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David A Cameron - Top 30 Publications

Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results.

Twelve months treatment is the current standard of care for adjuvant trastuzumab in patients with HER2 positive early breast cancer however the optimal duration is not known. Persephone is a non-inferiority randomised controlled trial comparing 6- to 12-months of trastuzumab. In this trial there will be a trade-off between a possible small decrease in disease-free survival (DFS) with 6-months and reduced cardiotoxicity and cost.

Do patients whose tumor achieved a pathological response relapse at specific sites? A substudy of the EORTC 10994/BIG-1-00 trial.

To determine the sites of first distant relapse in patients with or without pCR following neoadjuvant chemotherapy in breast cancer patients enrolled in the EORTC 10994/BIG-1-00 trial.

Concerns about cardiotoxicity in the HERA trial - Authors' reply.

Value of Information Analysis of Multiparameter Tests for Chemotherapy in Early Breast Cancer: The OPTIMA Prelim Trial.

Precision medicine is heralded as offering more effective treatments to smaller targeted patient populations. In breast cancer, adjuvant chemotherapy is standard for patients considered as high-risk after surgery. Molecular tests may identify patients who can safely avoid chemotherapy.

Ribociclib plus letrozole versus letrozole alone in patients with de novo HR+, HER2- advanced breast cancer in the randomized MONALEESA-2 trial.

Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer.

Trastuzumab-associated cardiac events in the Persephone trial.

We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer.

Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer.

The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) and negative for human epidermal growth factor receptor 2 (HER2).

Comparing Breast Cancer Multiparameter Tests in the OPTIMA Prelim Trial: No Test Is More Equal Than the Others.

Previous reports identifying discordance between multiparameter tests at the individual patient level have been largely attributed to methodological shortcomings of multiple in silico studies. Comparisons between tests, when performed using actual diagnostic assays, have been predicted to demonstrate high degrees of concordance. OPTIMA prelim compared predicted risk stratification and subtype classification of different multiparameter tests performed directly on the same population.

OPTIMA prelim: a randomised feasibility study of personalised care in the treatment of women with early breast cancer.

There is uncertainty about the chemotherapy sensitivity of some oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. Multiparameter assays that measure the expression of several tumour genes simultaneously have been developed to guide the use of adjuvant chemotherapy for this breast cancer subtype. The assays provide prognostic information and have been claimed to predict chemotherapy sensitivity. There is a dearth of prospective validation studies. The Optimal Personalised Treatment of early breast cancer usIng Multiparameter Analysis preliminary study (OPTIMA prelim) is the feasibility phase of a randomised controlled trial (RCT) designed to validate the use of multiparameter assay directed chemotherapy decisions in the NHS.

Characterizing and quantifying the effects of breast cancer therapy using mathematical modeling.

We designed a mathematical model to describe and quantify the mechanisms and dynamics of tumor growth, cell-kill and resistance as they affect durations of benefit after cancer treatment. Our aim was to explore how treatment efficacy may be related to primary tumor characteristics, with the potential to guide future trial design and appropriate selection of therapy. Assuming a log-normal distribution of both resistant disease and tumor doubling times generates disease-free survival (DFS) or invasive DFS curves with specific shapes. Using a multivariate mathematical model, both treatment and tumor characteristics are related to quantified resistant disease and tumor regrowth rates by allowing different mean values for the influence of different treatments or clinical subtypes on these two log-normal distributions. Application of the model to the CALGB 9741 adjuvant breast cancer trial showed that dose-dense therapy was estimated to achieve an extra 3/4 log of cell-kill compared to standard therapy, but only in patients with more rapidly growing ER-negative tumors. Application of the model to the AZURE trial of adjuvant bisphosphonate treatment suggested that the 5-year duration of zoledronic acid was adequate for ER-negative tumors, but may not be so for ER-positive cases, with increased recurrences after ceasing the intervention. Mathematical models can identify different effects of treatment by subgroup and may aid in treatment design, trial analysis, and appropriate selection of therapy. They may provide a more appropriate and insightful tool than the conventional Cox model for the statistical analysis of response durations.

Reelin Prevents Apical Neurite Retraction during Terminal Translocation and Dendrite Initiation.

