Publications by authors named "Khurum Khan"

46 Publications

Thermal ablation in colorectal liver metastases-the paradox of equipoise.

Hepatobiliary Surg Nutr 2021 Apr;10(2):276-278

Department of Gastrointestinal Oncology, University College London Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.21037/hbsn-21-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050574PMC
April 2021

A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors.

Future Oncol 2021 Jul 14;17(21):2747-2758. Epub 2021 Apr 14.

Department of Medical Oncology, Erasmus MC Cancer Institute, PO Box 2040, 3000 CA Rotterdam, The Netherlands.

This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. NCT00888108 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2021-0140DOI Listing
July 2021

COVID-19 and Its Impact on Upper Gastrointestinal (GI) Cancer Management.

Cancers (Basel) 2021 Jan 21;13(3). Epub 2021 Jan 21.

North Middlesex University Hospital, Sterling Way, London N181QX, UK.

Coronavirus disease 2019 (COVID-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has left dramatic footprints on human health and economy. Cancer, whilst not an infective disease, is prevalent in epidemic proportions and cannot be pretermitted due to the impact of COVID-19. As we emanate from the second national lockdown in the UK with mixed feelings of hope and despair-due to vaccination and new COVID-19 variant, respectively-we reflect on the impact of the first wave on the provision on diagnosis and management of with upper gastrointestinal (UGI) cancers. This review provides a critical analysis of available literature on COVID-19 and its impact on cancer management in general and that of UGI cancers in particular.
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http://dx.doi.org/10.3390/cancers13030397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865795PMC
January 2021

Multimodal Treatment in Metastatic Colorectal Cancer (mCRC) Improves Outcomes-The University College London Hospital (UCLH) Experience.

Cancers (Basel) 2020 Nov 27;12(12). Epub 2020 Nov 27.

Department of Gastrointestinal Oncology, University College London Hospital NHS Foundation Trust, London NW1 2PG, UK.

Background: Despite notable advances in the management of metastatic colorectal cancer (mCRC) over the last two decades, treatment intent in the vast majority of patients remains palliative due to technically unresectable disease, extensive disease, or co-morbidities precluding major surgery. Up to 30% of individuals with mCRC are considered potentially suitable for primary or metastasis-directed multimodal therapy, including surgical resection, ablative techniques, or stereotactic radiotherapy (RT), with the aim of improving survival outcomes. We reviewed the potential benefits of multimodal therapy on the survival of patients with mCRC treated at the UCLH.

Methods: Clinical data on baseline characteristics, multimodal treatments, and survival outcomes were retrospectively collected from all patients with mCRC receiving systemic chemotherapy between January 2013 and April 2017. Primary outcome was the impact of multimodal therapy on overall survival, compared to systemic therapy alone, and the effect of different types of multimodal therapy on survival outcome, and was assessed using the Kaplan-Meier approach. All analyses were adjusted for age, gender, and side of primary tumour.

Results: One-hundred and twenty-five patients with mCRC were treated during the study period (median age: 62 years (range 19-89). The liver was the most frequent metastatic site (78%; 97/125). A total of 52% (65/125) had ≥2 lines of systemic chemotherapy. Of the 125 patients having systemic chemotherapy, 74 (59%) underwent multimodal treatment to the primary tumour or metastasis. Median overall survival (OS) was 25.7 months [95% Confidence Interval (CI) 21.5-29.0], and 3-year survival, 26%. Univariate analysis demonstrated that patients who had additional procedures (surgery/ablation/RT) were significantly less likely to die (Hazard Ratio (HR) 0.18, 95% CI 0.12-0.29, < 0.0001) compared to those receiving systemic chemotherapy alone. Increasing number of multimodal procedures was associated with an incremental increase in survival-with median OS 28.4 m, 35.7 m, and 64.8 m, respectively, for 1, 2, or ≥3 procedures (log-rank < 0.0001). After exclusion of those who received systemic chemotherapy only ( = 51), metastatic resections were associated with improved survival (adjusted HR 0.36, 95% CI 0.20-0.63, < 0.0001), confirmed in multivariate analysis. Multiple single-organ procedures did not improve survival.

