| 1. |
- de Rinaldis, Emanuele, et al.
(author)
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Integrated genomic analysis of triple-negative breast cancers reveals novel microRNAs associated with clinical and molecular phenotypes and sheds light on the pathways they control
- 2013
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 14, s. 643-
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Journal article (peer-reviewed)abstract
- BACKGROUND: This study focuses on the analysis of miRNAs expression data in a cohort of 181 well characterised breast cancer samples composed primarily of triple-negative (ER/PR/HER2-negative) tumours with associated genome-wide DNA and mRNA data, extensive patient follow-up and pathological information.RESULTS: We identified 7 miRNAs associated with prognosis in the triple-negative tumours and an additional 7 when the analysis was extended to the set of all ER-negative cases. miRNAs linked to an unfavourable prognosis were associated with a broad spectrum of motility mechanisms involved in the invasion of stromal tissues, such as cell-adhesion, growth factor-mediated signalling pathways, interaction with the extracellular matrix and cytoskeleton remodelling. When we compared different intrinsic molecular subtypes we found 46 miRNAs that were specifically expressed in one or more intrinsic subtypes. Integrated genomic analyses indicated these miRNAs to be influenced by DNA genomic aberrations and to have an overall influence on the expression levels of their predicted targets. Among others, our analyses highlighted the role of miR-17-92 and miR-106b-25, two polycistronic miRNA clusters with known oncogenic functions. We showed that their basal-like subtype specific up-regulation is influenced by increased DNA copy number and contributes to the transcriptional phenotype as well as the activation of oncogenic pathways in basal-like tumours.CONCLUSIONS: This study analyses previously unreported miRNA, mRNA and DNA data and integrates these with pathological and clinical information, from a well-annotated cohort of breast cancers enriched for triple-negative subtypes. It provides a conceptual framework, as well as integrative methods and system-level results and contributes to elucidate the role of miRNAs as biomarkers and modulators of oncogenic processes in these types of tumours.
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| 2. |
- Gazinska, Patrycja, et al.
(author)
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Comparison of basal-like triple-negative breast cancer defined by morphology, immunohistochemistry and transcriptional profiles
- 2013
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In: Modern Pathology. - : Elsevier BV. - 0893-3952 .- 1530-0285. ; 26:7, s. 955-966
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Journal article (peer-reviewed)abstract
- Basal-like invasive breast cancer is an important clinical group because of its association with a triple-negative phenotype defined by the lack of expression of estrogen, progesterone and human epidermal growth factor receptors 2, relative lack of therapeutic options and poor prognosis. However, depending on the method used to define these lesions, morphological assessment, immunohistochemical markers or gene expression, a different set of tumors is captured. The aim of this study was to investigate the consequences of using different methodological approaches to define basal-like lesions among triple-negative breast carcinomas with regard to their clinicopathological features and patient outcome. The cohort consisted of 142 invasive breast cancers with a triple-negative receptor status. First, each was reviewed histologically and those with morphological basal-like features were characterized as 'Path-Basal'. Second, the 'Core Basal' immunohistochemical lesions, defined as cytokeratin 5/6 and/or epidermal growth factor receptor 1 positive, within the triple-negative breast cancers were identified, and third their classification based on gene expression profiling was retrieved and those in the molecular 'PAM50 basal-like' subtype recorded. A total of 116 basal-like breast cancers were identified among the 142 triple-negative breast cancers by at least one of these three classifications (80%), but only 13 samples were defined as basal-like with all three methods. None of these 13 tumors were associated with lymphovascular invasion. The 34 morphological 'Path-Basal' lesions were significantly associated with a lack of nodal metastases. Comparing the estimates of death in the three classifications, the highest risk of death was seen for the 'Core Basal' group. In this study, we highlight that the definition of basal-like breast cancer based on different methodologies varies significantly and does not identify the same lesions. This incomplete overlap of cases emphasizes the need for consistent or new approaches to improve precise identification.
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| 3. |
- Jurrius, Patriek, et al.
