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Combined crystallographic and spectroscopic methods were used to investigate the heterogeneity of breast calcifications found associated with ductal carcinoma in situ, revealing distinctive patterns in protein distribution and mineral... more
Combined crystallographic and spectroscopic methods were used to investigate the heterogeneity of breast calcifications found associated with ductal carcinoma in situ, revealing distinctive patterns in protein distribution and mineral composition.
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If you need additional information please do not hesitate to ask. You may also wish to discuss the study with a relative or friend or your doctor. If you wish to participate in this study you will need to sign the Consent Form. By signing... more
If you need additional information please do not hesitate to ask. You may also wish to discuss the study with a relative or friend or your doctor. If you wish to participate in this study you will need to sign the Consent Form. By signing the Consent Form, you indicate that you understand the information and that you give your consent to participate in the study. If you do not wish to participate, you have the alternative of getting the standard treatment for your condition. Your routine follow up will be continued as per the practice.
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Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour... more
Many primary tumours have low levels of molecular oxygen (hypoxia). Hypoxic tumours are more likely to metastasize to distant sites and respond poorly to multiple therapies. Surprisingly, then, the pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited understanding of its associations with specific mutational processes, non-coding driver genes and evolutionary features. To fill this gap, we quantified hypoxia in 1,188 tumours spanning 27 cancer types. We show that elevated hypoxia is associated with increased mutational load across cancers, irrespective of the underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology are directly associated with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in tumours with high hypoxia, and mutations in PTEN interact with hypoxia to direct the...
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Nature Communications 7 Article number:11479 (2016); Published: 10 May 2016; Updated: 6 June 2016. The original version of this Article contained an error in the spelling of ‘refine’ in the title of the paper. This has now been corrected... more
Nature Communications 7 Article number:11479 (2016); Published: 10 May 2016; Updated: 6 June 2016. The original version of this Article contained an error in the spelling of ‘refine’ in the title of the paper. This has now been corrected in both the PDF and HTML.
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Histologic grade is well recognized for its prognostic significance in cases of primary operable invasive breast carcinoma; however, the majority of studies in which grade has been assessed have been based on single-center trials. In... more
Histologic grade is well recognized for its prognostic significance in cases of primary operable invasive breast carcinoma; however, the majority of studies in which grade has been assessed have been based on single-center trials. In addition, the role of grade in predicting response to chemotherapy has not been examined in many previous studies. The authors assessed the value of Nottingham histologic grade (NHG) in a group of 465 patients enrolled in a multicenter, randomized International Breast Cancer Study Group clinical trial of adjuvant chemotherapy for patients with lymph node (LN) positive and LN negative primary breast carcinoma (formerly named Ludwig Trial V). NHG was a predictor of overall survival for both LN negative and LN positive patients (P=0.045 and P < 0.001, respectively). NHG was associated with a poorer prognosis for both LN positive and LN negative patients, with hazard ratios of 1.651 (P < 0.001) and 1.437 (P=0.045), respectively, for an increase of one grade. Among LN negative patients, this survival disadvantage was observed only for those who received perioperative chemotherapy. For LN positive patients, an increase of one grade resulted in a significant overall survival disadvantage regardless of whether prolonged or perioperative chemotherapy was given. For LN negative patients grouped by grade, there was no observed difference in overall or disease free survival according to whether perioperative chemotherapy or no adjuvant therapy was given. However, LN positive patients with Grade 3 tumors had a significantly greater overall and disease free survival benefit from prolonged chemotherapy than from perioperative chemotherapy (P=0.016 and P=0.013, respectively); LN positive patients with Grade 1 or 2 disease in both treatment arms had comparable overall and disease free survival. A strong correlation between the previously utilized Bloom-Richardson grading system (BRG) and NHG was observed (P < 0.001 and kappa=82%) and no apparent differences in overall and disease free survival were observed between the two systems. NHG did, however, identify a greater proportion of tumors as Grade 1, and BRG identified a greater proportion of breast carcinomas as Grade 3. This multicenter clinical study confirms the value of histologic grade, and the authors propose that this technique be used to identify Grade 3, LN positive patients who will benefit from prolonged rather than perioperative chemotherapy.
