Alexey A Larionov

Cranfield University · School of Water Energy and Environment

Background: Contralateral breast cancer (CBC) is associated with younger age at first diagnosis, family history and pathogenic germline variants (PGVs) in genes such as BRCA1, BRCA2 and PALB2. However, data regarding genetic factors predisposing to CBC among younger women who are BRCA1/2/PALB2-negative remain limited. Methods: In this nested cas...

Background Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants. Methods Whole genome sequenc...

Background: Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behavior compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours and guidance for surveillance and treatment strategies are lacking. Aim: To evaluate the...

Introduction Rhabdomyosarcomas (RMS) are the most prevalent form of paediatric soft tissue sarcomas. They arise from skeletal muscle progenitor cells and are divided predominantly into two subtypes, embryonic and alveolar, with relatively poor prognosis. The alveolar subtype appears to be driven by an oncogenic fusion gene protein, typically but no...

The median survival of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) has more than doubled, since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapie...

Background: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make info...

The median survival of patients with HER2-positive metastatic breast cancer has more than doubled since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapies included trastuzumab with taxanes in the 1st lin...

While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast can...

Neo-adjuvant endocrine therapy has an established place in the treatment of post-menopausal oestrogen-receptor positive breast cancers. However, a number of clinical questions still need to be addressed to realise the full potential of the neo-adjuvant endocrine treatment. Thus, there is a shortage of data about direct comparison between endocrine...

Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations b...

Aromatase inhibitors (AIs) have an established role in the treatment of breast cancer. Response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Accurate biomarkers are urgently needed to predict response in these settings and to determine which individuals will benefit from adjuvant AI therapy. Pretreatment and o...

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization...

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization...

Aromatase inhibitors (AIs) are major treatment options for the management of patients with breast cancer. The drugs are effective and response rates can be high. However, resistance, either primary or acquired during treatment, may occur. Optimal clinical management requires accurate predictors of response to identify those tumours, which are most...

Aromatase Inhibitors (AIs) treat postmenopausal estrogen receptor positive tumours, which constitute the majority of breast cancer patients. This comprehensive volume brings together the current knowledge from different relevant areas, including molecular mechanisms and translational aspects of drug resistance in AIs. Topics covered include researc...

Invasive lobular cancer (ILC) accounts for approximately 10-15% of breast carcinomas and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre- and on-treatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 post-menopausal women with ER+ histologically confir...

In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC...

Background: Invasive lobular carcinoma (ILC) is a special histological subtype accounting for 10–15% of breast cancers. ILC responds poorly to neoadjuvant chemotherapy, but appears to respond well to endocrine therapy. However, it is unclear whether the molecular changes that occur in response to letrozole differ between lobular and ductal carcinom...

Background 10% of all breast cancers are HER2+/ER+ and these cancers exhibit both intrinsic and acquired resistance to endocrine therapy. They have a worse prognosis than HER2-/ER+ cancers. Aims 1. To investigate the role of HER2 in response to neoadjuvant Letrozole. 2. To predict which HER2+ cancers do not respond to Letrozole. Methods 23 postmeno...

Background: Aromatase inhibitors (AIs) have an established role in the treatment of estrogen receptor alpha positive (ER+) post-menopausal breast cancer. Response rates are 50-70% in the neoadjuvant setting and lower in advanced disease. There is a need to identify biomarkers to predict response that outperform those currently available, to be able...

The epithelial-to-mesenchymal transition (EMT) is a widely studied program of development of cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility. Microarrays have become a well-established technique for simultaneously measuring the expression of thousands of transcripts encoded by the genom...

s: Thirty-Fifth Annual CTRC‐AACR San Antonio Breast Cancer Symposium‐‐ Dec 4‐8, 2012; San Antonio, TX Background: Resistance to endocrine therapy may be promoted by deregulation of growth factor signaling pathways in addition to its intimate bidirectional crosstalk with the estrogen receptor (ER) signaling pathway. We have previously shown HER-2/n...

Background: Older postmenopausal patients with large operable or locally advanced oestrogen receptor positive, invasive breast cancers are candidates for treatment with neoadjuvant letrozole. HER2 positivity is a potential marker for early endocrine therapy resistance. In this study we have evaluated the effects of HER2 amplification, gene and prot...