(author)
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Invasive breast cancer over four decades reveals persisting poor metastatic outcomes in treatment resistant subgroup - the "ATRESS" phenomenon
- 2020
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In: Breast. - : CHURCHILL LIVINGSTONE. - 0960-9776 .- 1532-3080. ; 50, s. 39-48
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Journal article (peer-reviewed)abstract
- Background: Major advances in breast cancer treatment have led to a reducuction in mortality. However, there are still women who are not cured. We hypothesize there is a sub-group of women with treatment-resistant cancers causing early death.Methods: Between 1975 and 2006, 5392 women with invasive breast cancer underwent surgery at Guy's Hospital, London. Data on patient demographics, tumour characteristics, treatment regimens, local recurrence, secondary metastasis, and death were prospectively recorded. We considered four time periods (1975-1982, 1983-1990, 1991-1998, 1999-2006). Risks and time to event analysis were performed with Cox proportional hazards model and Kaplan-Meier estimation.Results: Unadjusted hazard ratios for developing metastasis and overall mortality relative to the 1975-1982 cohort decreased steadily to 0.23 and 0.63, respectively in 1999-2006. However, metastasis-free interval shortened, with the proportion of women developing metastasis <= 5 years increasing from 73.9% to 83.0%. Furthermore, median post-metastatic survival decreased from 1.49 years to 0.94 years. Applying our risk criteria identified the presence of +/- 200 patients in each cohort who developed metastasis early and died within a much shorter time frame.Conclusions: Advances in treatment have decreased the risk of metastasis and improved survival in women with invasive breast cancer over the last 40 years. Despite this, a subpopulation with shorter metastasis-free and post-metastatic survival who are unresponsive to available treatment remains. This may be due to the ATRESS phenomenon (adjuvant therapy-related shortening of survival) secondary to preselection inherent in adjuvant therapy, successful treatment of less malignant tumour cells and treatment-induced resistance in the remaining tumour clones.
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| 4. |
- Lawler, Katherine, et al.
(author)
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Gene expression modules in primary breast cancers as risk factors for organotropic patterns of first metastatic spread : a case control study
- 2017
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In: Breast Cancer Research. - : BIOMED CENTRAL LTD. - 1465-5411 .- 1465-542X. ; 19
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Journal article (peer-reviewed)abstract
- Background: Metastases from primary breast cancers can involve single or multiple organs at metastatic disease diagnosis. Molecular risk factors for particular patterns of metastastic spread in a clinical population are limited.Methods: A case-control design including 1357 primary breast cancers was used to study three distinct clinical patterns of metastasis, which occur within the first six months of metastatic disease: bone and visceral metasynchronous spread, bone-only, and visceral-only metastasis. Whole-genome expression profiles were obtained using whole genome (WG)-DASL assays from formalin-fixed paraffin-embedded (FFPE) samples. A systematic protocol was developed for handling FFPE samples together with stringent data quality controls to identify robust expression profiling data. A panel of published and novel gene sets were tested for association with these specific patterns of metastatic spread and odds ratios (ORs) were calculated.Results: Metasynchronous metastasis to bone and viscera was found in all intrinsic breast cancer subtypes, while immunohistochemically (IHC)-defined receptor status and specific IntClust subgroups were risk factors for visceral-only or bone-only first metastases. Among gene modules, those related to proliferation increased the risk of metasynchronous metastasis (OR (95% CI) = 2.3 (1.1-4.8)) and visceral-only first metastasis (OR (95% CI) = 2.5 (1.2-5.1)) but not bone-only metastasis (OR (95% CI) = 0.97 (0.56-1.7)). A 21-gene module (BV) was identified in estrogen-receptor-positive breast cancers with metasynchronous metastasis to bone and viscera (area under the curve = 0.77), and its expression increased the risk of bone and visceral metasynchronous spread in this population. BV was further orthogonally validated with NanoString nCounter in primary breast cancers, and was reproducible in their matched lymph nodes metastases and an external cohort.Conclusion: This case-control study of WG-DASL global expression profiles from FFPE tumour samples, after careful quality control and RNA selection, revealed that gene modules in the primary tumour have differing risks for clinical patterns of metasynchronous first metastases. Moreover, a novel gene module was identified as a putative risk factor for metasynchronous bone and visceral first metastatic spread, with potential implications for disease monitoring and treatment planning.
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| 5. |
- Melvin, Jennifer C., et al.