Conclusion: Multimodal therapy for metastatic bowel cancer is associated with significant survival benefit. Resection/radical RT of the primary and resection of metastatic disease should be considered to improve survival outcomes following multidisciplinary team (MDT) discussion and individual assessment of fitness.
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http://dx.doi.org/10.3390/cancers12123545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760146PMC
November 2020

COVID-19 in cancer patients on systemic anti-cancer therapies: outcomes from the CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London) cohort study.

Ther Adv Med Oncol 2020 23;12:1758835920971147. Epub 2020 Oct 23.

Gastrointestinal Oncology Service and Cancer of Unknown Primary Service, University College London Hospital, UCL Cancer Institute and North Middlesex University Hospital, GI Cancer Lead North London Cancer Research Network and Oncology Research Lead North Middlesex University Hospital, 250 Euston Rd, London NW1 2PG, UK North Middlesex University Hospital, London, UK UCL Cancer Institute, 72 Huntley St, Bloomsbury, London WC1E 6DD, UK.

Background: Patients with cancer are hypothesised to be at increased risk of contracting COVID-19, leading to changes in treatment pathways in those treated with systemic anti-cancer treatments (SACT). This study investigated the outcomes of patients receiving SACT to assess whether they were at greater risk of contracting COVID-19 or having more severe outcomes.

Methods: Data was collected from all patients receiving SACT in two cancer centres as part of CAPITOL (COVID-19 Cancer PatIenT Outcomes in North London). The primary outcome was the effect of clinical characteristics on the incidence and severity of COVID-19 infection in patients on SACT. We used univariable and multivariable models to analyse outcomes, adjusting for age, gender and comorbidities.

Results: A total of 2871 patients receiving SACT from 2 March to 31 May 2020 were analysed; 68 (2.4%) were diagnosed with COVID-19. Cancer patients receiving SACT were more likely to die if they contracted COVID-19 than those who did not [adjusted (adj.) odds ratio (OR) 9.84; 95% confidence interval (CI) 5.73-16.9]. Receiving chemotherapy increased the risk of developing COVID-19 (adj. OR 2.99; 95% CI = 1.72-5.21), with high dose chemotherapy significantly increasing risk (adj. OR 2.36, 95% CI 1.35-6.48), as did the presence of comorbidities (adj. OR 2.29; 95% CI 1.19-4.38), and having a respiratory or intrathoracic neoplasm (adj. OR 2.12; 95% CI 1.04-4.36). Receiving targeted treatment had a protective effect (adj. OR 0.53; 95% CI 0.30-0.95). Treatment intent (curative palliative), hormonal- or immunotherapy and solid haematological cancers had no significant effect on risk.

Conclusion: Patients on SACT are more likely to die if they contract COVID-19. Those on chemotherapy, particularly high dose chemotherapy, are more likely to contract COVID-19, while targeted treatment appears to be protective.
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http://dx.doi.org/10.1177/1758835920971147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592172PMC
October 2020

Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data.

Front Oncol 2020 4;10:1634. Epub 2020 Sep 4.

Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden Hospital, London, United Kingdom.

Background: Image-guided tissue biopsies are critically important in the diagnosis and management of cancer patients. High-yield samples are also vital for biomarker and resistance mechanism discovery through molecular/genomic analyses.

Patients And Methods: All consecutive patients who underwent plugged image-guided biopsy at Royal Marsden from June 2013 until September 2016 were included in the analysis. In the next step, a second cohort of patients prospectively treated within two clinical trials (PROSPECT-C and PROSPECT-R) were assessed for the DNA yield from biopsies assessed for complex genomic analysis.

Results: A total of 522 plugged core biopsies were performed in 457 patients [men, 52%; median age, 63 years (range, 17-93)]. Histological diagnosis was achieved in 501 of 522 (96%) performed biopsies. Age, gender, modality, metastatic site, and seniority of the interventionist were not found to be significant factors associated with odds of failure on a logistic regression. Seventeen (3.3%) were admitted due to biopsy-related complications; nine, three, two, one, one, and one were admitted for grade I/II pain control, sepsis, vasovagal syncope, thrombosis, hematuria, and deranged liver functions, respectively; two patients with right upper quadrant pain after liver biopsy were found to have radiologically confirmed subcapsular hematoma requiring conservative treatment. One patient (0.2%) developed grade III hemorrhage following biopsy of a gastric gastrointestinal stromal tumor (GIST). Overall molecular analysis was successful in 89% (197/222 biopsies). Prospective validation in 62 biopsies gave success rates of 92.06 and 79.03% for DNA extraction of >1 μm and tmour content of >20%, respectively.

Conclusion: The probability of diagnostic success for complex molecular analysis is increased with plugged large coaxial needle biopsy technique, which also minimizes complications and reduces hospital stay. High-yield DNA acquisition allows genomic molecular characterization for personalized medicine.
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http://dx.doi.org/10.3389/fonc.2020.01634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500492PMC
September 2020

Outcomes of the 2019 novel coronavirus in patients with or without a history of cancer: a multi-centre North London experience.

Ther Adv Med Oncol 2020 14;12:1758835920956803. Epub 2020 Sep 14.

Gastrointestinal Oncology Service and Cancer of Unknown Primary Service; University College London Hospital NHS Foundation Trust, UCL Cancer Institute and North Middlesex University Hospital; GI Cancer Lead North London Cancer Research Netword, and Oncology Research Lead North Middlesex University Hospital, 250 Euston Rd, Kings Cross, London, NW1 2PG, UK.

Background: This study aims to compare the outcomes of COVID-19-positive disease in patients with a history of cancer to those without.

Methods: We retrospectively collected clinical data and outcomes of COVID-19 positive cancer patients treated consecutively in five North London hospitals (cohort A). Outcomes recorded included time interval between most recent anti-cancer treatment and admission, severe outcome [a composite endpoint of intensive care unit (ITU) admission, ventilation and/or death] and mortality. Outcomes were compared with consecutively admitted COVID-19 positive patients, without a history of cancer (cohort B), treated at the primary centre during the same time period (1 March-30 April 2020). Patients were matched for age, gender and comorbidity.

Results: The median age in both cohorts was 74 years, with 67% male, and comprised of 30 patients with cancer, and 90 without (1:3 ratio). For cohort B, 579 patients without a history of cancer and consecutively admitted were screened from the primary London hospital, 105 were COVID-19 positive and 90 were matched and included. Excluding cancer, both cohorts had a median of two comorbidities. The odds ratio (OR) for mortality, comparing patients with cancer to those without, was 1.05 [95% confidence interval (CI) 0.4-2.5], and severe outcome (OR 0.89, 95% CI 0.4-2.0) suggesting no increased risk of death or a severe outcome in patients with cancer. Cancer patients who received systemic treatment within 28 days had an OR for mortality of 4.05 (95% CI 0.68-23.95),  = 0.12. On presentation anaemia, hypokalaemia, hypoalbuminaemia and hypoproteinaemia were identified predominantly in cohort A. Median duration of admission was 8 days for cancer patients and 7 days for non-cancer.

Conclusion: A diagnosis of cancer does not appear to increase the risk of death or a severe outcome in COVID-19 patients with cancer compared with those without cancer. If a second spike of virus strikes, rational decision making is required to ensure optimal cancer care.
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http://dx.doi.org/10.1177/1758835920956803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493246PMC
September 2020

COVID-19 cancer conundrum-evidence driving decisions or the lack of it?

BMC Med 2020 06 9;18(1):182. Epub 2020 Jun 9.

Gastrointestinal Oncology Service & Cancer of Unknown Primary Service, University College London Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1186/s12916-020-01649-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282465PMC
June 2020

Immunotherapy in gastrointestinal cancer: The current scenario and future perspectives.

Cancer Treat Rev 2020 Aug 28;88:102030. Epub 2020 May 28.

Department of Oncology, North Middlesex University Hospital, Sterling Way, London N18 1QX, United Kingdom; Department of Medical Oncology, University College London Cancer Institute, 72 Huntly St., Fitzrovia, London WC1E 6AG, United Kingdom. Electronic address:

Gastrointestinal cancers include colorectal, gastric, oesophageal, pancreatic and liver cancers. They continue to be a significant cause of mortality and morbidity worldwide. Current treatment strategies include chemotherapy, surgery, radiotherapy and targeted therapies. Immunotherapy has recently been incorporated in treatment regimens for some gastrointestinal malignancies and research into different immune modifying treatments is being carried out in this context. Approaches to immune modulation such as vaccination, adoptive cell therapy and checkpoint inhibition have shown varying clinical benefit, with most of the benefit seen in checkpoint inhibition. This review summarises recent advances and future direction of immunotherapy in patients with gastrointestinal malignancies.
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http://dx.doi.org/10.1016/j.ctrv.2020.102030DOI Listing
August 2020

Imaging and clinical correlates with regorafenib in metastatic colorectal cancer.