Background: Estrogen is a key hormone involved in cancer cell development. It forms a complex with estrogen receptor alpha (ER) which binds to estrogen response elements (EREs) in the promoter regions of genes under its transcriptional control. Letrozole inhibits local production of estrogen. Despite the prevalent use of such drugs little is known...

Background: Approximately 75% of older postmenopausal patients with large operable or locally advanced oestrogen receptor positive breast cancer respond to treatment with neoadjuvant letrozole. Prediction of response is required as approximately 25% fail to respond. The aim of this study was to design a response predicting classifier with two dat...

Current approaches to identification of cancer-predisposing alleles are primarily based on the comparison of DNA sequences between affected and non-affected individuals. Many contemporary gene-seeking studies, be it genome-wide association scans or mutation analysis of candidate genes, utilize genetically enriched cancer cases. Genetic enrichment i...

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed cal...

Affymetrix GeneChips and Illumina BeadArrays are the most widely used commercial single channel gene expression microarrays. Public data repositories are an extremely valuable resource, providing array-derived gene expression measurements from many thousands of experiments. Unfortunately many of these studies are underpowered and it is desirable to...

Venn diagrams showing the overlaps between the 1000 most significant differentially expressed genes using A) pairwise SAM analysis and B&C) non–pairwise SAM analysis with Affymetrix (Green), Illumina (Blue) and combined (Teal).

A) Boxplots showing the Pearson correlation coefficients within and between labs. B) Plot showing the relationship between the false discovery rate and the number of genes identified comparing UHRR (A) with HBRR (B) using either 15 Affymetrix or 15 Illumina replicates or both together. C) Venn diagrams showing the overlaps between the 1000 most sig...

A) Boxplots showing the range of Pearson correlation coefficients between 18 matched samples (including baseline, 14-day and 3 month from 6 patients) for different correction methods. B) Affymetrix dataset and C) Illumina dataset boxplots showing the range of Pearson correlation coefficients between all possible sample combinations for different co...

Plots showing the relationship between false discovery rate against the number of significant differentially expressed genes identified across a range values of delta using SAM analysis in Affymetrix (Desmedt) and Illumina (Nadiri) datasets independently and when combined both before and after XPN correction to identify genes differentially express...

The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cance...

Background: Unlike recurrences with other therapies, ER+ breast cancers (BC) can recur ≥10 yrs after an apparent successful period of adjuvant endocrine therapy. The molecular basis for this pattern of resistance is unresolved. We addressed the hypothesis that early recurrences during tamoxifen (TAM) treatment exhibit different biological character...

The study aim was to identify early (within 14 days) and late changes (by 3 months) in breast cancer gene expression profiles associated with neoadjuvant therapy with letrozole. RNA from sequential tumour biopsies in 54 patients was analyzed on microarrays; changes were determined by frequency, magnitude and significance analyses. Substantially mor...

ABSTRACT: Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatme...

Breast cancer is the most frequent cancer in women in developed countries. Endocrine treatment is indicated to the majority of breast cancer patients. However, in some cases it does not work despite the current clinical indications. Eventually the resistance may develop in many of those who initially respond. Re-analysis of available breast cancer...

Protocols employing primary systemic therapy provide important basic knowledge about tumor behavior/response to therapy, but major challenges remain in how to obtain and use this information practically in the clinical setting.

This paper reviews the effects of oestrogen deprivation by third generation aromatase inhibitors on molecular profiles in breast cancers. It particularly focuses on results obtained as a result of pre-operative and neoadjuvant therapy in which primary breast cancers have been biopsied or excised before and during treatment with letrozole, anastrozo...

Background: Cross-talk between estrogen receptor (ER) and growth factor signaling pathways has been suggested to play a role in development of resistance to endocrine treatment with tamoxifen or aromatase inhibitors (AIs). While HER-2/neu amplification has been associated with lack of endocrine sensitivity in ER+ breast cancer, recent data have sug...

Background Endocrine resistance is a major clinical issue in breast cancer. Multiple studies provide data relating molecular features of primary tumours on their response to endocrine treatment. However, there is a paucity of data on molecular profiles of breast tumours at time when endocrine resistance has already manifested. Aim Provide mul...

Transcriptomic screens in breast cancer cell lines have identified a protein named anterior gradient-2 (AGR2) as a potentially novel oncogene overexpressed in estrogen receptor (ER) positive tumours. As targeting the ER is responsible for major improvements in cure rates and prevention of breast cancers, we have evaluated the pro-oncogenic function...