The mechanisms controlling cortical dendrite initiation and targeting are poorly understood. Multiphoton imaging of developing mouse cortex reveals that apical dendrites emerge by direct transformation of the neuron's leading process during the terminal phase of neuronal migration. During this ∼110 min period, the dendritic arbor increases ∼2.5-fold in size and migration arrest occurs below the first stable branch point in the developing arbor. This dendritic outgrowth is triggered at the time of leading process contact with the marginal zone (MZ) and occurs primarily by neurite extension into the extracellular matrix of the MZ. In reeler cortices that lack the secreted glycoprotein Reelin, a subset of neurons completed migration but then retracted and reorganized their arbor in a tangential direction away from the MZ soon after migration arrest. For these reeler neurons, the tangential oriented primary neurites were longer lived than the radially oriented primary neurites, whereas the opposite was true of wild-type (WT) neurons. Application of Reelin protein to reeler cortices destabilized tangential neurites while stabilizing radial neurites and stimulating dendritic growth in the MZ. Therefore, Reelin functions as part of a polarity signaling system that links dendritogenesis in the MZ with cellular positioning and cortical lamination.

Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial.

The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer.

Predicting Anthracycline Benefit: TOP2A and CEP17-Not Only but Also.

Evidence supporting the clinical utility of predictive biomarkers of anthracycline activity is weak, with a recent meta-analysis failing to provide strong evidence for either HER2 or TOP2A. Having previously shown that duplication of chromosome 17 pericentromeric alpha satellite as measured with a centromere enumeration probe (CEP17) predicted sensitivity to anthracyclines, we report here an individual patient-level pooled analysis of data from five trials comparing anthracycline-based chemotherapy with CMF (cyclophosphamide, methotrexate, and fluorouracil) as adjuvant chemotherapy for early breast cancer.

Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.

For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years.

Maastricht Delphi consensus on event definitions for classification of recurrence in breast cancer research.

In breast cancer studies, many different endpoints are used. Definitions are often not provided or vary between studies. For instance, "local recurrence" may include different components in similar studies. This limits transparency and comparability of results. This project aimed to reach consensus on the definitions of local event, second primary breast cancer, regional and distant event for breast cancer studies.

A highly-sensitive anti-Müllerian hormone assay improves analysis of ovarian function following chemotherapy for early breast cancer.

Anti-Müllerian hormone (AMH) shows promise as a biomarker of the ovarian reserve but current assays are insufficiently sensitive to allow assessment of this post-chemotherapy in most women. We have assessed a new highly sensitive AMH assay (Ansh picoAMH) in the evaluation of ovarian activity in women with very low ovarian reserve after chemotherapy.

Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01).

To document the rate and outcome of trastuzumab-associated cardiac dysfunction in patients following 1 or 2 years of adjuvant therapy.

A catalyst for change: the European cancer Patient's Bill of Rights.

Breast cancer chemoprevention: little progress in practice?

Pertuzumab for the treatment of metastatic breast cancer.

Approximately 15% of primary breast cancers have amplification/overexpression of the cell surface receptor HER2. Despite the major improvements in survival achieved by the use of adjuvant trastuzumab, many of these patients still develop metastatic disease, and other patients with HER2 overexpressing breast cancer have overt metastases at first diagnosis. There remains therefore a pressing medical need to identify better therapies for these patients. Pertuzumab is a humanized antibody that targets and binds HER2. Although only modestly active against breast cancer when used as a single agent, pertuzumab has demonstrated significant activity when combined with trastuzumab against trastuzumab-resistant and -sensitive disease. Multiple clinical trials are underway to define the optimal use of pertuzumab (combined with either trastuzumab or trastuzumab-DM1) together with a range of cytotoxic agents or endocrine therapy in multiple settings of HER2-overexpressing breast cancer. This article summarizes the use of pertuzumab in the metastatic disease setting.

Pretreatment anti-Müllerian hormone predicts for loss of ovarian function after chemotherapy for early breast cancer.

Improving survival for women with early breast cancer (eBC) requires greater attention to the consequences of treatment, including risk to ovarian function. We have assessed whether biochemical markers of the ovarian reserve might improve prediction of chemotherapy related amenorrhoea.

Beware using secular trends in deaths to judge effectiveness of breast screening.

Is TIMP-1 immunoreactivity alone or in combination with other markers a predictor of benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial?

Predictive cancer biomarkers to guide the right treatment to the right patient at the right time are strongly needed. The purpose of the present study was to validate prior results that tissue inhibitor of metalloproteinase 1 (TIMP-1) alone or in combination with either HER2 or TOP2A copy number can be used to predict benefit from epirubicin (E) containing chemotherapy compared with cyclophosphamide, methotrexate and fluorouracil (CMF) treatment.

Phosphorylation of AKT pathway proteins is not predictive of benefit of taxane therapy in early breast cancer.