Cancer Treat Rev 2020 Jun 4;86:102020. Epub 2020 Apr 4.

Institut Jules Bordet, 121 Boulevard de Waterloo, 1000 Brussels, Belgium. Electronic address:

In colorectal cancer (CRC), imaging is important in determining tumor stage, selecting treatment strategies, and in assessing response to therapy. However, some challenges remain with established imaging techniques, such as computed tomography, and with some commonly used response criteria, such as Response Evaluation Criteria in Solid Tumors, which measures change in size of several target lesions instead of change in tumor morphology or metabolic function. In addition, these assessments are not typically conducted until after 8 weeks of treatment, meaning that potential non-responders are often not identified in a timely manner. Regorafenib, an oral tyrosine kinase inhibitor indicated for the treatment of metastatic CRC, blocks the activity of several protein kinases involved in angiogenesis, oncogenesis, metastasis, and tumor immunity. Timely differentiation of regorafenib responders from non-responders using appropriate imaging techniques that recognize not only changes in tumor size but also changes in tumor density or vasculature, may reduce unnecessary drug-related toxicity in patients who are unlikely to respond to treatment. This review discusses the latest developments in computed tomography, magnetic resonance imaging, and positron emission tomography tumor imaging modalities, and how these aid in identifying patients with metastatic CRC who are responders or non-responders to regorafenib treatment.
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http://dx.doi.org/10.1016/j.ctrv.2020.102020DOI Listing
June 2020

Challenges in the treatment of gastric cancer in the older patient.

Cancer Treat Rev 2020 Apr 10;85:101980. Epub 2020 Feb 10.

Gastrointestinal Oncology, Department of Medicine, University College London NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK. Electronic address:

Gastric cancer is considered an age-related disease, with the majority of new cases in the UK diagnosed in individuals over the age of 75. At present most guidance related to the management of gastric cancer is based on trials undertaken in the fit, younger patient. Historically the elderly have been underrepresented in clinical trials, which frequently have a restricted inclusion to an upper age limit of 75. The European Society for Medical Oncology (ESMO) recommends use of a geriatric assessment to determine functional age when initiating treatment in elderly patients with gastric cancer, which has been shown to be a better predictor of treatment response than chronological age. The physiological changes that occur with age, including reduced organ function and pharmacokinetic and pharmacodynamic variability, together with impaired functional status, necessitate a more individualised approach to treatment decisions in the older patient to provide them with the same advantages from radical treatment and palliative chemotherapy as younger patients. This review summarises the current evidence extrapolated from trial data on how best to optimise treatment for elderly patients with gastric cancer.
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http://dx.doi.org/10.1016/j.ctrv.2020.101980DOI Listing
April 2020

Targeting EGFR pathway in metastatic colorectal cancer- tumour heterogeniety and convergent evolution.

Crit Rev Oncol Hematol 2019 Nov 7;143:153-163. Epub 2019 Sep 7.

Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton SM2 5PT, UK. Electronic address:

Despite significant progress in management of metastatic colorectal cancer (mCRC) pertaining to better screening procedures and amelioration of the therapeutic armamentarium with targeted therapies, prognosis remains poor. Targeting epidermal growth factor receptor (EGFR) has been of particular interest owing to favourable efficacy benefits demonstrated by monoclonal antibodies (cetuximab and panitumumab) in various clinical settings and development of predictive biomarkers informing treatment decisions respectively. In spite of optimal patient selection based on RAS mutation status, primary and secondary resistance to monoclonal antibodies is higher than desired. Further research into predictive biomarkers is therefore essential, but has, to date, been conducted with considerable limitations. Whilst molecular heterogeneity has been demonstrated by several studies in mCRC, for incomprehensible reasons, multiple resistant genetic alterations that emerge under the selective pressure of EGFR-targeted therapies are somehow able to influence the biological and clinical behaviour of cancer cells, despite being detectable at extremely low frequencies. Intriguingly, these subclonal events largely seem to converge on RAS/RAF/MAPK pathway in patients treated with EGFR-targeted monoclonal antibodies. This review describes the clinical and biological evolution and development of EGFR targeted therapies in mCRC, the challenges in the presence of molecular complexities, the role of cell free (cf)-DNA and future strategies that could lead to further optimal discovery of clinically meaningful biomarkers and application of precision medicine.
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http://dx.doi.org/10.1016/j.critrevonc.2019.09.001DOI Listing
November 2019

Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.

Cancer Cell 2019 07;36(1):35-50.e9

Tumour Microenvironment Lab, The Institute of Cancer Research, London SW3 6JB, UK.

Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.
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http://dx.doi.org/10.1016/j.ccell.2019.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617392PMC
July 2019

Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis.

J Natl Cancer Inst 2019 08;111(8):782-794

See the Notes section for the full list of authors' affiliations.

Background: FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.

Methods: We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.

Results: We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX.

Conclusions: This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.
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http://dx.doi.org/10.1093/jnci/djz073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695305PMC
August 2019

CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids.

J Immunother Cancer 2019 04 15;7(1):101. Epub 2019 Apr 15.

Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

Background: The T cell bispecific antibody cibisatamab (CEA-TCB) binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells, which triggers T cell killing of cancer cell lines expressing moderate to high levels of CEA at the cell surface. Patient derived colorectal cancer organoids (PDOs) may more accurately represent patient tumors than established cell lines which potentially enables more detailed insights into mechanisms of cibisatamab resistance and sensitivity.

Methods: We established PDOs from multidrug-resistant metastatic CRCs. CEA expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of PDOs and allogeneic CD8 T cells.

Results: PDOs could be categorized into 3 groups based on CEA cell-surface expression: CEA (n = 3), CEA (n = 1) and CEA PDOs (n = 4), that stably maintained populations of CEA and CEA cells, which has not previously been described in CRC cell lines. CEA PDOs were sensitive whereas CEA PDOs showed resistance to cibisatamab. PDOs with mixed expression showed low sensitivity to cibisatamab, suggesting that CEA cells maintain cancer cell growth. Culture of FACS-sorted CEA and CEA cells from PDOs with mixed CEA expression demonstrated high plasticity of CEA expression, contributing to resistance acquisition through CEA antigen loss. RNA-sequencing revealed increased WNT/β-catenin pathway activity in CEA cells. Cell surface CEA expression was up-regulated by inhibitors of the WNT/β-catenin pathway.

Conclusions: Based on these preclinical findings, heterogeneity and plasticity of CEA expression appear to confer low cibisatamab sensitivity in PDOs, supporting further clinical evaluation of their predictive effect in CRC. Pharmacological inhibition of the WNT/β-catenin pathway may be a rational combination to sensitize CRCs to cibisatamab. Our novel PDO and T cell co-culture immunotherapy models enable pre-clinical discovery of candidate biomarkers and combination therapies that may inform and accelerate the development of immuno-oncology agents in the clinic.
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http://dx.doi.org/10.1186/s40425-019-0575-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463631PMC
April 2019

miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial.

Clin Cancer Res 2019 07 5;25(13):3830-3838. Epub 2019 Apr 5.

Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.

Purpose: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs.

Experimental Design: miR-31-3p was tested by hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination.

Results: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer).

Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3769DOI Listing
July 2019

Efficacy and Cardiotoxic Safety Profile of Raltitrexed in Fluoropyrimidines-Pretreated or High-Risk Cardiac Patients With GI Malignancies: Large Single-Center Experience.

Clin Colorectal Cancer 2019 03 29;18(1):64-71.e1. Epub 2018 Sep 29.

Department of Medicine, GI and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, London and Surrey, UK. Electronic address:

Background: Gastrointestinal (GI) cancer patients may not be considered for therapy with fluoropyrimidines (FPs) because of previous cardiovascular (CV) toxicity or preexisting risk factors; such patients may benefit from raltitrexed-based therapy.

Patients And Methods: Patient, tumor, and treatment characteristics, as well as clinical outcomes of all consecutively treated patients with raltitrexed at the Royal Marsden Hospital between October 1998 and July 2011 were examined. GI cancer patients who developed CV toxicity as a result of FPs and those with significant CV risk factors receiving raltitrexed were included in this analysis.

Results: A total of 247 patients (155 and 92 with CV FP-related CV toxicities and significant CV risk factors, respectively) treated with raltitrexed alone or in combination were examined after a median follow-up of 47.1 months. CV toxicity profiles of patients receiving capecitabine (n = 110) and 5-fluorouracil (n = 45) were largely similar. Of raltitrexed-treated patients, 13 (5%) experienced CV toxicities and 1 (< 0.1%) died as a result of myocardial infarction. The median progression-free survival (PFS) and overall survival (OS) were 36.0 months (95% confidence interval [CI], 26.5-48.6) and 44.3 months (95% CI, 33.1-56.8), respectively. The 5-year survival for early stage GI malignancies (n = 140) was 62.0% (95% CI, 50.1-71.9). Median PFS and OS were not reached in this group (interquartile range = 38.4 months to NR); median PFS and OS for advanced GI malignancies (n = 107) were 18.8 (95% CI, 11.9-25.7) and 23.7 months (95% CI, 17.0-26.9), respectively.

Conclusion: A raltitrexed-based regimen is well-tolerated therapy with comparable efficacy to FPs in patients with GI malignancies with significant CV toxicities or risk factors.
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http://dx.doi.org/10.1016/j.clcc.2018.09.010DOI Listing
March 2019

Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.

Oncogene 2019 03 23;38(10):1717-1733. Epub 2018 Oct 23.

Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.

Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.
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http://dx.doi.org/10.1038/s41388-018-0554-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462854PMC
March 2019

Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial.

Cancer Discov 2018 10 30;8(10):1270-1285. Epub 2018 Aug 30.

Clinical Genomics, The Centre for Molecular Pathology, The Royal Marsden NHS Trust, London and Sutton, United Kingdom.

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies. Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380469PMC
October 2018

Clinical outcomes of adolescents and young adults with advanced solid tumours participating in phase I trials.

Eur J Cancer 2018 09 17;101:55-61. Epub 2018 Jul 17.

Sarcoma Unit, The Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, UK. Electronic address:

Background: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before.

Aim: To study the outcome of AYA patients in phase I clinical trials.

Methods: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed.

Results: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations.

Conclusion: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.
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http://dx.doi.org/10.1016/j.ejca.2018.06.003DOI Listing
September 2018

Translational research and application of basic biology to clinical trial development in GI cancers.

Ann Transl Med 2018 May;6(9):164

Department of Gastrointestinal Cancer and Lymphoma, Royal Marsden, UK.

Cancers of the gastrointestinal tract have limited available treatments and are often associated with a poor prognosis. Clinical trials and translational work associated with these trials provide the opportunity to increase understanding of the mechanisms of sensitivity and resistance to cytotoxic chemotherapy and targeted therapy in these diseases. In this review we discuss the rationale for intensive translational work within the context of academic clinical trials and the successes and challenges which have been associated with translational work at our institution over the past number of years. We reflect on tissue, plasma and radiological biomarker work including a novel patient derived organoid programme and discuss the iterative application of previous results to next generation trial design.
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http://dx.doi.org/10.21037/atm.2018.05.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985276PMC
May 2018

Patient-derived organoids model treatment response of metastatic gastrointestinal cancers.

Science 2018 02;359(6378):920-926

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs.
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http://dx.doi.org/10.1126/science.aao2774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112415PMC
February 2018

MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma.

Gastroenterology 2018 03 4;154(4):1066-1079.e5. Epub 2017 Nov 4.

The Royal Marsden NHS Trust, London and Surrey, UK.

Background & Aims: Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small-molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors.

Methods: We performed a high-throughput screen of 484 small-molecule compounds to identify those that reduced viability of 6 human CCA cell lines. We tested the effects of HSP90 inhibitors on cells with disruption of the MIR21 gene, cells incubated with MIR21 inhibitors, and stable cell lines with inducible expression of MIR21. We obtained CCA biopsies from patients, cultured them as organoids (patient-derived organoids). We assessed their architecture, mutation and gene expression patterns, response to compounds in culture, and when grown as subcutaneous xenograft tumors in mice.