Clinical resistance is a major factor limiting benefits to endocrine therapy. Causes of resistance may be diverse and the mechanism of resistance in individual breast cancers is usually unknown. The present study illustrates how changes in the expression of proliferation and oestrogen-regulated genes occurring during neoadjuvant treatment with the...

Supplementary table S1. PCR primers' sequences.

ZIP file containing VBA macros (PCR1.xls), test data for the above macros (Target1.csv, Target2.csv, Target3.csv, Target4.csv, Target5.csv, Reference1.csv, Reference2.csv) and instruction to the above macros (Instructions.pdf). Unzip file into a separate folder on your PC and follow the instructions.

Background: Neoadjuvant endocrine therapy allows biological studies of de novo response and resistance but not of acquired resistance based on clinical endpoints as surgery is usually carried out after around 4 months. Response is associated with a significant fall in Ki67 (proliferation) after 2 weeks treatment. However, at 12/16 weeks, c.15% of t...

Breast cancer is one of the most common malignant tumours in women. More than a century ago it was noted that oophorectomy helps some but not all breast cancer patients. Further milestones in the development of endocrine treatment included the discovery of oestrogen receptors in breast tumours, introduction of tamoxifen, pharmacological ovarian abl...

RNA expression profiles from breast cancer biopsies taken before and after 10–14 days of neoadjuvant treatment with the aromatase inhibitor, letrozole, together with change in expression between the time points were compared in tumors classified as clinically responsive or resistant to treatment. Statistical analysis for microarrays identified 31 e...

Aim: To identify molecular sub-classes of endocrine-resistant breast tumours. Methods: Whole genome expression profiles of 55 endocrine-resistant tumours were obtained using Illumina HT-12 BeadChip arrays. Endocrine resistance was defined as either (i) tumour increased in size during hormonal treatment or (ii) appearance of local recurrence or...

Rationale: miRNAs are a relatively recently discovered class of molecules with major implications in cellular biology, including tumorigenesis; yet little is known about their possible involvement in the development of endocrine resistance in breast cancer. The aim of this study was to identify sub-groups of endocrine-resistant tumours with dis...

Rationale: Change in genes expression is one of the major molecular drivers of tumour growth. Mechanisms controlling genes expression include transcriptional factors, mutations, aberrations in gene copy number, epigenetic mechanisms and micro-RNA (miRNA) regulation. The last mechanism has been discovered recently and there is a need to investigate...

Endocrine therapy is a major treatment modality for hormone-dependent breast cancer. It has a relatively low morbidity, and there is evidence that antihormonal treatments have had a significant effect in reducing mortality for breast cancer. Despite this, resistance to endocrine therapy, either primary or acquired during treatment, occurs in the ma...

Some breast cancers have been shown to contain a small fraction of cells characterized by CD44(+)/CD24(-/low) cell-surface antigen profile that have high tumor-initiating potential. In addition, breast cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have...

Endocrine agents, such as letrozole, are established in the treatment of hormone-dependent breast cancer. However, response rates are only 50% to 70% in the neoadjuvant setting and lower in advanced disease. Thus there is a need to identify novel markers predicting for response and to understand molecular mechanisms of resistance. Sequential tumor...

Selection for endocrine therapy requires the identification of markers that accurately predict response/resistance. In this report, the authors review their published work and abstract results from an unpublished study to illustrate the potential of RNA microarrays from sequential tumor biopsies from patients who were offered neoadjuvant endocrine...

The aim of the study was to identify changes in tumour expression profiling associated with short-term therapy of breast cancer patients with letrozole. Microarray analysis was performed on RNA extracted from paired tumour core biopsies taken before and after 14 days of treatment with letrozole (2.5 mg/daily) in 58 patients. Changes in expression p...

Microarray analysis of tumour RNA is an extremely powerful tool which allows global gene expression to be measured. When used in combination with neoadjuvant treatment protocols in which therapy is given with the primary tumour within the breast, sequential biopsies may be analysed and results correlated with clinical and pathological response. In...

Primer sequences used in RT-PCR

A summary of relevant patient information

Java Treeview data for figure 1

Java Treeview data for figure 1

A table of individual results used to plot GIDE correlations in figure 2

Java Treeview data for figure 4

An excel sheet listing all genes positively and negatively correlated with ESR1 expression

An excel sheet listing all genes significantly up- and downregulated by AI treatment

Java Treeview data for figure 4

Annotation of the Breakthrough 17K microarray