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Summary Tumor organoids have been proposed as a model system for precision medicine. The ability of tumor organoids to retain characteristics of the original tumor makes them unique for cancer research on an individual patient level. Hence, the idea to use tumor organoids for clinical decision making and optimize patient outcome is tempting. In vitro responses of tumor organoids to a wide array of drugs have been positively correlated to patient responses. However, substantial challenges remain and prospective studies with large cohorts are highly needed before implementation in clinical cancer care can be considered. Because of their personalized characteristics and the immediate link with patient data, tumor organoids also have great potential in preclinical research. Here, we provide a critical overview of both clinical and preclinical advances using tumor organoids.

Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.Whole-genome sequencing of metastatic biopsies longitudinally sampled during the course of anticancer treatment reveals that the actionable metastatic cancer genome remains relatively stable over time.

Owing to clinical success of immune-checkpoint blockade, immunotherapy is becoming a cornerstone of modern oncology, and immuno-oncology is at the forefront of basic cancer research. This commentary outlines future opportunities for immuno-oncology modeling.

Highlights • We evaluated the effect of the second-generation TRAIL receptor agonist APG-880 on radiation-induced cytotoxicity. • The combined effect was studied in short-term and long-term cytotoxicity assays in established CRC cell lines, and tumor organoids derived from colon cancer patients. • We observed a supra-additive effect on cytotoxicity when APG-880 and radiation were combined simultaneously, with combination indices around 0.7. • In long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5., Background For many cancer types, including colorectal carcinoma (CRC), combined modality treatments have shown to improve outcome, but are frequently associated with significant toxicity, illustrating the need for new therapeutic approaches. Based on preclinical data, TRAIL receptor agonists appeared to be promising agents for cancer therapy especially in combination with DNA damaging regimens. Here, we present the combination of the second-generation TRAIL receptor agonist APG-880 with radiation in a new and clinically relevant 3D model system. Methods To investigate the effect of APG-880 in combination with radiation we performed short-term cytotoxicity and long-term clonogenic survival assays in established CRC cell lines, and in tumor organoids derived from colon cancer patients. Results APG-880 is a potent inducer of apoptosis in CRC cell lines and in patient-derived CRC organoids. Furthermore, a supra-additive effect on cytotoxicity was found when APG-880 and radiation were combined simultaneously, with combination indices around 0.7. Lastly, in the long-term survival assays, we demonstrated a radiosensitizing effect of APG-880 with dose enhancement factors between 1.3 and 1.5. Conclusions In a new, clinically relevant CRC-organoid model system we demonstrated a more than additive combined effect between the second-generation TRAIL receptor agonist APG-880 and radiation.

Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic gene fusions, with fusion frequencies of 0.2%–3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the impact of the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare BRAF fusions containing various partner genes (AGAP3, DLG1, and TRIM24) with respect to cellular behavior, downstream signaling activation, and response to targeted therapies. We demonstrate that 5′ fusion partners mainly promote canonical oncogenic BRAF activity by replacing the auto-inhibitory N-terminal region. In addition, the 5′ partner of BRAF fusions influences their subcellular localization and intracellular signaling capacity, revealing distinct subsets of affected signaling pathways and altered gene expression. Presence of the different BRAF fusions resulted in varying sensitivities to combinatorial inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify patients with metastatic colorectal cancer to exclude from anti-EGFR–targeted treatment. Implications: Although intracellular signaling and sensitivity to targeted therapies of BRAF fusion genes are influenced by their 5′ fusion partner, we show that all investigated BRAF fusions confer resistance to clinically relevant EGFR inhibition.

After marketing authorisation, the development of a medicinal product often continues with studies investigating new therapeutic indications. Positive results can potentially lead to changes to the terms of the marketing authorisation, such as an extension of therapeutic indication(s). These studies can be initiated and sponsored by the marketing authorisation holder (MAH) or by others. When results from an investigator-initiated trial suggest that an authorised medicinal product is safe and effective for a new therapeutic indication, physicians may want to treat their patients with this medicinal product. In such a situation, it is desirable to extend the therapeutic indication(s) via the regulatory approval process, as this can facilitate patient access within the European Union. There may however be challenges when the MAH did not conduct the study and might not have access to the data. In this perspective, we focus on the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product based on results from investigator-initiated trials. We address: (1) the advantages of an extension of indication; (2) the regulatory requirements for a variation application; (3) investigator-initiated trials as a basis for regulatory approval; (4) the role of the MAH in extending the indication. With this article, we want to emphasize the importance of a collaborative approach and dialogue between stakeholders with the aim to facilitate access to effective medicinal products.

Purpose:To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type.Patients and Methods:Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model.Results:Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types.Conclusions:These data indicate that using PARPis is a promising treatment strategy for patients with non–BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.

Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer., The mutational landscape of metastatic cancer genomes is analysed in a large-scale, pan-cancer study of metastatic solid tumours that includes whole-genome sequencing of 2,520 tumour–normal tissue pairs.

