Simon Lord

Imaging tumour hypoxia with positron emission tomography

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers.

Gene expression and hypoxia in breast cancer

Hypoxia is a feature of most solid tumors and is associated with poor prognosis in several cancer types, including breast cancer. The master regulator of the hypoxic response is the Hypoxia-inducible factor 1α (HIF-1α). It is becoming clear that HIF-1α expression alone is not a reliable marker of tumor response to hypoxia, and recent studies have focused on determining gene and microRNA (miRNA) signatures for this complex process. The results of these studies are likely to pave the way towards the development of a robust hypoxia signature for breast and other cancers that will be useful for diagnosis and therapy. In this review, we outline the existing markers of hypoxia and recently identified gene and miRNA expression signatures, and discuss their potential as prognostic and predictive biomarkers. We also highlight how the hypoxia response is being targeted in the development of cancer therapies.

Factors predicting outcome for advanced gastroesophageal cancer in elderly patients receiving palliative chemotherapy.

AIMS Most patients with advanced gastroesophageal cancer are elderly, but current standard regimens have emerged from trials predominantly involving patients with a median age <65 years. The aim of this study was to assess the factors influencing survival outcome for an elderly gastroesophageal cancer non-trial population. MATERIALS AND METHODS We reviewed the case notes of all patients in our centre over the age of 65 years who received palliative chemotherapy for gastroesophageal cancer over a period of 3.5 years. Patients were classified as having received standard, non-standard combination or single-agent chemotherapy. After an initial univariate analysis, a multivariate analysis of the most significant prognostic factors was carried out. RESULTS In total, 120 patients were suitable for analysis. The median overall survival for patients receiving standard chemotherapy was 8.1 months, non-standard combination 8.3 months and single-agent fluoropyrimidines 3.9 months. Poor prognosis was predicted by two independent factors: poor performance status (hazard ratio 2.402; 95% confidence interval 1.53-3.77, P<0.001) and the presence of cancer symptoms (hazard ratio 2.235; 95% confidence interval 1.32-3.79, P=0.003). CONCLUSIONS An assessment of the performance status and the level of symptoms is vital in this vulnerable group of patients. Prospective randomised trials to assess the benefit of chemotherapy in elderly patients with gastroesophageal cancer are required.

Angiogenesis - still a worthwhile target for breast cancer therapy?

Mechanisms of resistance to anti-angiogenic therapy Several mechanisms for intrinsic and acquired tumour resistance to anti-angiogenic therapy have now been proposed. It is now clear that revascularisation can occur after the inhibition of VEGF signalling due to the upregulation of alternative angiogenic signalling pathways. Th is was fi rst revealed in a mouse model of pancreatic neuroendocrine cancer treated with the antiVEGF receptor (VEGFR) monoclonal antibody DC101; in this model an initial response was followed by tumour regrowth and revascularisation. Th is was associated with higher levels of mRNAs for the pro-angiogenic factors fi broblast growth factor 1 and 2, Ephrin A1 and A2 (Efna1 and Efna2) and Angiopoietin 1 (Angpt1) [1]. Further in vivo studies have suggested the importance of the promotion of a multitude of pro-angiogenic factors in response to anti-angiogenic therapy, including interleukin-8, VEGF, platelet derived growth factor (PDGF)A and placental growth factor [2-4].

Radiogenomics Monitoring in Breast Cancer Identifies Metabolism and Immune Checkpoints as Early Actionable Mechanisms of Resistance to Anti-angiogenic Treatment.

Anti-VEGF antibody bevacizumab has prolonged progression-free survival in several cancer types, however acquired resistance is common. Adaption has been observed pre-clinically, but no human study has shown timing and genes involved, enabling formulation of new clinical paradigms. In a window-of-opportunity study in 35 ductal breast cancer patients for 2 weeks prior to neoadjuvant chemotherapy, we monitored bevacizumab response by Dynamic Contrast-Enhanced Magnetic Resonance [DCE-MRI], transcriptomic and pathology. Initial treatment response showed significant overall decrease in DCE-MRI median Ktrans, angiogenic factors such ESM1 and FLT1, and proliferation. However, it also revealed great heterogeneity, spanning from downregulation of blood vessel density and central necrosis to continued growth with new vasculature. Crucially, significantly upregulated pathways leading to resistance included glycolysis and pH adaptation, PI3K-Akt and immune checkpoint signaling, for which inhibitors exist, making a strong case to investigate such combinations. These findings support that anti-angiogenesis trials should incorporate initial enrichment of patients with high Ktrans, and a range of targeted therapeutic options to meet potential early resistance pathways. Multi-arm adaptive trials are ongoing using molecular markers for targeted agents, but our results suggest this needs to be further modified by much earlier adaptation when using drugs affecting the tumor microenvironment.

Non-cancer medications for patients with incurable cancer: time to stop and think?

Patients starting palliative systemic therapy for incurable cancer will often be taking medications on repeat prescription for pre-existing medical disorders. Common examples include antihypertensives, statins, and anticoagulants for the primary or secondary prevention of cardiovascular disorders. Such drugs have uncertain benefits in patients whose life-expectancy is now dominated by advanced cancer, rather than future non-cancer risks. Most landmark studies establishing common preventative medications did not include significant numbers of cancer patients, or excluded them altogether. There is also uncertainty around the risks and side effects of non-cancer medications in patients with cancer. Indeed it appears that, at least within the medical literature, this issue has been almost entirely overlooked by the oncology and wider healthcare communities. Attention is needed as practitioners remain uncertain about how to manage their patients comorbidities alongside a new diagnosis of cancer. The important role of the GP as an expert in primary and secondary prevention may not be appreciated by patients, oncologists, and the GPs themselves, where the assumption exists that an oncologist will manage, with competence, all aspects of a cancer patients care. We shall consider some examples. In the case of statins for the primary prevention of coronary heart disease, the WOSCOPS study was a pivotal randomised controlled trial that justified the use of pravastatin in this setting. With an average follow-up of 5 years, the …