Research Interests: Cancer, Breast Cancer, Forecasting, Chemotherapy, Medicine, and 15 moreHumans, Internal Medicine, Female, Mastectomy, Carcinoma, Methotrexate, Breast carcinoma, Cyclophosphamide, Cohort Studies, Lymph nodes, Breast Neoplasms, Estrogen antagonists, Disease Free Survival, fluorouracil, and hazard ratio
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Background Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble... more
Background Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker. Methods We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay. Results Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the ...
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Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the... more
Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5–10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.
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TPS614 Background: Mammographic screening programmes reduce breast cancer mortality but detect many small tumours with favourable biology which may not progress. These are treated with surgery and adjuvant therapies, but associated... more
TPS614 Background: Mammographic screening programmes reduce breast cancer mortality but detect many small tumours with favourable biology which may not progress. These are treated with surgery and adjuvant therapies, but associated morbidities mean there is a need to reduce overtreatment. Minimally invasive treatments such as vacuum-assisted excision (VAE) have been described but there is no prospective randomised evidence to support their routine use. SMALL (ISRCTN 12240119) is designed to establish the feasibility of using VAE to treat small tumours detected within the UK NHS Breast Screening Programme (BSP). Methods: Phase III multicenter randomized trial comparing surgery with VAE for screen-detected good prognosis cancers. Eligibility criteria are age ≥47 years, unifocal grade 1 tumors (maximum diameter 15mm), strongly ER/PR+ve and HER2-ve, with negative axillary staging. Patients are randomized 2:1 to VAE or surgery, with no axillary surgery in the VAE arm. Excision is assesse...
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567 Background: Tumor gene expression tests are increasingly used in breast cancer management. The Ki67 biomarker has been proposed as an inexpensive alternative for making chemotherapy decisions, has demonstrated utility for... more
567 Background: Tumor gene expression tests are increasingly used in breast cancer management. The Ki67 biomarker has been proposed as an inexpensive alternative for making chemotherapy decisions, has demonstrated utility for determination of endocrine therapy responsiveness and is included in the FDA license for adjuvant abemaciclib. We have compared Ki67 measurements with tumor gene expression test results for patients included in the OPTIMA prelim trial. Methods: We compared Ki67 %staining with the results of Oncotype DX, Prosigna and MammaPrint performed by the test vendor. Ki67 was determined in a single laboratory on triplicate tissue micro-arrays using quantitative image analysis including a 10% manual quality control check. We used kappa statistics to measure agreement between tests, divided into groups using the pre-defined test score boundaries for high vs. not high risk. Results: Data were available for 259 patients. Using ≥20% staining to define a high Ki67 score, kappa ...
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IntroductionThe National Health Service (NHS) Breast Screening Programme aims to detect cancer earlier when treatment is more effective but can harm women by over diagnosing and overtreating cancers which would never have become... more
IntroductionThe National Health Service (NHS) Breast Screening Programme aims to detect cancer earlier when treatment is more effective but can harm women by over diagnosing and overtreating cancers which would never have become symptomatic. As well as breast cancer, a spectrum of atypical epithelial proliferations (atypia) can also be detected as part of screening. This spectrum of changes, while not cancer, may mean that a woman is more likely to develop breast cancer in the future. Follow-up of atypia is not evidence based. We currently do not know which atypia should be detected to avoid future cancer. This study will explore how atypia develops into breast cancer in terms of number of women, time of cancer development, cancer type and severity, and whether this varies for different types of atypia.Methods and analysisThe Sloane cohort study began in April 2003 with ongoing data collection including atypia diagnosed through screening at screening units in the UK. The database fo...
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The level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We... more
The level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We previously demonstrated that histological alterations in axillary lymph nodes (LNs) carry clinical relevance. Here, we capture local immune responses by scoring TILs at the primary tumor and systemic immune responses by recording the formation of secondary follicles, also known as germinal centers, in 2,857 cancer-free and involved axillary LNs on haematoxylin and eosin (H&E) stained sections from a retrospective cohort of 161 LN-positive triple-negative and HER2-positive breast cancer patients. Our data demonstrate that the number of germinal center formations across all cancer-free LNs, similar to high levels of TILs, is associated with a good prognosis in low TILs TNBC. This highlights the importance of assessing both primary and LN immune response...
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Background The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2... more
Background The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). Methods 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. Results 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). Conclusion No difference in pCR was detected...
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In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing... more
In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD− isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine–cytokine receptor interactions, cytotoxic T-cell activation, and T-cell–dependent B-cell activation. TIL-B–upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction vi...