(author)
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Family history of breast cancer and its association with disease severity and mortality
- 2016
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In: Cancer Medicine. - : Wiley. - 2045-7634. ; 5:5, s. 942-949
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Journal article (peer-reviewed)abstract
- A family history (FH) of breast cancer (BC) is known to increase an individual's risk of disease onset. However, its role in disease severity and mortality is less clear. We aimed to ascertain associations between FH of BC, severity and BC-specific mortality in a hospital-based cohort of 5354 women with prospective information on FH. We included women diagnosed at Guy's and St Thomas' NHS Foundation Trust between 1975 and 2012 (n = 5354). BC severity was defined and categorized as good, moderate, and poor prognosis. Data on BC-specific mortality was obtained from the National Cancer Registry and medical records. Associations between FH and disease severity or BC-specific mortality were evaluated using proportional odds models and Cox proportional hazard regression models, respectively. Available data allowed adjustment for potential confounders (e.g., treatment, socioeconomic status, and ethnicity). FH of any degree was not associated with disease severity at time of diagnosis (adjusted proportional OR: 1.00 [95% CI: 0.85 to 1.17]), which remained true also after stratification by period of diagnosis. FH of BC was not associated with BC-mortality HR: 0.99 (95% CI: 0.93 to 1.05). We did not find evidence to support an association between FH of BC and severity and BC-specific mortality. Our results indicate that clinical management should not differ between women with and without FH, when the underlying mutation is unknown.
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| 6. |
- Melvin, Jennifer C., et al.
(author)
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Progression of breast cancer following locoregional ipsilateral recurrence : importance of interval time
- 2016
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 114:1, s. 88-95
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Journal article (peer-reviewed)abstract
- Background: Studies comparing prognosis of breast cancer (BC) patients with and without locoregional recurrence (LR) present conflicting results. We aimed to improve our understanding of the impact of LR on prognosis by examining a large cohort of patients treated at Guy's and St Thomas' NHS Foundation Trust. Methods: Risk factors associated with BC-specific death were investigated using Cox proportional hazards regression in 5199 women diagnosed between 1975 and 2007. Breast cancer-specific death following LR was assessed with Poisson regression. Results: Overall, 552 women (11%) developed LR, with a median follow-up time of 4.28 years. Known factors associated with BC-specific death (tumour stage, grade, and nodal status) were of significance in our data. Women with a shorter disease-free interval had a worse prognosis. For instance, the HR for BC-specific death among women undergoing mastectomy with an LR 0.5-1 year after diagnosis of their primary tumour was 6.67 (95% CI: 3.71-11.99), when compared with women who did not experience LR. Conclusions: It often remains difficult to distinguish between a genuine LR and a new primary. The HRs for risk of BC-specific death following a second lesion suggest that they may act as a marker of systemic disease, large tumour burden, or depleted host defence. The clinically highly relevant impairment in prognosis calls for further research into the underlying mechanisms. We showed that for at least 15 years of follow-up, the prognosis in women following the occurrence of an LR may benefit from careful diagnostic and therapeutic management.
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| 7. |
- Noor, Aisyah Mohd, et al.
(author)
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Big Data : the challenge for small research groups in the era of cancer genomics
- 2015
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 113:10, s. 1405-1412
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Research review (peer-reviewed)abstract
- In the past decade, cancer research has seen an increasing trend towards high-throughput techniques and translational approaches. The increasing availability of assays that utilise smaller quantities of source material and produce higher volumes of data output have resulted in the necessity for data storage solutions beyond those previously used. Multifactorial data, both large in sample size and heterogeneous in context, needs to be integrated in a standardised, cost-effective and secure manner. This requires technical solutions and administrative support not normally financially accounted for in small- to moderate-sized research groups. In this review, we highlight the Big Data challenges faced by translational research groups in the precision medicine era; an era in which the genomes of over 75 000 patients will be sequenced by the National Health Service over the next 3 years to advance healthcare. In particular, we have looked at three main themes of data management in relation to cancer research, namely (1) cancer ontology management, (2) IT infrastructures that have been developed to support data management and (3) the unique ethical challenges introduced by utilising Big Data in research.
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| 8. |
- Vichapat, Voralak, et al.