Male breast cancer (MBC) is extremely rare and accounts for less than 1% of all breast malignancies. Therefore, clinical management of MBC is currently guided by research on the disease in females. In this study, DNA obtained from 45 formalin-fixed paraffin-embedded (FFPE) MBCs with and 90 MBCs (52 FFPE and 38 fresh-frozen) without matched normal tissues was subjected to massively parallel sequencing targeting all exons of 1943 cancer-related genes. The landscape of mutations and copy number alterations was compared to that of publicly available estrogen receptor (ER)-positive female breast cancers (smFBCs) and correlated to prognosis. From the 135 MBCs, 90% showed ductal histology, 96% were ER-positive, 66% were progesterone receptor (PR)-positive, and 2% HER2-positive, resulting in 50, 46 and 4% luminal A-like, luminal B-like and basal-like cases, respectively. Five patients had Klinefelter syndrome (4%) and 11% of patients harbored pathogenic BRCA2 germline mutations. The genomic landscape of MBC to some extent recapitulated that of smFBC, with recurrent PIK3CA (36%) and GATA3 (15%) somatic mutations, and with 40% of the most frequently amplified genes overlapping between both sexes. TP53 (3%) somatic mutations were significantly less frequent in MBC compared to smFBC, whereas somatic mutations in genes regulating chromatin function and homologous recombination deficiency-related signatures were more prevalent. MDM2 amplifications were frequent (13%), correlated with protein overexpression (P = 0.001) and predicted poor outcome (P = 0.007). In conclusion, despite similarities in the genomic landscape between MBC and smFBC, MBC is a molecularly unique and heterogeneous disease requiring its own clinical trials and treatment guidelines.

Background: In depth sequencing of primary breast cancer (BC) has identified a heterogeneous repertoire of disease drivers, evidence of clonal evolution and underlying mutational processes. As cancer evolves over time and under treatment pressure, whole genome sequencing (WGS) of metastatic BC (MBC) tissue is crucial to gain further insight into its genetic make-up and driving forces, thereby allowing improved patient management. Methods: Metastatic tissue and matched germline DNA of patients with MBC (N=501) were prospectively recruited under the biopsy protocol of the Center of Personalized Cancer Treatment (CPCT-02; NCT01855477) and analyzed by WGS. Sequence reads were mapped to the reference genome to call somatic single nucleotide variants (SNV), small insertions and deletions (InDels) and copy number variations from which mutational signatures and tumor mutational burden (TMB; the number of SNV and InDels relative to the genome) were derived. The incidence of called aberrations in our cohort was compared to previously reported WGS data of 560 primary BC (BASIS cohort, Nik-Zainal et al. Nature 2016) (Table 1). Results: According to routine diagnostics 303 patients (60.5%) were ER+/HER2-, 70 (14%) triple negative (TNBC), 95 (19%) HER2+ and the remaining 33 (6.6%) had as of yet an unknown subtype. Top 5 recurrently affected genes were TP53 (47%), ATM (33%), MAP2K4 (32%), NCOR1 (31%), ERBB2 (30%). In the metastatic lesions, median TMB was 2.9 per million base pairs (IQR: 1.7-5.3). Interestingly, 53 (11%) patients had a high TMB (≥10). Compared to primary BC (BASIS cohort), we found (subtype-specific) enrichment of alterations in multiple genes such as ATM (0.4% to 33%), GPS2 (1.3% to 29%), MAP2K4 (6.4% to 32%), CBFB (2.7% to 25%), and, as previously reported, ESR1 (1.3% to 20%). APOBEC signature mutations appeared to be enriched in MBC while HRD signature mutations seemed less prevalent. Analyses to reveal additional genomic features is ongoing as well as the association of genomic alterations with uniquely collected information on prior treatments and response to treatment received directly after biopsy (i.e. endocrine therapy alone or combined with CDK4/6 inhibitors and chemotherapy). Also, to exclude methodological bias the raw data of the BASIS cohort will be processed through our pipeline. Table 1:Comparison of ER+/HER2- and TNBC subtypes: BASIS versus CPCT-02 MBC BASISCPCT-02 MBC ER+/HER2-(%)TNBC(%)ER+/HER2-(%)TNBC(%)Number of samples32615530370Median TMB0.962.632.732.91SNV burden/Mbp0.892.52.412.64InDel burden/Mbp0.060.120.210.3Top 5 affected genesPIK3CA (37)TP53 (83)TP53 (43)TP53 (61) TP53 (20)PTEN (37)ATM (43)MYC (37) CCND1 (20)MYC (26)MAP2K4 (37)CDKN2A (33) GATA3 (15)RB1 (24)NCOR1 (35)CDKN2B (33) MYC (14)PIK3CA (17)CDH1 (34)RB1 (33)Mutational signatures (median relative contribution) Age23.27.213.711.8APOBEC6.97.814.68.3Homologous-recombinant deficiency4.439.94.919.8DNA mismatch Repair Deficiency0.600.30 Conclusion: WGS of this unique cohort of patients with MBC shows a genetic make-up roughly similar to primary BC, but does show subtype-specific enrichment of selected driver mutations in metastatic disease. This study provides better insight into the tumor biology of MBC potentially improving management of these patients. Citation Format: Angus L, Wilting SM, van Riet J, Smid M, Steenbruggen TG, Tjan-Heijnen VC, Labots M, van Riel JM, Bloemendal HJ, Steeghs N, van de Werken HJ, Lolkema MP, Voest EE, Jager A, Cuppen E, Sleijfer S, Martens JW. The genomic landscape of 501 metastatic breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS1-07.

Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer—two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire. Intratumoral T cells that are capable of recognizing adjacent tumor tissue antigens can be exceedingly rare.

Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a poorly understood disease with limited treatment options. A better understanding of this disease would greatly benefit from the availability of representative preclinical models. Here, we present the potential of tumor organoids, three-dimensional cultures of tumor cells, to model GEP-NEC. We established three GEP-NEC organoid lines, originating from the stomach and colon, and characterized them using DNA sequencing and immunohistochemistry. Organoids largely resembled the original tumor in expression of synaptophysin, chromogranin and Ki-67. Models derived from tumors containing both neuroendocrine and non-neuroendocrine components were at risk of overgrowth by non-neuroendocrine tumor cells. Organoids were derived from patients treated with cisplatin and everolimus and for the three patients studied, organoid chemosensitivity paralleled clinical response. We demonstrate the feasibility of establishing NEC organoid lines and their potential applications. Organoid culture has the potential to greatly extend the repertoire of preclinical models for GEP-NEC, supporting drug development for this difficult-to-treat tumor type.

Background Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling. Materials and methods The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of ≥20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro. Results Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment. Conclusions Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies., Highlights • The first prospective clinical trial that leverages tumor organoids to guide experimental treatment decisions. • Clinical implementation of tumor-organoid-guided treatment is challenging. • Patients that received organoid-informed treatment did not experience clinical benefit. • Organoid drug screening can distinguish differential drug responses in identical genetic genotypes.

Background ‘Precision oncology’ can ensure the best suitable treatment at the right time by tailoring treatment towards individual patient and comprehensive tumour characteristics. In current molecular pathology, diagnostic tests which are part of the standard of care (SOC) only cover a limited part of the spectrum of genomic changes, and often are performed in an iterative way. This occurs at the expense of valuable patient time, available tissue sample, and interferes with ‘first time right’ treatment decisions. Whole Genome Sequencing (WGS) captures a near complete view of genomic characteristics of a tumour in a single test. Moreover, WGS facilitates faster implementation of new treatment relevant biomarkers. At present, WGS mainly has been applied in study settings, but its performance in a routine diagnostic setting remains to be evaluated. The WIDE study aims to investigate the feasibility and validity of WGS-based diagnostics in clinical practice. Methods 1200 consecutive patients in a single comprehensive cancer centre with (suspicion of) a metastasized solid tumour will be enrolled with the intention to analyse tumour tissue with WGS, in parallel to SOC diagnostics. Primary endpoints are (1) feasibility of implementation of WGS-based diagnostics into routine clinical care and (2) clinical validation of WGS by comparing identification of treatment-relevant variants between WGS and SOC molecular diagnostics. Secondary endpoints entail (1) added clinical value in terms of additional treatment options and (2) cost-effectiveness of WGS compared to SOC diagnostics through a Health Technology Assessment (HTA) analysis. Furthermore, the (3) perceived impact of WGS-based diagnostics on clinical decision making will be evaluated through questionnaires. The number of patients included in (experimental) therapies initiated based on SOC or WGS diagnostics will be reported with at least 3 months follow-up. The clinical efficacy is beyond the scope of WIDE. Key performance indicators will be evaluated after every 200 patients enrolled, and procedures optimized accordingly, to continuously improve the diagnostic performance of WGS in a routine clinical setting. Discussion WIDE will yield the optimal conditions under which WGS can be implemented in a routine molecular diagnostics setting and establish the position of WGS compared to SOC diagnostics in routine clinical care.

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibidor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibidor therapy., This work was supported by a grant from the Dutch Cancer Society through the Oncode Institute. Al.V. was supported by the Fondo de Investigaciones Sanitarias, FIS (PI16-01898, and by the Spanish Association Against Cancer, AECC (CGB14142035THOM) and Ideas Semilla project (IDEAS098VILL-IDEAS16) and Generalitat de Catalunya (2014SGR364). L.F. received a European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie, grant agreement number 799850. E.N. was funded by Instituto Carlos III through the project PI18/00920. We thank CERCA Program/Generalitat de Catalunya for their institutional support and grant 2017SGR448.

Summary: Clinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >70 non-small cell lung cancer (NSCLC) samples. We systematically evaluate several methods to identify tumor purity of organoids established from intrapulmonary tumors. Eighty percent of organoids from intrapulmonary lesions have a normal copy number profile, suggesting overgrowth by normal airway organoids (AOs). This is further supported by the failure to detect mutations found in the original tumor in organoids. Histomorphology alone is insufficient to determine tumor purity, but when combined with p63 immunostaining, tumor and normal AOs can be distinguished. Taking into account overgrowth by normal AOs, the establishment rate of pure NSCLC organoids is 17%. Therefore, current methods are insufficient to establish pure NSCLC organoids from intrapulmonary lesions. We discourage their use unless steps are taken to prevent overgrowth by normal AOs.

Background In precision medicine, somatic and germline DNA sequencing are essential to make genome-guided treatment decisions in patients with cancer. However, it can also uncover unsolicited findings (UFs) in germline DNA that could have a substantial impact on the lives of patients and their relatives. It is therefore critical to understand the preferences of patients with cancer concerning UFs derived from whole-exome (WES) or whole-genome sequencing (WGS). Methods In a quantitative multicentre study, adult patients with cancer (any stage and origin of disease) were surveyed through a digital questionnaire based on previous semi-structured interviews. Background knowledge was provided by showing two videos, introducing basic concepts of genetics and general information about different categories of UFs (actionable, non-actionable, reproductive significance, unknown significance). Results In total 1072 patients were included of whom 701 participants completed the whole questionnaire. Overall, 686 (85.1%) participants wanted to be informed about UFs in general. After introduction of four UFs categories, 113 participants (14.8%) changed their answer: 718 (94.2%) participants opted for actionable variants, 537 (72.4%) for non-actionable variants, 635 (87.0%) participants for UFs of reproductive significance and 521 (71.8%) for UFs of unknown significance. Men were more interested in receiving certain UFs than women: non-actionable: OR 3.32; 95%CI 2.05 to 5.37, reproductive significance: OR 1.97; 95%CI 1.05 to 3.67 and unknown significance: OR 2.00; 95%CI 1.25 to 3.21. In total, 244 (33%) participants conceded family members to have access to their UFs while still alive. 603 (82%) participants agreed to information being shared with relatives, after they would pass away. Conclusion Our study showed that the vast majority of patients with cancer desires to receive all UFs of genome testing, although a substantial minority does not wish to receive non-actionable findings. Incorporation of categories in informed consent procedures supports patients in making informed decisions on UFs

This is a prospective, non-randomized clinical trial that aims to describe the efficacy and toxicity of commercially available, targeted anticancer drugs* prescribed for treatment of patients with advanced cancer with a potentially actionable variant as revealed by a genomic or protein expression test. The study also aims to simplify patient access to approved targeted therapies that are contributed to the program by collaborating pharmaceutical companies and to perform next generation sequencing on tumor biopsies for biomarker analyses. Eligible patients have an advanced solid tumor, multiple myeloma or non-Hodgkin lymphoma for which standard treatment options are no longer available and acceptable performance status and organ function. A genomic or protein expression test must have been performed on the tumor and the results must identify at least one potentially actionable molecular variant as defined in the protocol. Results from the molecular profiling test will be used to determine an appropriate drug(s) from among those available in the protocol. The choice of drug will be supported by a list of potential profiles, a molecular tumor board, a knowledge library and by study coordinators for review and approval of the match. The protocol-specified treatment will be administered to the patient once any drug-specific eligibility criteria are confirmed and a fresh pre-treatment biopsy is performed for future biomarker studies. All patients who receive treatment with a drug available in the protocol will be followed for standard efficacy outcomes including tumor response, progression-free and overall survival as well as duration of treatment. In addition, treatment related toxicity will be evaluated.

Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK–a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A comprehensive cancer approach covering the entire research–care–prevention continuum can achieve a 10‐year cancer‐specific survival for 75% of patients diagnosed in EU member states with well‐developed health care by 2030. To ensure access to a critical mass of patient biological and technological resources, infrastructures for translational research, clinical and prevention trials, and outcomes research are needed. Here, we provide recommendations for achieving key targets and prioritize research areas., A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research–care–prevention continuum has the potential to achieve in 2030 a 10‐year cancer‐specific survival for 75% of patients diagnosed in European Union (EU) member states with a well‐developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high‐quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science‐driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC‐like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long‐term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans‐border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence‐based advice.

Purpose Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The Targeted Agent and Profiling Utilization Registry (TAPUR) study, a phase II prospective, nonrandomized, multibasket pragmatic clinical trial, aims to identify signals of drug activity when US Food and Drug Administration–approved drugs are matched to prespecified genomic targets in patients with advanced cancer, outside of approved indications. Methods Patients eligible to participate in TAPUR are age ≥ 12 years and have advanced measurable or evaluable solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma. Eligible participants are matched to any of the 16 US Food and Drug Administration–approved study drugs based on protocol-specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration, and drug. The primary study end point within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary end points include safety, progression-free survival, and overall survival. Results More than 1,000 participants have thus far been registered, and more than 800 have been treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment because of lack of antitumor activity, and 12 have expanded to the second stage of enrollment after promising preliminary activity. Conclusion The TAPUR study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant.

As many biosimilars come to market in the next several years, their use in oncology will play an important role in the future care of patients with cancer. ASCO is committed to providing education and guidance to the oncology community on the use of biosimilars in the cancer setting; therefore, ASCO has developed this statement to offer guidance in the following areas: (1) naming, labeling, and other regulatory considerations, (2) safety and efficacy of biosimilars, (3) interchangeability, switching, and substitution, (4) value of biosimilars, and (5) prescriber and patient education.

Objective: Next-generation sequencing (NGS) is increasingly being employed in the context of personalized cancer treatment. Anticipating unsolicited findings that may arise during a NGS procedure is a key consideration; however, little is known about cancer patients' intentions, needs, and preferences concerning the return of unsolicited findings. Methods: A qualitative design using individual semi-structured interviews with 24 cancer patients was utilized to explore patients' decisions on whether to receive unsolicited findings from NGS. These interviews were subsequently analyzed using the constant comparative method to develop codes and themes. Results: We identified 4 interrelated themes that emerged in the context of the return of unsolicited findings. First, we describe how cancer patients expressed a strong need to control their lives. Second, we show the importance of family dynamics. Third, the NGS procedure regarding unsolicited findings is perceived as cognitively complex, and fourth, the procedure is also considered emotionally complex. Conclusions: The results of our study contribute to a better understanding of what cancer patients consider important and what may motivate and influence them when making decisions on the disclosure of unsolicited findings following NGS. We show how Joel Feinberg's classification of autonomy may help clinicians to better understand cancer patients' desire for autonomous decision making while also acknowledging the emotional and cognitive difficulties regarding the disclosure of unsolicited findings. These insights could be helpful for clinicians to guide patients through this complex process.

Introduction At the clinical introduction of antiangiogenic agents as anticancer agents, no major toxicities were expected as merely just endothelial cells (ECs) in tumors would be affected. However, several (serious) toxicities became apparent, of which underlying mechanisms are largely unknown. We investigated to what extent sunitinib (multitargeted antiangiogenic tyrosine kinase inhibitor (TKI)), sorafenib (TKI) and bevacizumab [specific antibody against vascular endothelial growth factor (VEGF)] may impair platelet function, which might explain treatment-related bleedings. Materials and methods In vitro, the influence of sunitinib, sorafenib, and bevacizumab on platelet aggregation, P-selectin expression and fibrinogen binding, platelet–EC interaction, and tyrosine phosphorylation of c-Src was studied by optical aggregation, flow cytometry, real-time perfusion, and western blotting. Ex vivo, platelet aggregation was analyzed in 25 patients upon sunitinib or bevacizumab treatment. Concentrations of sunitinib, VEGF, and platelet and EC activation markers were measured by LC–MS/MS and ELISA. Results In vitro, sunitinib and sorafenib significantly inhibited platelet aggregation (20 μM sunitinib: 71.3%, p

Background: von Hippel-Lindau (VHL) disease is characterized by the development of benign and malignant tumours in many organ systems, including renal cysts and clear cell renal cell carcinoma. It is not completely understood what underlies the development of renal pathology, and the use of murine Vhl models has been challenging due to limitations in disease conservation. We previously described a zebrafish model bearing inactivating mutations in the orthologue of the human VHL gene. Methods: We used histopathological and functional assays to investigate the pronephric and glomerular developmental defects in vhl mutant zebrafish, supported by human cell culture assays. Results: Here, we report that vhl is required to maintain pronephric tubule and glomerulus integrity in zebrafish embryos. vhl mutant glomeruli are enlarged, cxcr4a+ capillary loops are dilated and the Bowman space is widened. While we did not observe pronephric cysts, the cells of the proximal convoluted and anterior proximal straight tubule are enlarged, periodic acid schiff (PAS) and Oil Red O positive, and display a clear cytoplasm after hematoxylin and eosine staining. Ultrastructural analysis showed the vhl–/– tubule to accumulate large numbers of vesicles of variable size and electron density. Microinjection of the endocytic fluorescent marker AM1–43 in zebrafish embryos revealed an accumulation of endocytic vesicles in the vhl mutant pronephric tubule, which we can recapitulate in human cells lacking VHL. Conclusions: Our data indicates that vhl is required to maintain pronephric tubule and glomerulus integrity during zebrafish development, and suggests a role for VHL in endocytic vesicle trafficking.

Contains fulltext : 207194.pdf (Publisher’s version ) (Open Access) Advances in molecular tumour diagnostics and the number of targeted therapies increase rapidly. Molecular tumour boards (MTBs) are designated to interpret these data and provide clinical recommendations. Not all patients with cancer have access to advice of an MTB. We aimed to determine the current status, opportunities, and challenges of the organisation of MTBs in the Netherlands. We interviewed several stakeholders about their experiences with an MTB, using template analysis. Most clinicians and patient representatives underscore the significance of an MTB, because it can stimulate rational treatment options, enrolment in clinical trials, and interdisciplinary knowledge transfer. Health insurance companies and financial managers are concerned about increasing costs. Registries to assess the clinical benefit of MTBs, guidelines on quality control, financial agreements, and logistical resources are lacking. The national organisation of MTBs and a registry of molecular and clinical data are important issues to address.

Genomic rearrangements that give rise to oncogenic gene fusions can offer actionable targets for cancer therapy. Here we present a systematic analysis of oncogenic gene fusions among a clinically well-characterized, prospectively collected set of 278 primary colon cancers spanning diverse tumor stages and clinical outcomes. Gene fusions and somatic genetic variations were identified in fresh frozen clinical specimens by Illumina RNA-sequencing, the STAR fusion gene detection pipeline, and GATK RNA-seq variant calling. We considered gene fusions to be pathogenically relevant when recurrent, producing divergent gene expression (outlier analysis), or as functionally important (e.g., kinase fusions). Overall, 2.5% of all specimens were defined as harboring a relevant gene fusion (kinase fusions 1.8%). Novel configurations of BRAF, NTRK3, and RET gene fusions resulting from chromosomal translocations were identified. An R-spondin fusion was found in only one tumor (0.35%), much less than an earlier reported frequency of 10% in colorectal cancers. We also found a novel fusion involving USP9X-ERAS formed by chromothripsis and leading to high expression of ERAS, a constitutively active RAS protein normally expressed only in embryonic stem cells. This USP9X–ERAS fusion appeared highly oncogenic on the basis of its ability to activate AKT signaling. Oncogenic fusions were identified only in lymph node–negative tumors that lacked BRAF or KRAS mutations. In summary, we identified several novel oncogenic gene fusions in colorectal cancer that may drive malignant development and offer new targets for personalized therapy. Cancer Res; 77(14); 3814–22. ©2017 AACR.

Background: While next generation sequencing has enhanced our understanding of the biological basis of malignancy, current knowledge on global practices for sequencing cancer samples is limited. To address this deficiency, we developed a survey to provide a snapshot of current sequencing activities globally, identify barriers to data sharing and use this information to develop sustainable solutions for the cancer research community.Methods: A multi-item survey was conducted assessing demographics, clinical data collection, genomic platforms, privacy/ethics concerns, funding sources and data sharing barriers for sequencing initiatives globally. Additionally, respondents were asked as to provide the primary intent of their initiative (clinical diagnostic, research or combination).Results: Of 107 initiatives invited to participate, 59 responded (response rate = 55%). Whole exome sequencing (P = 0.03) and whole genome sequencing (P = 0.01) were utilized less frequently in clinical diagnostic than in research initiatives. Procedures to identify cancer-specific variants were heterogeneous, with bioinformatics pipelines employing different mutation calling/variant annotation algorithms. Measurement of treatment efficacy varied amongst initiatives, with time on treatment (57%) and RECIST (53%) being the most common; however, other parameters were also employed. Whilst 72% of initiatives indicated data sharing, its scope varied, with a number of restrictions in place (e.g. transfer of raw data). The largest perceived barriers to data harmonization were the lack of financial support (P Conclusions: These results identify the main barriers, as perceived by the cancer sequencing community, to effective sharing of cancer genomic and clinical data. They highlight the need for greater harmonization of technical, ethical and data capture processes in cancer sample sequencing worldwide, in order to support effective and responsible data sharing for the benefit of patients.

Importance To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma. Objective To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib. Design, Setting, and Participants This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year. Interventions First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm). Main Outcome and Measures The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life. Results A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) ( P = .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed. Conclusions and Relevance Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma. Trial Registration clinicaltrials.gov Identifier:NCT01408004

Background The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS) but also for making other emerging systematic techniques such as proteomics and metabolomics possible. Here, we describe the first 469 image-guided biopsies collected in a large collaboration in The Netherlands (Center for Personalized Cancer Treatment) and show the utility of these specimens for NGS analysis. Patients and Methods Image-guided tumor biopsies were performed in advanced cancer patients. Samples were fresh frozen, vital tumor cellularity was estimated, and DNA was isolated after macrodissection of tumor-rich areas. Safety of the image-guided biopsy procedures was assessed by reporting of serious adverse events within 14 days after the biopsy procedure. Results Biopsy procedures were generally well tolerated. Major complications occurred in 2.1%, most frequently consisting of pain. In 7.3% of the percutaneous lung biopsies, pneumothorax requiring drainage occurred. The majority of samples (81%) contained a vital tumor percentage of at least 30%, from which at least 500 ng DNA could be isolated in 91%. Given our preset criteria, 74% of samples were of sufficient quality for biomarker discovery. The NGS results in this cohort were in line with those in other groups. Conclusion Image-guided biopsy procedures for biomarker discovery to enable personalized cancer treatment are safe and feasible and yield a highly valuable biobank.

Background: Due to rapid technical advances, steeply declining sequencing costs, and the ever-increasing number of targeted therapies, it can be expected that extensive tumor sequencing such as whole-exome and whole-genome sequencing will soon be applied in standard care. Clinicians will thus be confronted with increasingly complex genetic information and multiple test-platforms to choose from. General medical training, meanwhile, can hardly keep up with the pace of innovation. Consequently, there is a rapidly growing gap between clinical knowledge and genetic potential in cancer care. Multidisciplinary Molecular Tumor Boards (MTBs) have been suggested as a means to address this disparity, but shared experiences are scarce in literature and no quality requirements or guidelines have been published to date.Methods: Based on literature review, a survey among hospitals in The Netherlands, and our own experience with the establishment of a nationally operating MTB, this article evaluates current knowledge and unmet needs and lays out a strategy for successful MTB implementation.Results: Having access to an MTB can improve and increase the application of genetics-guided cancer care. In our survey, however, Conclusions: This article acknowledges a leading role for MTBs to govern (extensive) tumor sequencing into daily practice and proposes three basic necessities for successful MTB implementation: (i) global harmonization in cancer sequencing practices and procedures, (ii) minimal member and operational requirements, and (iii) an appropriate unsolicited findings policy. Meeting these prerequisites would not only optimize MTB functioning but also improve general interpretation and application of genomics-guided cancer care.