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Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of... more
Pure ductal carcinoma in situ (DCIS) is being diagnosed more frequently through breast screening programmes and is associated with an increased risk of developing invasive breast cancer. We assessed the clonal relatedness of 143 cases of pure DCIS and their subsequent events using a combination of whole exome, targeted and copy number sequencing, supplemented by single cell analysis. Unexpectedly, 18% of all invasive events after DCIS were clonally unrelated to the primary DCIS. Single cell sequencing of selected pairs confirmed our findings. In contrast, synchronous DCIS and invasive disease (n=44) were almost always (93%) clonally related. This challenges the dogma that almost all invasive events after DCIS represent invasive transformation of the initial DCIS and suggests that DCIS could be an independent risk factor for developing invasive disease as well as a precursor lesion. Our findings support a paradigm shift that confirms a more complex role for DCIS than previously recog...
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Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused... more
Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected populati...
Research Interests: Oncology, Immunology, Breast Cancer, Cell Biology, DNA repair, and 15 moreMedicine, Humans, Internal Medicine, Mutation, Female, Promoter Methylation, Fanconi anemia, Science Technology, Ovarian Carcinoma, Homologous Recombination, Open Label, Progression Free Survival, Carboplatin, Docetaxel, and Medical and Health Sciences
The natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear. Women diagnosed with DCIS on needle biopsy after 1997 who did not undergo... more
The natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear. Women diagnosed with DCIS on needle biopsy after 1997 who did not undergo surgical resection for ≥1 year after diagnosis were identified by breast centres and the cancer registry and outcomes were reviewed. Eighty-nine women with DCIS diagnosed 1998-2010 were identified. The median age at diagnosis was 75 (range 44-94) years with median follow-up (diagnosis to death, invasive disease or last review) of 59 (12-180) months. Twenty-nine women (33%) developed invasive breast cancer after a median interval of 45 (12-144) months. 14/29 (48%) with high grade, 10/31 (32%) with intermediate grade and 3/17 (18%) with low grade DCIS developed invasive cancer after median intervals of 38, 60 and 51 months. The cumulative incidence of invasion was significantly higher in high grade DCIS than other grades (p = .0016, log-rank test). Inva...
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To explore how the concept of randomisation is described by clinicians and understood by patients in randomised clinical trials (RCTs), and how it contributes to patient understanding and recruitment. Qualitative analysis of seventy-three... more
To explore how the concept of randomisation is described by clinicians and understood by patients in randomised clinical trials (RCTs), and how it contributes to patient understanding and recruitment. Qualitative analysis of seventy-three audio recordings of recruitment consultations from five, multi-centre, UK based RCTs with identified or anticipated recruitment difficulties. One in ten appointments did not include any mention of randomisation. Most included a description of the method or process of allocation. Descriptions often drew on gambling-related metaphors or similies, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was 'best for them'. Descriptions of the rationale for randomisation were rarely present, and often only came about as a consequence of patients questioning the reason for a random allocation. The methods and processes of randomisation were usually describe...
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Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms... more
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci. To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip. Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing. Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. ...
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Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to... more
Neoadjuvant systemic therapy (NAST) provides the unique opportunity to assess response to treatment after months rather than years of follow-up. However, significant variability exists in methods of pathologic assessment of response to NAST, and thus its interpretation for subsequent clinical decisions. Our international multidisciplinary working group was convened by the Breast International Group-North American Breast Cancer Group (BIG-NABCG) collaboration and tasked to recommend practical methods for standardized evaluation of the post-NAST surgical breast cancer specimen for clinical trials that promote accurate and reliable designation of pathologic complete response (pCR) and meaningful characterization of residual disease. Recommendations include multidisciplinary communication; clinical marking of the tumor site (clips); and radiologic, photographic, or pictorial imaging of the sliced specimen, to map the tissue sections and reconcile macroscopic and microscopic findings. Th...