Results: Cells with IDH1 and PBRM1 mutations had the highest level of sensitivity to histone deacetylase inhibitors. HSP90 inhibitors were effective in all cell lines, irrespective of mutations. Sensitivity of cells to HSP90 inhibitors correlated inversely with baseline level of MIR21. Disruption of MIR21 increased cell sensitivity to HSP90 inhibitors. CCA cells that expressed transgenic MIR21 were more resistant to HSP90 inhibitors than cells transfected with control vectors; inactivation of MIR21 in these cells restored sensitivity to these agents. MIR21 was shown to target the DnaJ heat shock protein family (Hsp40) member B5 (DNAJB5). Transgenic expression of DNAJB5 in CCA cells that overexpressed MIR21 re-sensitized them to HSP90 inhibitors. Sensitivity of patient-derived organoids to HSP90 inhibitors, in culture and when grown as xenograft tumors in mice, depended on expression of miRNA21.

Conclusions: miRNA21 appears to mediate resistance of CCA cells to HSP90 inhibitors by reducing levels of DNAJB5. HSP90 inhibitors might be developed for the treatment of CCA and miRNA21 might be a marker of sensitivity to these agents.
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http://dx.doi.org/10.1053/j.gastro.2017.10.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863695PMC
March 2018

In Reply.

Oncologist 2017 11 10;22(11):1411-1412. Epub 2017 Aug 10.

GI and Lymphoma Unit, Department of Medicine, The Royal Marsden National Health Service Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1634/theoncologist.2017-0258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679830PMC
November 2017

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study.

Gut 2018 08 8;67(8):1484-1492. Epub 2017 Aug 8.

Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK.

Objective: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.

Design: Patients with mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (K), enhancing fraction (EF) and their product KEF (summarised median values of K× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.

Results: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06).

Conclusions: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.
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http://dx.doi.org/10.1136/gutjnl-2017-314178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204951PMC
August 2018

Survival Outcomes in Asymptomatic Patients With Normal Conventional Imaging but Raised Carcinoembryonic Antigen Levels in Colorectal Cancer Following Positron Emission Tomography-Computed Tomography Imaging.

Oncologist 2016 12 14;21(12):1502-1508. Epub 2016 Oct 14.

GI and Lymphoma Unit, Department of Medicine, The Royal Marsden National Health Service Foundation Trust, London, United Kingdom

Background: This study had two aims: (a) to evaluate the utility of fluorine 18-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) in detecting occult disease recurrence with raised carcinoembryonic antigen (CEA) and (b) to establish the prognostic effects of early detection of disease recurrence in patients with colorectal cancer (CRC).

Patients And Methods: Clinico-pathological data were obtained from all consecutive patients undergoing CRC surveillance from 2004 to 2010 who had an elevated CEA level (>3 ng/mL in nonsmokers, >5 ng/mL in smokers) but normal or equivocal conventional investigations. Histopathological confirmation or a minimum of 12 months' clinical and radiological follow-up were required to ascertain disease relapse.

Results: A total of 1,200 patients were screened; of those, 88 (59% men; mean age, 66 years [SD, 9.6]) eligible patients (67 with normal and 21 with equivocal results on conventional investigations) were identified. Recurrent disease was detected in 56 of 88 patients (64%). The sensitivity of FDG PET-CT to detect recurrence was 49 of 56 (88%; 95% confidence interval [CI], 76%-95%) and specificity was 28 of 32 (88%; 95% CI, 71%-97%). Twenty-seven of 49 (55%) patients with PET-CT-detected relapsed disease were deemed eligible for further curative therapy; 19 (70%) went on to receive potentially curative therapy. The median time to progression (8.8 months [interquartile range (IQR), 4.5-19.1 months] vs. 2.2 months [IQR, 0.7-5.6]), median overall survival (39.9 months [IQR, 23.6-65.4 months] vs. 15.6 months [IQR, 7.3-25.7 months]), and 5-year survival (36.8% [95% CI, 16.5%-57.5%] vs. 6.1% [95% CI, 1.1%-17.6%]; p ≤ .001) were higher in patients who received potentially curative therapy than in those who received noncurative therapy.

