminal breast epithelial cells and what gene expression changes result as a consequence of the mutations. Here, using gene editing, we have created two sets of isogenic human luminal breast cancer cell lines with and without a hotspot truncating GATA3 mutation. GATA3 mutation enhanced tumor growth in vivo but did not affect sensitivity to clinically used hormonal therapies or chemotherapeutic agents. We identified genes with upregulated and downregulated expression in GATA3 mutant cells, a subset of which was concordantly differentially expressed in GATA3 mutant primary luminal breast cancers. Addback of mutant GATA3 recapitulated mutation-specific gene expression changes and enhanced soft agar colony formation, suggesting a gain of function for the mutant protein.

Comparison of visual assessment and image analysis in the evaluation of Ki-67 expression and their prognostic significance in immunohistochemically defined luminal breast carcinoma

To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer-assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma. Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells. Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P<0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P<0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P<0.00001) and visual counting (cut-off value: 28.5%; P<0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67labeling index values determined by automated analysis (cut-off value: 11.5%; P<0.0001) and visual counting (cut-off value: 19.7%, P<0. 0001). The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy.

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib.

Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers, and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, P < 0.01), combined KD reduced proliferation greater than either alone (52% reduction, P < 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C, and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated through the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response.

81P Response to Endocrine and Targeted Therapies in A Large Panel of Patient-Derived Luminal Breast Cancer Xenografts

ABSTRACT Introduction Resistance to endocrine therapy (ET) is a major complication of luminal breast cancers (BC). The aims of this study were to generate hormone-resistant xenograft models from patients' tumor and to evaluate the response to endocrine (ET) and targeted therapies. Methods More than 400 primaries ER+ BC have been grafted in Swiss nude mice. Established xenograft tumors have been validated by pathology and immunohistochemistry examination (ER, PR, HER2 and Ki67). In vivo response to different ET (tamoxifen, fulvestrant, ovariectomy and letrozole) was evaluated. Xenograft tumor variants with acquired resistance to ET were generated under continuous in vivo therapeutic pressure. The response to the mTOR inhibitor RAD001 was assessed in ET resistant xenograft models. Affymetrix 1.0 ST gene expression analyses will be performed. Results We have established 12 luminal B xenografts. The luminal phenotype, determined at the gene and protein expression levels, was conserved. Different patterns of in vivo response to ET were observed, thus exhibiting heterogeneity similar to what is observed in the clinic. 5 xenograft models with acquired resistance to ET were generated from tumors resistant to tamoxifen and ovariectomy. Expression of ER and PR was conserved in the variant models, while proliferation status (Ki67 expression) was generally higher. RAD001 treatment resulted in a strong anti-tumor effect in both models with intrinsic and acquired resistance to tamoxifen, and an additive effect was observed in combination with tamoxifen or fulvestrant. The evaluation of response to endocrine treatments combined with RAD001 is being completed by the analysis of gene expression and the PI3K/mTOR pathway status. Final results will be presented at the meeting. Conclusion A large panel of primary luminal BC xenografts was characterized, recapitulating the biological and clinical behaviors of patient tumors. Tumors showing intrinsic and acquired resistance to ET were generated. mTOR pathway targeting is efficient in ET resistance reversal, and molecular studies will give an insight of the mechanisms associated with acquired resistance. Disclosure All authors have declared no conflicts of interest.

Abstract LB-352: Reversal of resistance to endocrine therapy by mTOR pathway targeting in a panel of patient derived breast cancer xenografts

Abstract Introduction: Resistance to endocrine therapy (ET) is a major complication of luminal breast cancers. The aims of this study were: 1) to evaluate the response to endocrine and targeted therapies in a large series of luminal breast cancer xenografts, 2) to generate hormone-resistant xenograft models and 3) to use these models as a support to study ET resistance reversal by mTOR targeting Methods: More than 400 tumor fragments obtained directly from patients with ER+ve breast cancer have been grafted in Swiss nude mice. After stable engraftment, xenografted tumors have been validated by pathology and immunohistochemistry (IHC) examination (ER, PR, HER2 and Ki67). In vivo response to different endocrine treatments (tamoxifen, fulvestrant, ovariectomy and letrozole) was evaluated. ET-resistant variants were generated from tumors growing under continuous therapeutic pressure. Models with intrinsic or acquired resistance to ET were tested with the mTOR inhibitor RAD001, alone and in combination with ET. Molecular analyses will be performed. Results: 12 luminal breast cancer xenografts have been characterized and consistently showed maintenance of the luminal phenotype The genetic profile measured by aCGH for both the patient and xenograft tumors showed a similar profile, stable through the in vivo mice generations. Different patterns of response to ET were observed, thus exhibiting heterogeneity similar to what is observed in the clinic. Five xenograft models with acquired resistance to ET were generated after several months of continuous endocrine therapy and were maintained as independent hormono-resistant variants. Two of them were derived from tumors resistant to tamoxifen and 3 from tumors resistant to ovariectomy, used as a surrogate to estrogen deprivation. IHC analysis showed that expression of ER and PR receptors was conserved in the variant models, while proliferation status assessed by Ki67 expression was generally higher. For all 5 models, resistance to ET was confirmed in further engraftment and ET experiments. RAD001 treatment resulted in a strong anti-tumor effect in the tamoxifen resistant xenograft models and an additive effect was observed when RAD001 was given in combination with tamoxifen or fulvestrant.The PI3K/mTOR pathway status and gene expression profiles will be analyzed in all experiments. Detailed results will be presented at the meeting. Conclusion: We have established a large panel of primary luminal breast cancer xenografts, recapitulating the biological and clinical features of patient tumors. ET resistant variants have been generated, which serve as a preclinical platform to test reversal of resistance to ET, e.g; by mTOR pathway targeting. Molecular studies at the gene and protein expression levels will give an insight of the mechanisms associated with acquired resistance to endocrine treatments. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-352. doi:1538-7445.AM2012-LB-352