Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients : an expert taskforce review

The importance of mutation identification for advanced colorectal cancer treatment with anti-epidermal growth factor receptor agents is well established. However, due to delays in turnaround time, low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that Kirsten rat sarcoma and neuroblastoma rat sarcoma (RAS) testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS colorectal cancer testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally invasive method, such as early detection of emergent resistance to anti-epidermal growth factor receptor therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes

Treatment of subclinical hyperthyroidism: Effect on body composition

Background: subclinical hyperthyroidism (SHT) is associated with harmful effects on cardiovascular system, bone metabolism and progression to clinical hyperthyroidism. Loss of weight is a common fact in patients with clinical hyperthyroidism and of particular relevance in elderly patients. Objective: to assess changes in body composition after radioiodine therapy for SHT due to toxic nodular goiter. Subjects and methods: prospective controlled cohort study. Patients with persistent SHT due to toxic nodular goiter were purposed to receive treatment with radioiodine (treatment group) or to delay treatment until the study was over (control group). All treated patients received 555 MBq of 131I. Body composition (lean mass, fat mass and bone mineral content) was determined by dual-energy X-ray absorptiometry (DEXA) at baseline and 12 months after. Results: twenty-nine patients were studied (age 69.5 ± 11.5; 75.9% women; BMI 27.1 ± 5.7 kg/m²; serum thyrotropin (TSH) 0.20 ± 0.21 µUI/mL; serum free thyroxine (T4) 1.01 ± 0.19 ng/dL), 17 belonging to the treatment group and 12 to the control group. Study groups were comparable, although there was a trend for the treatment group to have more fat mass. No longitudinal changes in body composition were noted in either group, except for a trend to gain fat mass. However, when individuals with age > 65 years were selected, only patients who received radioiodine therapy showed a significant increase in body weight (from 64.1 ± 10.0 to 66.9 ± 9.2 kg), BMI (from 27.3 ± 4.8 to 28.7 ± 4.5 kg/m²), fat mass (from 26.1 ± 8.5 to 27.8 ± 7.9 kg), lean mass (from 36.3 ± 0.4 to 37.4 ± 0.4 kg) and skeletal muscle mass index (SMI) (from 6.0 ± 0.6 to 6.3 ± 0.6 kg/m²). Conclusions: treatment of SHT has impact on body composition in subjects older than 65 years. Weight gain reflects increases in fat and, more interestingly, in lean mass

Active study: undetected prevalence and clinical inertia in the treatment of breakthrough cancer pain (BTcP)

Aims To prove if there is clinical inertia in the identification and treatment of episodes of breakthrough cancer pain (BTcP), comparing actual results from clinical practice with clinical oncologists’ prior perception. Design Observational and descriptive study, using information collected by practising medical oncologists, at three moments: (a) questionnaire regarding their professional judgement of the handling of patients with BTcP in their practice, (b) cross-sectional clinical screening, to detect possible existing cases of BTcP in a representative sample of their patients, (c) retrospective self-audit of clinical case histories of patients diagnosed with BTcP to find out about how it has been handled. Participants and study period A random sample on a state level of 108 specialists in medical oncology. 540 patients who suffer some type of cancer pain on the designated study date for each specialist (July–December 2016). Results The global prevalence of BTcP in the study sample covered 91.3% of the patients who were suffering some type of cancer pain. Barely 2% of the doctors surveyed suspected figures around this mark. 40.9% of the cases had not been previously detected as BTcP by their doctors. Although 90% of the patients who had previously been diagnosed with BTcP received a specific analgesic treatment for the symptoms, 42% of those patients with known BTcP were not able to control their episodes of pain. Conclusions Clinical inertia is a serious problem in the handling of BTcP in medical oncology services, where it is the subject of a significantly low level of detection and treatment, despite the contrasting perception of specialists.pre-print339 K

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08–4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.This clinical trial was approved and supported by Merck S.L., an affiliate of Merck KGaA, Darmstadt. Germany [research project number 2010-023580-18, date: 05-06-2014

Oncological translational research in the Spanish national health system: the INTRO study

Under the auspices of the Foundation for Excellence and Quality in Oncology (ECO), the Translational Research in Oncology Medical Services Study (INTRO) was conducted with the aim of describing the current state of, and future expectations for translational cancer research in Spanish medical centres. The first step in the investigation was intended to analyse the current condition of the national Medical Oncology Services network by examining different aspects of the oncology research field. A descriptive and observational multicentre study was performed at a statewide level; information was collected by surveying a cross-section of all those responsible for Medical Oncology Services in Spain. The survey was completed by key informants, who were selected independently by each service, between September 2010 and April 2011. We were able to gather comprehensive data from a total of 27 Spanish hospitals. These data enabled us to describe the allocation of human and material resources devoted to clinical and translational research across the Medical Oncology Services and to describe the organisational and functional components of these services and units. These data included information pertaining to the activities developed, their funding sources, and their functional dependence on other internal or external bodies. Finally, we explored the degree of dissemination and use of some specific techniques used for the genetic diagnosis of cancer, which have recently been introduced in Medical Oncology within the Spanish healthcare system. A wide range of variability exists between different oncology services in Spanish hospitals. Time should be spent reflecting on the need and opportunities for improvement in the development of translational research within the field of oncology.Caballero, C.; Jantus-Lewintre, E.; Carrato, A.; García Foncillas, J.; Gascon, P.; Blasco, A.; Moreno Nogueira, JA.... (2014). Oncological translational research in the Spanish national health system: the INTRO study. Clinical and Translational Oncology. 16(8):686-695. doi:10.1007/s12094-013-1138-6S686695168Díaz-Rubio E. Translational research in clinical oncology: challenges and opportunities. Farm Hosp. 2010;34(Supl.1):1–7.Marincola FM. Translational medicine: a two-way road. J Transl Med. 2003;1(1):1.Ablin RJ, Marincola FM, Natali PG. The “excellence in translational medicine” and “bedside-to-bench” awards 2008–09. J Transl Med. 2010;13(8):95.García-Sáenz JA, Bueno C, SanPedro T, Díaz-Rubio E. La nueva oncología médica: aportación de la biología molecular al diagnóstico y tratamiento del cáncer. In: Díaz-Rubio E, editor. Tomo IV. Madrid: You and Us; 2006. p. 1–24.ORDEN SCO/709/2002, Boletín Oficial del Estado, 3 de abril de 2003, núm. 80, pp. 12742–12746. http://www.boe.es/boe/dias/2002/04/03/pdfs/A12742-12746.pdf . Accessed 30 sept 2013.Soto-Martínez JL, Baselga-Torres J, Carrato-Mena A. La investigación Translacional en Oncología Médica. En Primer Libro blanco de la Oncología Médica en España. Dosier 2006. Madrid: Editorial Dispublic SL; 2007. p. 177–99.Ministerio de Sanidad y Consumo. Agencia de Calidad del Sistema Nacional de Salud. Estrategia en Cáncer del Sistema Nacional de Salud. 2006. http://www.msc.es/organizacion/ sns/planCalidadSNS/docs/estratCancerSNS.pdf. Accessed 30 sept 2013.Lenfant C. Shattuck lecture–clinical research to clinical practice-lost in translation? N Engl J Med. 2003;349(9):868–74.Laurence J. Translating translational research. Transl Res. 2006;148(1):1–3.Lemieux-Charles L, McGuire WL. What do we know about health care team effectiveness? A review of the literature. Med Care Res Rev. 2006;63(3):263–300.Oandasan I, Baker RG, Barker K, Bosco C, D’Amour D, Jones L, et al. Teamwork in health care: promoting effective teamwork in healthcare in Canada; policy synthesis and recommendations. June 2006. http://www.chsrf.ca/Migrated/PDF/teamwork-synthesis-report_e.pdf . Accessed 30 Sep 2013.Mankoff SP, Brander C, Ferrone S, Marincola FM. Lost in Translation: obstacles to translational medicine. J Transl Med. 2004;2(1):14.Curran T. Lost in translation: the future of cancer research? Clin Cancer Res. 2005;11(13):4644.Valladares Y. Memoria y actas del primer congreso de investigación sobre el cáncer en España. Madrid; 1983.Vicente J. Apuntes para una historia de la Oncología en España. Los orígenes. Oncología. 2000;23(7):310–7.Legido-Quigley H, Otero L, la Parra D, Alvarez-Dardet C, Martin-Moreno JM, McKee M. Will austerity cuts dismantle the Spanish healthcare system? BMJ. 2013;13(346):f2363

Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer (Scientific Reports, (2019), 9, 1, (2589), 10.1038/s41598-019-39291-2)

The original version of this Article contained an error in the spelling of the author P. Garcia-Alfonso, which was incorrectly given as P. Garcia. This error has now been corrected in the PDF and HTML versions of this Article

The hippo pathway transducers YAP1/TEAD induce acquired resistance to trastuzumab in HER2-Positive breast cancer

Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer, leading to improved overall survival. However, acquired resistance inevitably occurs. We aimed to identify, quantify, and assess the mechanisms of acquired resistance to trastuzumab. We established an acquired trastuzumab-resistant model in vitro from BT-474, a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples. YAP1 dephosphorylation and TEAD2 overexpression were detected as significant alterations in the Hippo pathway in trastuzumab-resistant breast cancer. Because of the emerging role of these proteins as mediators of normal growth and tumorigenesis, we assessed the exogenous modulation of their activity, either by in vitro gene silencing or by pharmacological inhibition of the YAP1/TEAD complexes, both in vitro and in vivo. Moreover, we identified increased signaling through the Hippo pathway in human samples after progression following trastuzumab treatment. Finally, YAP1/TAZ nuclear accumulation in malignant cells in HER2 breast tumor was significantly associated with worse progression-free and overall survival in metastatic HER2-positive breast-cancer patients. Our results suggest the involvement of Hippo signaling in acquired trastuzumab resistance in breast cancer. Additionally, we provide novel evidence for a potential breast-cancer treatment strategy based on dual targeting of HER2 and Hippo pathway effectors, which may improve the antitumor activity of trastuzumab and help overcome resistance