Conclusion: FDG PET-CT is a highly sensitive and specific tool for the detection of occult CRC recurrence. In >50% of patients, recurrent disease may still be potentially amenable to curative therapy. Long-term survival can be achieved in such patients.

Implications For Practice: Colorectal cancer (CRC) patients who, on follow-up, have normal or equivocal results on clinical investigations but raised carcinoembryonic antigen (CEA) levels pose a significant challenge to treating physicians. This study supported the notion that the early use of fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) may have predictive and prognostic value in management of such patients. Long-term disease control and cure can be achieved in a subgroup of this patient population with low-volume disease relapse who are amenable to potentially curative treatment strategies. Reassuringly, the sensitivity and specificity for recurrence did not significantly vary as a function of the CEA level, suggesting that even with a minimal CEA rise, benefit can be attained by conducting FDG PET-CT in a timely manner.
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http://dx.doi.org/10.1634/theoncologist.2016-0222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153343PMC
December 2016

Hyperglycemia and Phosphatidylinositol 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) Inhibitors in Phase I Trials: Incidence, Predictive Factors, and Management.

Oncologist 2016 07 5;21(7):855-60. Epub 2016 May 5.

Drug Development Unit, Royal Marsden National Health Service Trust, London, United Kingdom

Background: Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management.

Materials And Methods: Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables.

Results: A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age <65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p < .0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort.

Conclusion: Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation.

Implications For Practice: This study reviewed the clinical data of 341 patients treated in 12 phase I trials of agents targeting phosphatidylinositol3-kinase (PI3), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), as well as dual inhibitors. Hyperglycemia was evident in 87.4% of patients but was ≥grade 3 in just 6.7%. Age <65 years, history of diabetes, and treatment with AKT and dual PI3K/mTOR inhibitors were each associated with grade 3 hyperglycemia. Management of patients was uncomplicated, and no permanent drug discontinuations were necessary. Despite the small study size, these findings support continued caution about enrolling patients with a history of diabetes into such trials. However, clinicians may be reassured, pending prospective validation of these results, that significant hyperglycemia is not frequent and, when it occurs, is manageable.
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http://dx.doi.org/10.1634/theoncologist.2015-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943382PMC
July 2016

miR-21 expression and clinical outcome in locally advanced pancreatic cancer: exploratory analysis of the pancreatic cancer Erbitux, radiotherapy and UFT (PERU) trial.

Oncotarget 2016 Mar;7(11):12672-81

Gastrointestinal Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.

Background: Locally advanced pancreatic cancer (LAPC) is associated with high mortality, and biomarker-driven treatment approach is currently lacking. This study evaluated safety and efficacy of a combination approach of chemotherapy followed by chemo-radiotherapy (CRT) +/- cetuximab, and the prognostic role of miR-21 in patients with LAPC treated with a multimodality approach.

Patients And Methods: This was a randomised phase II trial in which patients with inoperable LAPC were offered gemcitabine and capecitabine (GEM-CAP) for 16 weeks. Patients with stable disease or response after GEM-CAP were randomised to capecitabine or UFT plus radiotherapy (RT) (A), or capecitabine or UFT plus cetuximab plus RT (B). The primary outcome of the study was overall survival (OS). Clinical outcome was compared according to baseline circulating miR-21 levels.

Results: 17 patients were enrolled and treated with GEM-CAP, with 13 patients achieving disease control and being randomised to arms A (n:7) and B (n:6). After a median follow-up of 61.2 months, median progression free survival (PFS) was 10.4 months and 12.7 months, median OS was 15.8 months and 22.0 months in arms A and B respectively (p > 0.05). Patients with high baseline plasma miR-21 had worse PFS (3.5 vs. 12.7 months; p:0.032) and OS (5.1 vs 15.3 months; p:0.5) compared to patients with low miR-21. Circulating miR-21 levels reflected miR-21 expression within the tissues.

Conclusions: Addition of Cetuximab to CRT following induction chemotherapy did not improve survival. High miR-21 baseline plasma expression was associated with poor clinical outcome in LAPC patients treated with induction chemotherapy followed by chemo-radiotherapy.
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http://dx.doi.org/10.18632/oncotarget.7208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914313PMC
March 2016
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