A randomised phase II trial and feasibility study of palliative chemotherapy in frail or elderly patients with advanced gastroesophageal cancer (321GO)

Background:Elderly patients are commonly under-represented in cancer clinical trials. The 321GO was undertaken in preparation for a definitive phase three trial assessing different chemotherapy regimens in a frail and/or elderly population with advanced gastroesophageal (GO) cancer.Methods:Patients with advanced GO cancer considered unfit for conventional dose chemotherapy were randomly assigned in a 1 : 1 : 1 ratio to: epirubicin, oxaliplatin and capecitabine (EOX); oxaliplatin and capecitabine (OX); and capecitabine alone (X) (all 80% of full dose and unblinded). The primary end point was patient recruitment over an 18-month period. A registration study recorded treatment choice for all patients with advanced GO cancer at trial centres.Results:A total of 313 patients were considered for palliative chemotherapy for GO cancer over the 18-month period: 115 received full dose treatment, 89 less than standard treatment or entered 321GO and 111 no treatment. Within 321GO, 55 patients were randomly assigned (19 to OX and X; 17 to EOX). Progression-free survival (PFS) for all patients was 4.4 months and by arm 5.4, 5.6 and 3.0 months for EOX, OX and X, respectively. The number of patients with a good overall treatment utility (OTU), a novel patient-centred endpoint, at 12 weeks was 3 (18%), 6 (32%) and 1 (6%) for EOX, OX and X, respectively. At 6 weeks, 22 patients (41%) had experienced a non-haematologic toxicity ⩾grade 3, most commonly lethargy or diarrhoea. The OTU was prognostic for overall survival in patients alive at week 12 (logrank test P=0.0001).Conclusions:It is feasible to recruit elderly and/or frail patients with advanced GO cancer to a randomised clinical trial. The OX is the preferred regimen for further study. Overall treatment utility shows promise as a comparator between treatment regimens for feasibility and randomised trials in the elderly and/or frail GO cancer population.

Neoadjuvant Window Studies of Metformin and Biomarker Development for Drugs Targeting Cancer Metabolism

There has been growing interest in the potential of the altered metabolic state typical of cancer cells as a drug target. The antidiabetes drug, metformin, is now under intense investigation as a safe method to modify cancer metabolism. Several studies have used window of opportunity in breast cancer patients before neoadjuvant chemotherapy to correlate gene expression analysis, metabolomics, immunohistochemical markers, and metabolic serum markers with those likely to benefit. We review the role metabolite measurement, functional imaging and gene sequencing analysis play in elucidating the effects of metabolically targeted drugs in cancer treatment and determining patient selection.

Concomitant medications in cancer patients: should we be more active in their management?

We thank Riechelmann and Del Giglio [1] for their recent article in Annals of Oncology ‘Drug interactions in oncology: how common are they?’. They make the point that dangerous drug–drug interactions (DDIs) are common in oncology patients and may have serious consequences. We believe other important aspects of concomitant medications in cancer patients should also be considered. Many cancer patients are already taking noncancer medications at the time of starting cancer therapy, and this prevalence is increasing together with the average age of the patient receiving cancer treatment [2]. But there is wide variance among oncologists in how these co-medications are managed. A recent audit at our institution showed, in common with other studies [3], that patients starting palliative chemotherapy continued to take a wide variety of drugs prescribed before the cancer diagnosis. These medications had often been prescribed not for symptomatic illnesses but for primary or secondary prevention. Drugs given with no immediate gain will have reduced benefits in patients whose life expectancy is now dominated by advanced cancer rather than future noncancer risks. Most landmark studies establishing common preventative medications did not include significant numbers of cancer patients, or excluded them altogether, for this reason. As well as reduced benefits, noncancer medications may carry greater risks and unwanted effects in the cancer patient. For example, cancer patients on warfarin have a greater risk of serious bleeding events [4]. Similarly, it is possible that a cancer patient on antihypertensive drugs who then develops neutropenic sepsis will be less able to mount a haemodynamic response: in an analogous situation, the recent Perioperative Ischemic Evaluation Study found a higher risk of death due to postoperative sepsis in surgical patients who had received preoperative b blockers [5]. Thus, at the time of cancer diagnosis, the cost : benefit balance of noncancer medications will shift, and although some may still be worthwhile, others will not. However, oncologists may be poorly equipped or unconfident to re-evaluate these issues for their patients, while the original non-oncology prescriber may be less engaged with the decision process after the cancer diagnosis. ‘No change’ may be the default position, but it is unlikely to be the best option for patients. Finally, financial cost has to be another consideration, especially for preventive medications which have gained market access with borderline cost-effectiveness in noncancer patients. At a societal level, it is highly unlikely that continuing such drugs in cancer patients will result in net benefit. For those most at risk, the elderly and those with significant comorbidities, there should be close collaboration between oncologists, hospital physicians, primary care providers and pharmacists to manage their medications proactively. The concept of ‘Comprehensive Geriatric Assessment’ offers a potential solution [6]. Withdrawal of medications requires sensitive discussion between patients and their medical team. However, in our experience, the majority of patients are keen to keep the number of medications to a minimum. Ultimately, we require evidence to guide practice. Mathematical modelling of noncancer treatment effects in cancer populations may help to quantify potential benefits, and more careful analysis and reporting of concomitant medication data collected during cancer clinical trials may help to spot potential harm. More robust evidence could be provided by a clinical trial randomising patients between rationalisation of concomitant medications or usual care: a challenging prospect.

Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality

Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.