(author)
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Prognosis of metachronous contralateral breast cancer : importance of stage, age and interval time between the two diagnoses
- 2011
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In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 130:2, s. 609-618
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Journal article (peer-reviewed)abstract
- Studies comparing the prognosis after contralateral breast cancer (CBC) with that after unilateral breast cancer (UBC) shows conflicting results. We assessed the risk of breast cancer-specific death for women with metachronous CBC compared to those with a UBC in 8,478 women with invasive primary breast cancer registered in the Guy's and St. Thomas' Breast Cancer Tissue and Data Bank. Risk factors associated with breast cancer-specific death for women with CBC were estimated using Cox proportional hazards modelling. Prognoses after UBC and CBC were compared, with survival time for women with CBC calculated: (i) from CBC, (ii) from the initial cancer with CBC as a time-dependent covariate. Women diagnosed with CBC within 5 years after the initial primary breast cancer had a worse prognosis than those with CBC after 5 years and those with UBC. Women with CBC who had positive lymph nodes at the initial breast cancer diagnosis were at an increased risk of dying from breast cancer compared to those without [HR 2.5 (95% CI 1.5-4.0)]. For all stages of the initial breast cancer, a worse prognosis was observed after CBC. CBC increased the hazard originating from the initial cancer at any follow-up time, but the highest hazards were associated with a short interval to CBC. Metachronous CBC adds to the risk of dying from breast cancer. The risk increases substantially when it occurs shortly after the initial cancer, indicating a CBC in some instances may be an indicator of active distant disease. The occurrence of CBC implies a new surveillance and therapeutic situation.
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| 9. |
- Vichapat, Voralak, et al.
(author)
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Risk factors for metachronous contralateral breast cancer suggest two aetiological pathways
- 2011
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In: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 47:13, s. 1919-1927
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Journal article (peer-reviewed)abstract
- Although many studies show an increased risk of metachronous contralateral breast cancer (CBC) in women with a positive family history and young age at diagnosis of the initial breast cancer, the aetiological pathways are still enigmatic. In a cohort of 8478 primary breast cancer patients diagnosed between 1975 and 2006, 558 cases of metachronous CBC were identified. Using multivariate Cox proportional hazards models, we analysed risk factors assessed at the time of the first primary tumour, including patient demographics, tumour characteristics and treatment among 4681 breast cancer patients for whom data on key variables were available. The analysis was performed separately in patients who developed CBC without and with prior recurrence(s). Risk of CBC without prior recurrent disease was increased by a positive family history [adjusted relative risk (RR) 2.8 (95% confidence interval (CI) 1.4-5.5)]; and decreased by endocrine treatment [RR 0.6 (95% CI 0.4-1.0)]. We found an increased risk of CBC with prior recurrent disease with younger age [RR 1.2 (95% CI 1.4-3.0)]; positive family history [RR 2.1 (95%CI 0.8-5.0)]; and extensive lymph node involvement [RR 2.0 (95% CI 1.2-3.6)]. Our results suggest that nodal status of the primary tumour may be as important a risk factor as family history or age, which indicates a high susceptibility to breast cancer or an impaired host defence mechanism. It may also imply that some CBCs are metastases from the first primary tumour, particularly in patients who present with recurrent disease before CBC.
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| 10. |
- Watkins, Johnathan, et al.
(author)
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Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers
- 2015
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In: Cancer Discovery. - 2159-8274 .- 2159-8290. ; 5:5, s. 488-505
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Journal article (peer-reviewed)abstract
- Triple-negative breast cancers (TNBC) are characterized by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that allelic-imbalanced copy-number aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene, HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs, as well as sensitizing cancer cells to HR-targeting therapies. Our data therefore provide a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability, and an association with response to platinum-based chemotherapy in TNBC. SIGNIFICANCE: Previous studies have shown correlation between mutational "scars" and sensitivity to platinums extending beyond associations with BRCA1/2 mutation, but do not elucidate the mechanism. Here, a novel allele-specific copy-number characterization of genome instability identifies and functionally validates the inappropriate expression of the meiotic gene HORMAD1 as a driver of HR deficiency in TNBC, acting to induce allelic imbalance and moderate platinum and PARP inhibitor sensitivity with implications for the use of such "scars" and expression of meiotic genes as predictive biomarkers.
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