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Research Interests: Cancer, Breast Cancer, Clinical Pathology, Humans, Ductal carcinoma in situ, and 15 moreFemale, Clinical, Diagnosis, External Quality Assessment, Consistency, Follow Up, Clinical Sciences, Medical Diagnosis, Great Britain, Criteria, Clinical Competence, Lesions, Local Recurrence, Breast Neoplasms, and mass Screening
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ABSTRACT
Research Interests: Oncology, Breast Cancer, Medicine, Multivariate Analysis, Humans, and 15 moreInternal Medicine, Female, Aged, Middle Aged, Neoplasm Invasiveness, Adult, Breast carcinoma, Prognosis, Lymph Node, ADJUVANT THERAPY, Overall Survival, Lymphovascular invasion, Lymph nodes, Breast Neoplasms, and Neoplasm staging
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Background: Primary anaplastic large-cell lymphoma (ALCL) occurring in women with breast implants is very rare. It is usually described as tumor cells infiltrating the periprosthetic capsule. These are most often revealed by a... more
Background: Primary anaplastic large-cell lymphoma (ALCL) occurring in women with breast implants is very rare. It is usually described as tumor cells infiltrating the periprosthetic capsule. These are most often revealed by a periprosthetic recurrent isolated effusion (seroma cavity), occurring late after implantation of the prosthesis. ALCL is more rarely a tumor or periprosthetic capsular contracture. Case: We report a 66-year-old woman, initially diagnosed by cytological examination of breast effusion, in whom ALCL appeared two and a half months after the removal of a ruptured implant. Repeated biopsies of the periprosthetic capsule performed in parallel showed fibrous tissue, without tumor proliferation. Only meticulous histological examination of the total capsulectomy identified tumor cells as a thin and discontinuous layer along the inner surface of the capsule without capsular invasion. Conclusion: Awareness of the histological pattern of this new clinical entity is importa...
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Background The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. Methods We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the... more
Background The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. Methods We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. Results Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0–25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of pat...
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Background There is uncertainty about the benefit of chemotherapy for some patients with ER-positive HER2-negative early breast cancer. Multi-parameter assays of gene expression may enhance the value of chemotherapy through personalised... more
Background There is uncertainty about the benefit of chemotherapy for some patients with ER-positive HER2-negative early breast cancer. Multi-parameter assays of gene expression may enhance the value of chemotherapy through personalised treatment decisions. An economic evaluation was undertaken in the context of the feasibility phase of an RCT (OPTIMA prelim) designed to validate prospectively the use of such an assay as a treatment decision tool in the UK National Health Service (NHS). The aim of the economic evaluation was to confirm value in an ongoing RCT and optimise its design for economic endpoints. Comparators included (i) All patients treated with chemotherapy, (ii) Oncotype DX, (iii) MammaPrint/BluePrint and (iv) Prosigna. Methods A model-based cost-effectiveness analysis was conducted to the standards of the UK National Institute for Care Excellence (NICE) reference case. A Markov model was constructed to simulate the care pathway of a cohort of patients with characteristics identified in the OPTIMA prelim study or, where unavailable, from the published literature. The costs (GBP) and benefits (QALYs) were estimated over a time horizon of the patient life-time. Alternative scenarios of recurrence rates and chemotherapy effect were explored in patients identified high or low risk by the tests and treated with and without chemotherapy. Scenarios included estimates based on the SWOG-8814 trial, the EBCTCG and outcomes forecasted using Adjuvant! Online. Uncertainty introduced by discrepancy in patient selection between tests was modelled using a Bayesian decision analytic framework. Probabilistic sensitivity analysis and value of information analysis was conducted using Monte Carlo simulation. Results There were 285 randomised patients. Multi-parameter analyses were performed on tumour samples and baseline factors were included in the model. The cost-effectiveness of all tests was uncertain. Uncertainty was predominantly driven by assumptions about long term recurrence rates in test-selected groups and the ability of tests to predict benefit from chemotherapy. The relationship between recurrence-free survival and life expectancy in test-selected groups and in patients who did or did not receive adjuvant chemotherapy was also important. The incremental cost-effectiveness ratio (ICER) for Oncotype DX compared with chemotherapy for all was cost-effective in many scenarios, ranging from GBP26,000 per QALY to resulting in increased QALYs with cost savings (dominate), depending on assumptions. The value of information analysis placed high societal value in further research into recurrence-free survival for test-directed chemotherapy, irrespective of the test evaluated. Conclusion There is substantial value in prospective comparative research into all tests evaluated, including long term outcomes, to resolve uncertainties in the clinical and economic optimal choice of test. Acknowledgements This project was funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) Programme (project number 10/34/01). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health. Citation Format: Peter S Hall, Alison F Smith, Armando Vargas-Palacios, Robert C Stein, John Bartlett, Jane Bayani, Andrea Marshall, Janet A Dunn, Amy F Campbell, Carrie Cunningham, Leila Rooshenas, Monika Sobol, Adrienne Morgan, Christopher Poole, Sarah E Pinder, David A Cameron, Nigel Stallard, Jenny Donovan, Luke Hugh-Davies, Helena Earl, Andreas Makris, Claire Hulme, Christopher McCabe. UK OPTIMA-prelim study demonstrates economic value in more clinical evaluation of multi-parameter prognostic tests in early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-11.
