Target-based therapeutic matching of phase I trials in patients with metastatic breast cancer in a tertiary referral centre.

Background Greater understanding of the molecular classification of breast cancer has permitted the development of rational drug design strategies. In a phase I clinical trial setting, molecular profiling with next-generation sequencing of individual tumour samples has been employed to guide treatment.Methods We conducted a retrospective evaluation of clinical outcomes of patients with metastatic breast cancer (MBC) treated in phase I clinical trials at our institution to assess the benefit of molecularly matched compared to non-matched treatments.Results A total of 97 consecutive patients with MBC were enrolled onto ≥1 trial between 2009 and 2015. Fourteen patients participated in multiple trials, and a total of 113 trial encounters were reviewed in this retrospective study. Eighty-three percent of patients with molecular data available were able to participate in trials matched to molecular aberrations. Patients who were treated on matched studies had improved clinical benefit (RR: 1.80, p = 0.005), progression-free (HR: 0.52, p = 0.003) and overall survival (HR: 0.54, p < 0.001). Treatment was well tolerated with low rates of treatment discontinuation for toxicity (8% overall) that did not differ between groups. No toxicity-related deaths were observed.Conclusions Molecular profiling for MBC patients in a phase I setting is feasible and aids therapeutic decisions with improved patient outcomes

The different faces of metastatic melanoma in the gastrointestinal tract.

Melanoma is the most aggressive form of skin cancer, with tendency to spread to any organ of the human body, including the gastrointestinal tract (GIT). The diagnosis of metastases to the GIT can be difficult, as they may be clinically silent for somewhile and may occur years after the initial melanoma diagnosis. CT imaging remains the standard modality for staging and surveillance of melanoma patients, and in most cases, it will be the first imaging modality to identify GIT lesions. However, interpretation of CT studies in patients with melanoma can be challenging as lesions may be subtle and random in distribution, as well as sometimes mimicking other conditions. Even so, early diagnosis of GIT metastases is critical to avoid emergency hospitalisations, whilst surgical intervention can be curative in some cases. In this review, we illustrate the various imaging presentations of melanoma metastases within the GIT, discuss the clinical aspects and offer advice on investigation and management. We offer tips intended to aid radiologists in their diagnostic skills and interpretation of melanoma imaging scans

The forgotten appearance of metastatic melanoma in the small bowel.

BACKGROUND: Melanoma is the most aggressive form of skin cancer, with a tendency to metastasise to any organ of the human body. While the most common body organs affected include liver, lungs, brain and soft tissues, spread to the gastrointestinal tract is not uncommon. In the bowel, it can present with a multitude of imaging appearances, more rarely as an aneurysmal dilatation. This appearance is classically associated with lymphoma, but it has more rarely been associated with other forms of malignancy. CASE PRESENTATION: We report a case series of three patients with aneurysmal dilatation in the small bowel (SB) confirmed to be due to metastatic melanoma (MM). All patients had non-specific symptoms; most times being attributed initially to causes other than melanoma. On CT the identified aneurysmal SB dilatations were diagnosed as presumed lymphoma in all cases. In two cases, the aneurysmal dilatation was the first presentation of metastatic disease and in two of the cases more than one site of the gastrointestinal tract was concomitantly involved. All patients underwent surgical resection with histological confirmation of MM. CONCLUSIONS: Recognition of unusual SB presentation of MM, such as aneurysmal SB dilatation, is important to expedite diagnosis, provide appropriate treatment, and consequently improve quality of life and likely survival of these patients. As the most common cancer to metastasise to the SB and as a known imaging mimicker, MM should remain in any radiologist's differential diagnosis for SB lesions with aneurysmal dilatation.Acknowledgements The authors acknowledge support from National Institute of Health Research Cambridge Biomedical Research Centre, Cancer Research UK (Cambridge Imaging Centre grant number C197/A16465), the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre. Funding source and conflicts of interest E.M.S is funded by NIHR Clinical Lectureship (Reference number: NIHR CL-2017-14-502) and is also supported by the Academy of Medical Sciences, the Wellcome Trust, the Medical Research Council (MRC), the British Heart Foundation, Versus Arthritis, Diabetes UK and the British Thoracic Society (Helen and Andrew Douglas bequest) Starter Grant award [SGL019\1007]. The views expressed are those of the authors and not necessarily those of the funders. No conflicts of interest to disclosure

Testosterone deficiency and quality of life in Australasian testicular cancer survivors: a prospective cohort study

This is the first prospective study in a contemporary Australian/New Zealand population to determine the prevalence of testosterone deficiency in testicular cancer survivors at 12 months from treatment, and any association with poorer quality of life. Hormone assays from 54 evaluable patients in a prospective cohort study revealed biochemical hypogonadism in 18 patients (33%) and low-normal testosterone in 13 patients (24%). We found no association between testosterone levels and quality of life (all P > 0.05). Hypogonadal patients should be considered for testosterone replacement to prevent long-term morbidity.B. O'Carrigan, M. Fournier, I. N. Olver, M. R. Stockler, H. Whitford, G. C. Toner, D. B. Thomson, I. D. Davis, F. Hanning, N. Singhal, C. Underhill, P. Clingan, A. McDonald, A. Boland, P. Grimison and Australian and New Zealand Urogenital and Prostate Cancer Trials Grou

A Phase 1 first-in-human trial to evaluate the safety and tolerability of CCT3833, an oral panRAF inhibitor, in patients with advanced solid tumours, including metastatic melanoma

Background: Over 70,000 patients are diagnosed with malignant melanoma in the USA every year with a high proportion occurring in young people. Although treatments targeting the mitogen activated protein kinase signal transduction pathway including BRAF inhibitors have improved survival for patients with BRAF mutated melanoma, their utility is limited by intrinsic and acquired resistance of diverse mechanisms. Patients with a RAS mutated melanoma also represent a current unmet need. CCT3833 is a potent inhibitor of mutant BRAF, CRAF and SRC kinases. Preclinical data using CCT3833 in a range of mutant RAF or RAS cell lines in vitro and human tumour xenograft models in vivo demonstrated activity, including melanoma patient-derived xenografts with intrinsic or acquired resistance to selective BRAF inhibitors. These data support clinical development of CCT3833 in humans. Methods: This ongoing open-label, multi-centre Phase I trial of CCT3833 is in two parts; an initial dose escalation stage (Part A) in a rolling six design, followed by a dose expansion (Part B). The primary objectives are to evaluate the safety and tolerability profile of CCT3833 and establish the Recommended Phase 2 Dose (RP2D). CCT3833 is administered orally once daily on a continuous basis over a 28-day cycle. In Part A, a single dose is administered for safety and pharmacokinetic (PK) purposes prior to commencing continuous dosing. Secondary objectives include characterisation of the PK profile and correlation with tolerability / efficacy of CCT3833 in humans and assessment of response (radiological or clinical), supported by PD analyses. Eligible subjects include patients with advanced solid malignancies with performance status 0 to 1, fit for entry into a Phase 1 clinical trial. Part B will enrol patients with BRAF- or RAS- mutated metastatic melanoma into 3 cohorts i) treatment naïve V600E BRAF mutant melanoma ii) V600E BRAF mutant melanoma with progression on BRAF inhibitor therapy or iii) RAS mutant melanoma. Three cohorts of the dose escalation have been completed without DLT. Enrolment to cohort 4 began in January 2016. Clinical trial information: NCT02437227. Clinical trial information: NCT02437227