Bevacizumab is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF). Recurrence after resection of colorectal liver metastases (CRLMs), presumably caused by VEGF-mediated outgrowth of micrometastases, might decrease when VEGF is inhibited. This study examines the efficacy and safety of adding bevacizumab to an adjuvant regimen of CAPOX in patients undergoing radical resection for their CRLMs. Patients with resected CRLMs were randomized after surgery to receive CAPOX and bevacizumab (arm A) or CAPOX alone (arm B) as adjuvant treatment. CAPOX was given in both arms for a total of eight cycles. Bevacizumab was administered for 16 cycles. The primary end point was disease-free survival (DFS). Secondary outcomes were overall survival (OS), toxicity, and quality of life (QoL). In total, 79 patients were randomized. At the time of analysis, 23 events were encountered in arm A and 20 in arm B. One-year DFS rate was 79% [95% confidence interval (CI): 68%-93%] and 68% (95% CI: 55%-85%) for arm A and B, respectively ( P =.89). Toxicity was evaluated for 75 patients. No significant differences in toxicity between the two arms were found. QoL scores were higher in arm A, of which emotional functioning and global QoL scores were significant. Adding bevacizumab to a CAPOX regimen in patients undergoing a resection for their CLM is safe and showed higher QoL scores compared with CAPOX alone. Because of premature closure of the study, conclusions about the effect on DFS of additional VEGF inhibition in this setting could not yet be made.

T cells are a key player in cancer immunotherapy, but strategies to expand tumor-reactive cells and study their interaction with tumor cells at the level of an individual patient are limited. This protocol describes the generation and functional assessment of tumor-reactive T cells based on co-cultures of tumor organoids and autologous peripheral blood lymphocytes. The procedure consists of an initial co-culture of two weeks in which tumor-reactive T cells are first expanded in the presence of (IFNγ-stimulated) autologous tumor cells. Subsequently, T cells may be evaluated for their capacity to carry out effector functions (IFNγ secretion, degranulation) upon recognition of tumor cells, and their capacity to kill tumor organoids. This strategy is unique in its use of peripheral blood as a source of tumor-reactive T cells in an antigen-agnostic manner. In two weeks, tumor-reactive CD8(+) T cell populations can be obtained for ~33-50% of non-small cell lung cancer (NSCLC) and microsatellite instable (MSI) colorectal cancer (CRC) patient samples. It thereby allows the establishment of ex vivo test systems for T cell-based immunotherapy at the level of the individual patient.

Targeted cancer drugs often elicit powerful initial responses, but generally fail to deliver long-term benefit due to the emergence of resistant cells1,2. This is thought to be the consequence of strong selective pressure exerted on the cancer drug target by a Maximum Tolerated Dose (MTD) of a drug3–5. We hypothesized that partial inhibition of multiple components in the same oncogenic signalling pathway might add up to complete pathway inhibition, while at the same time decreasing the selective pressure on each individual component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) model of drug administration in Epidermal Growth Factor Receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We show that as little as 20% of the individual drug doses required for full inhibition of cell viability is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF+MEK+ERK inhibitors) or 4D (EGFR+RAF+MEK+ERK inhibitors) combinations. Importantly,EGFRmutant NSCLC cells treated with EGFR inhibitors at a high dose rapidly developed resistance in vitro, but the cells treated with 3D or 4D MLD therapy did not. Moreover, NSCLC cells that had gained resistance to high dose anti-EGFR therapies were still sensitive to MLD therapy. Using several animal models, including patient derived xenografts of NSCLC tumours that are resistant to EGFR inhibitors erlotinib and osimertinib6,7, we found durable responses to MLD therapy without associated toxicity. These data support the notion that partial inhibition of multiple components of cancer-activated signalling pathways is difficult to circumvent and suggest that MLD therapy could deliver clinical benefit. We propose that MLD strategy could be an effective treatment option for EGFR mutant NSCLC patients, especially those having acquired resistance to even third generation EGFR inhibitor therapy.

There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy.

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data. Results from the NICHE study show remarkable pathological responses to neoadjuvant combination immunotherapy in patients with early-stage colon cancer and uncover potential biomarkers of response.

Contains fulltext : 207396.pdf (Publisher’s version ) (Open Access)

Nine per cent of patients with metastatic cancer harbour genomic alterations that are recognised as biomarkers for optimal treatment selection in current standard of care. An additional 27% carries genomic aberrations for which compelling clinical evidence exists supporting the use of these alterations as predictive biomarkers for drug response outside the registered indication.1 As novel molecular and genomic treatment indications are explored in rapid pace, the generation and correct interpretation of molecular tumour profiles are quickly becoming a necessity for offering optimal cancer treatment. The complexity and vast amounts of data generated through molecular profiling techniques, like next-generation sequencing, make expert review an absolute requirement in order to translate molecular profiles into clinical benefit for our patients. Leading cancer care providers are currently trying to address this by developing the so called ‘molecular tumour boards’ (MTBs), which comprise experts of various disciplines who help clinicians to interpret the molecular profiles of their patients. This is a challenging task and many uncertainties about the optimal implementation of these boards remain. Among different institutions, implementations can differ on various grounds: technically (eg, the used sequencing techniques, bioinformatics pipelines), composition wise (eg, which types of specialists are involved) or organisationally (eg, centralised vs localised). Recently, Moore and colleagues share how they implemented an MTB in the UK: the Sarah Cannon Research Institute (SRCI) UK/UCL Genomics Review Board (GRB). The paper describes the molecular profiling results, given recommendations and clinical trial enrolment of 895 patients reviewed by the GRB. In addition to these prospective data, the authors share the challenges encountered during the establishment of the GRB. A multidisciplinary team comprising physicians, a molecular oncologist, …

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

Here we present whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 castration-resistant prostate cancer patients. Using hierarchical unsupervised clustering based on genomic aberrations only, we defined eight different clusters. We detected four distinct and potentially clinically relevant genotypes harboring unique genomic features, including: 1) Microsatellite Instability; 2) Homologous Recombination Deficiency (HRD) with enriched genomic deletions and BRCA2 aberrations; 3) tandem duplication phenotype associated with biallelic CDK12 mutations; and 4) a subgroup enriched for chromothripsis events. Our data suggest that classifying patients using WGS characteristics may improve classification of HRD patients. Moreover, we confirmed that important regulators of AR-mediated signaling are located in non-coding regions. Using ChIP sequencing data, we showed that the amplified AR and MYC promoter regions contain open chromatin and bind AR, suggesting a role in AR mediated biology. Thus, high-resolution WGS may be used to improve patient stratification.

Alliance; Cancer research; Infrastructure Aliança; Recerca oncològica; Infraestructura Alianza; Investigación oncológica; Infraestructura Cancer Core Europe is a European legal alliance consisting of seven leading cancer centres - most of them Comprehensive Cancer Centres (CCCs) - with a single portal system to engage in various research projects with partners. Cancer Core Europe was established to create a sustainable, high-level, shared research infrastructure platform hosting research collaborations and task forces (data sharing, clinical trials, genomics, immunotherapy, imaging, education and training, and legal and ethical issues), with a controlled expansion agenda. Translational cancer research covers the cancer research continuum from basic to preclinical to early clinical, late clinical, and outcomes research. Basic-preclinical research serves as the 'engine' for early clinical research by bridging the early translational research gap and is the primary and current focus of the consortium as exemplified by the launching of the Basket of Baskets trial, Europe's largest precision cancer medicine trial. Inspired by the creation of Cancer Core Europe, the prevention community established Cancer Prevention Europe, a consortium of ten cancer prevention centres aimed at supporting the complete prevention research continuum. Presently, Cancer Core Europe and Cancer Prevention Europe are integrating therapeutics and prevention strategies to address in partnership the widening cancer problem. By providing innovative approaches for cancer research, links to healthcare systems, development of quality-assured multidisciplinary cancer care, and assessment of long-term outcomes, the virtual infrastructure will serve as a hub to connect and interact with other centres across Europe and beyond. Together, Cancer Core Europe and Cancer Prevention Europe are prepared to function as a central engine to tackle, in collaboration with various partners, a potential 'mission on cancer' addressing the cancer burden.

Metastatic castration-resistant prostate cancer (mCRPC) has a highly complex genomic landscape. With the recent development of novel treatments, accurate stratification strategies are needed. Here we present the whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 mCRPC patients. Using unsupervised clustering based on genomic features, we define eight distinct genomic clusters. We observe potentially clinically relevant genotypes, including microsatellite instability (MSI), homologous recombination deficiency (HRD) enriched with genomic deletions and BRCA2 aberrations, a tandem duplication genotype associated with CDK12−/− and a chromothripsis-enriched subgroup. Our data suggests that stratification on WGS characteristics may improve identification of MSI, CDK12−/− and HRD patients. From WGS and ChIP-seq data, we show the potential relevance of recurrent alterations in non-coding regions identified with WGS and highlight the central role of AR signaling in tumor progression. These data underline the potential value of using WGS to accurately stratify mCRPC patients into clinically actionable subgroups., Detecting genomic abnormalities in metastatic castration-resistant prostate cancer (mCRPC) may impact clinical treatment. Here, the authors present whole-genome sequencing of metastatic biopsies from 197 mCRPC patients, highlighting the landscape of microsatellite stability, homologous repair deficiency, and other genomic subgroups.

Contains fulltext : 215543.pdf (Publisher’s version ) (Closed access) The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.