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Introduction The LORIS Trial is a UK randomized clinical trial comparing active monitoring with surgery for low risk ductal carcinoma in situ (DCIS), defined as low or low-intermediate grade DCIS without comedo necrosis, as diagnosed on... more
Introduction The LORIS Trial is a UK randomized clinical trial comparing active monitoring with surgery for low risk ductal carcinoma in situ (DCIS), defined as low or low-intermediate grade DCIS without comedo necrosis, as diagnosed on vacuum-assisted (wide bore) core needle samples. Because of the inconsistency of grading DCIS, we have underpinned this trial with a Central Histopathology Review (CHR) before randomisation. The process of the CHR for the first 22 months of a two year pilot study between July 2014 and May 2016 is reported here. Patients and methods Patients were eligible for CHR if they satisfied all of the eligibility criteria and had locally reported low or intermediate grade DCIS. Patients were identified at 28 pilot sites and were registered for potential trial entry following written informed consent before being subjected to CHR. CHR comprised online examination of digitally scanned histology slides of all material from all diagnostic biopsies and was performed by at least two of the three LORIS specialist breast pathologists. Histology slides were submitted using Royal Mail Safebox® to the University of Birmingham where they were digitally scanned and made available for review via the Leica digital image hub. The outcome of the review was reported in a separate secure online database by completion of a Central Pathology Review Form. Access to both online systems is password protected. Eligibility was confirmed if two pathologists agreed that there was low or low to intermediate grade DCIS and no comedo necrosis. A maximum of 7 calendar days from receipt of the diagnostic material was allowed for the central review process. The digital images of the histology slides are stored by the Leica system for future reference. Results 100 patients were registered and their slides reviewed. 55 of these were deemed eligible by CHR; of these 38 have been randomised. 45 patients were deemed ineligible, most commonly due to grade being in the upper half of the intermediate category and/or comedo necrosis. In addition, 9 patients were deemed not to have DCIS and 1 patient had invasive disease. Grouping the grade categories as low and low to intermediate grade (low risk and eligible for randomisation) Vs intermediate to high and high cytonuclear grade (ineligible for randomisation) showed 91% agreement on grade category amongst the reviewing pathologists. Results of the central review were made available to sites within 7 days for 97% of cases submitted. On average, central review was completed within 4 days. Average time between registration and randomisation was 3 weeks. The LORIS central review pathologists found online viewing and reporting of sections acceptable. Conclusions Central Histopathology Review using online viewing of digital slides provides timely and efficient pathology Quality Assurance in this clinical trial setting, with acceptable turnaround times and good agreement between reviewing specialist breast pathologists. This process will be continued in the main phase of the trial. Citation Format: Thomas J, Hanby A, Pinder S, Pirrie S, Rea D, Gaunt C, Young J, Francis A. LORIS trial of active monitoring for DCIS: How does the online pathology eligibility review process work? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-17-06.
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Background: Invasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the... more
Background: Invasive lobular breast cancer (ILC) accounts for approximately 15% of invasive breast carcinomas and is commonly associated with lobular carcinoma in situ (LCIS). Both have been shown to have higher familial risks than the more common ductal cancers. However, there are little data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in ILC. The aim of this study was to assess the frequency of germline variants in CDH1, BRCA2, BRCA1, CHEK2, PALB2, and TP53 in sporadic ILC and LCIS diagnosed in women ages ≤60 years. Methods: Access Array technology (Fluidigm) was used to amplify all exons of CDH1, BRCA2, BRCA1, TP53, CHEK2, and PALB2 using a custom-made targeted sequencing panel in 1,434 cases of ILC and 368 cases of pure LCIS together with 1,611 controls. Results: Case–control analysis revealed an excess of pathogenic variants in BRCA2, CHEK2, PALB2, and CDH1 in women with ILC. CHEK2 was the only gene that showed an association w...