Results from the NSABP B-28 trial suggest AKT activation may predict reduced benefit from taxanes following standard anthracycline therapy. Pre-clinical data support a link between PI3 K/AKT signalling and taxane resistance. Using the UK taxotere as adjuvant chemotherapy trial (TACT), we tested the hypothesis that activation of AKT or downstream markers, p70S6K or p90RSK, identifies patients with reduced benefit from taxane chemotherapy. TACT is a multi-centre open-label phase III trial comparing four cycles of standard FEC (fluorouracil, epirubicin, cyclophosphamide) followed by four cycles of docetaxel versus eight cycles of anthracycline-based chemotherapy. Samples from 3,596 patients were available for the current study. We performed immunohistochemical analysis of activation of AKT, p70S6 K and p90RSK. Using a training set with multiple cut-offs for predictive values (10 % increments in expression), we found no evidence for a treatment by marker interaction for pAKT473, pS6 or p90RSK. pAKT473, pS6 and p90RSK expression levels were weakly correlated. A robust, preplanned statistical analysis in the TACT trial found no evidence that pAKT473, pS6 or p90RSK identifies patients deriving reduced benefit from adjuvant docetaxel. This result is consistent with the recent NASBP B28 study where the pAKT473 effect is not statistically significant for the treatment interaction test. Therefore, neither TACT nor NASBP-B28 provides statistically robust evidence of a treatment by marker interaction between pAKT473 and taxane treatment. Alternative methods for selecting patients benefitting from taxanes should be explored.

Authors' reply.

Trial design on prophylaxis and treatment of brain metastases: lessons learned from the EORTC Brain Metastases Strategic Meeting 2012.

Brain metastases (BM) occur in a significant proportion of cancer patients and are associated with considerable morbidity and poor prognosis. The trial design in BM patients is particularly challenging, as many disease and patient variables, statistical issues, and the selection of appropriate end-points have to be taken into account. During a meeting organised on behalf of the European Organisation for Research and Treatment of Cancer (EORTC), methodological aspects of trial design in BM were discussed. This paper summarises the issues and potential trial strategies discussed during this meeting and may provide some guidance for the design of trials in BM patients.

Hierarchical clustering of gene expression patterns in the Eomes + lineage of excitatory neurons during early neocortical development.

Cortical neurons display dynamic patterns of gene expression during the coincident processes of differentiation and migration through the developing cerebrum. To identify genes selectively expressed by the Eomes + (Tbr2) lineage of excitatory cortical neurons, GFP-expressing cells from Tg(Eomes::eGFP) Gsat embryos were isolated to > 99% purity and profiled.

Layer 6 cortical neurons require Reelin-Dab1 signaling for cellular orientation, Golgi deployment, and directed neurite growth into the marginal zone.

The secreted ligand Reelin is believed to regulate the translocation of prospective layer 6 (L6) neocortical neurons into the preplate, a loose layer of pioneer neurons that overlies the ventricular zone. Recent studies have also suggested that Reelin controls neuronal orientation and polarized dendritic growth during this period of early cortical development. To explicitly characterize and quantify how Reelin controls this critical aspect of neurite initiation and growth we used a new ex utero explant model of early cortical development to selectively label a subset of L6 cortical neurons for complete 3-D reconstruction.

Expression of activated type I receptor tyrosine kinases in early breast cancer.

Overexpression of EGFR, HER2 and HER3 are known to be associated with poor outcome in breast cancer. Few studies have examined the clinical impact of activation of these proteins. In the present study, we evaluated EGFR, HER2 and HER3 and the activated (phosphorylated) forms of these proteins in patients with early breast cancer. EGFR, HER2, HER3, pEGFR, pHER2 and pHER3 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully-documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate overexpression of HER2 and pHER2 to be associated with a significant reduction in overall survival (OS) (HR: 1.66, 95 % CI 1.22-2.26, p = 0.001 and HR: 1.57, 95 % CI 1.22-2.03, p = 0.001, respectively) and distant relapse-free survival (DRFS) (HR: 1.63, 95 % CI 1.23-2.18, p = 0.001 and HR: 1.55, 95 % CI 1.23-1.97, p = 0.0002, respectively). Paradoxically, expression of pEGFR was associated with a significantly improved OS (HR: 0.67 95 % CI 0.50-0.91, p = 0.01) and DRFS (HR: 0.73, 95 % CI 0.56-0.96, p = 0.025). Expression of activated EGFR/HER2 provides additional information on ER positive breast cancer patients and suggests alternative treatment for those in this subgroup.

Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression.

The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine-treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform-specific activation (phosphorylation) of Akt1 and Akt2 in formalin-fixed, paraffin-embedded cell lines and breast cancer tumour tissues in situ. PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.14-1.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.10-1.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.34-2.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.32-2.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples.