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  • The genomic landscape of unsuspected, incidentally detected Gleason 7 prostate cancer found on autopsy

    Foucal, A.; Livingstone, J.; Salcedo, A.; Kuk, C.; Fraser, M.; Pushkar, D.; Govorov, A.; Kovylina, M.; Bristow, Robert G; Fleshner, N. E.; et al. (2021)
    Introduction & Objectives: Changes in our way of thinking in medicine are sometimes driven by observations in a small number of patients. For instance, when whole-genome sequencing used to track the lethal cell clone in a single patient who died of prostate cancer (PCa), surprisingly, revealed that it arose from a small, low-grade PCa focus. The genomic landscape of unsuspected, incidentally detected PCa on autopsy in men never found with the disease during their lifetime is virtually unknown. Intriguingly, while the field has anticipated that most autopsy-detected PCa are of low tumor volume and low Gleason score (GS), we and others have shown that nearly 25% of unsuspected autopsy detected PCa in Caucasian men were GS≥7. Materials & Methods: We used prostate glands prospectively collected during autopsy from Caucasian men, deceased with no known history of PCa, accrued by the University of Moscow, Russia and analyzed in Toronto, Canada. We limited the scope of our study to unifocal GS7 tumors with good DNA quantity and quality. DNA was isolated from the autopsy-detected tumors using QIAamp DNA Mini Kit (Hilden, Germany). To profile genome-wide copy number aberrations (CNAs), we used the OncoScan® FFPE Express v3 platform, optimized for highly degraded samples. BioDiscovery Nexus Express TM for OncoScan 3 was used to call CNAs using the SNP-FASST2 algorithm. We compared autopsy CNA data to intermediate-risk prostate cancer cases from the Canadian Prostate Cancer Genome Network (CPC-GENE project), all of whom underwent radiotherapy or radical prostatectomy for localized, non-indolent GS6-7 disease. Results: Three autopsy incidentally detected tumors were analyzed (ages 63, 70, 80) and compared to 300 surgical and biopsy-specimens from CPC-GENE. Driver gene hits were common in autopsy specimens: deletions in TP53 were observed in all three, BRCA2 in two and RB1 loss in two. A TMPRSS2:ERG fusion, caused by a deletion of chr21:39988436-42859011, was observed in one sample. Two of the three autopsy samples were indistinguishable from the diagnosed tumors in the CPC-GENE set. A limitation of this study is that although the three GS 7 were found incidentally on autopsy, they were not necessarily indolent: These men could have died of something else before their PCa became diagnosed. Conclusions: To our surprise, this study has shown, to the best of our knowledge, for the first time that unsuspected PCa GS7 detected incidentally on autopsy is genomically indistinguishable from clinically detected tumors. Autopsy studies have revealed the presence of a large reservoir of PCa, including GS7, which exist in the population and do not cause clinical symptoms or death. Most GS7 tumors found on autopsy in this study, intriguingly displayed mutations usually observed in more aggressive forms of the disease. This may suggest that other factors such as epigenetics could play an important role.
  • Tumor heterogeneity

    Pe'er, D.; Ogawa, S.; Elhanani, O.; Keren, L.; Oliver, T. G; Wedge, David C; Not available (2021)
    Tumor heterogeneity was traditionally considered in the genetic terms, but it has now been broadened into many more facets. These facets represent a challenge in our understanding of cancer etiology but also provide opportunity for us to understand prognosis and therapy response.
  • Epidemiology of anal human papillomavirus infection and high-grade squamous intraepithelial lesions in 29 900 men according to HIV status, sexuality, and age: a collaborative pooled analysis of 64 studies

    Wei, F.; Gaisa, M. M.; D'Souza, G.; Xia, N.; Giuliano, A. R.; Hawes, S. E.; Gao, L.; Cheng, S. H.; Donà, M. G.; Goldstone, S. E.; et al. (2021)
    Background: Robust age-specific estimates of anal human papillomavirus (HPV) and high-grade squamous intraepithelial lesions (HSIL) in men can inform anal cancer prevention efforts. We aimed to evaluate the age-specific prevalence of anal HPV, HSIL, and their combination, in men, stratified by HIV status and sexuality. Methods: We did a systematic review for studies on anal HPV infection in men and a pooled analysis of individual-level data from eligible studies across four groups: HIV-positive men who have sex with men (MSM), HIV-negative MSM, HIV-positive men who have sex with women (MSW), and HIV-negative MSW. Studies were required to inform on type-specific HPV infection (at least HPV16), detected by use of a PCR-based test from anal swabs, HIV status, sexuality (MSM, including those who have sex with men only or also with women, or MSW), and age. Authors of eligible studies with a sample size of 200 participants or more were invited to share deidentified individual-level data on the above four variables. Authors of studies including 40 or more HIV-positive MSW or 40 or more men from Africa (irrespective of HIV status and sexuality) were also invited to share these data. Pooled estimates of anal high-risk HPV (HR-HPV, including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), and HSIL or worse (HSIL+), were compared by use of adjusted prevalence ratios (aPRs) from generalised linear models. Findings: The systematic review identified 93 eligible studies, of which 64 contributed data on 29 900 men to the pooled analysis. Among HIV-negative MSW anal HPV16 prevalence was 1·8% (91 of 5190) and HR-HPV prevalence was 6·9% (345 of 5003); among HIV-positive MSW the prevalences were 8·7% (59 of 682) and 26·9% (179 of 666); among HIV-negative MSM they were 13·7% (1455 of 10 617) and 41·2% (3798 of 9215), and among HIV-positive MSM 28·5% (3819 of 13 411) and 74·3% (8765 of 11 803). In HIV-positive MSM, HPV16 prevalence was 5·6% (two of 36) among those age 15-18 years and 28·8% (141 of 490) among those age 23-24 years (ptrend=0·0091); prevalence was 31·7% (1057 of 3337) among those age 25-34 years and 22·8% (451 of 1979) among those age 55 and older (ptrend<0·0001). HPV16 prevalence in HIV-negative MSM was 6·7% (15 of 223) among those age 15-18 and 13·9% (166 of 1192) among those age 23-24 years (ptrend=0·0076); the prevalence plateaued thereafter (ptrend=0·72). Similar age-specific patterns were observed for HR-HPV. No significant differences for HPV16 or HR-HPV were found by age for either HIV-positive or HIV-negative MSW. HSIL+ detection ranged from 7·5% (12 of 160) to 54·5% (61 of 112) in HIV-positive MSM; after adjustment for heterogeneity, HIV was a significant predictor of HSIL+ (aPR 1·54, 95% CI 1·36-1·73), HPV16-positive HSIL+ (1·66, 1·36-2·03), and HSIL+ in HPV16-positive MSM (1·19, 1·04-1·37). Among HPV16-positive MSM, HSIL+ prevalence increased with age. Interpretation: High anal HPV prevalence among young HIV-positive and HIV-negative MSM highlights the benefits of gender-neutral HPV vaccination before sexual activity over catch-up vaccination. HIV-positive MSM are a priority for anal cancer screening research and initiatives targeting HPV16-positive HSIL+.
  • PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

    Alhalabi, K. T.; Stichel, D.; Sievers, P.; Peterziel, H.; Sommerkamp, A. C.; Sturm, D.; Wittmann, A.; Sill, M.; Jäger, N.; Beck, P.; et al. (2021)
    Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.
  • Subclone eradication analysis identifies targets for enhanced cancer therapy and reveals L1 retrotransposition as a dynamic source of cancer heterogeneity

    Ketola, K.; Kaljunen, H.; Taavitsainen, S.; Kaarijärvi, R.; Järvelä, E.; Rodriguez Martin, B.; Haase, K.; Woodcock, D. J.; Tubio, J.; Wedge, David C; et al. (2021)
    Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance Analysis (DSER), a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and post-treatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC-3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected post-castration in LuCaP 77 and LuCaP 105 xenograft models and post-chemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance.
  • Prostate cancer

    Sandhu, S.; Moore, C. M.; Chiong, E.; Beltran, H.; Bristow, Robert G; Williams, S. G.; Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia. (2021)
    The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.
  • Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers

    McAteer, M. A.; O'Connor, James P B; Koh, D. M.; Leung, H. Y.; Doran, S. J.; Jauregui-Osoro, M.; Muirhead, N.; Brew-Graves, C.; Plummer, E. R.; Sala, E.; et al. (2021)
    The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.
  • Impact of SARS-CoV-2 on training and mental well-being of surgical gynecological oncology trainees

    Gaba, F.; Blyuss, O.; Rodriguez, I.; Dilley, J.; Wan, Yee-loi L; Saiz, A.; Razumova, Z.; Zalewski, K.; Nikolova, T.; Selcuk, I.; et al. (2021)
    Introduction: The SARS-CoV-2 global pandemic has caused a crisis disrupting health systems worldwide. While efforts are being made to determine the extent of the disruption, the impact on gynecological oncology trainees/training has not been explored. We conducted an international survey of the impact of SARS-CoV-2 on clinical practice, medical education, and mental well-being of surgical gynecological oncology trainees. Methods: In our cross-sectional study, a customized web-based survey was circulated to surgical gynecological oncology trainees from national/international organizations from May to November 2020. Validated questionnaires assessed mental well-being. The Wilcoxon rank-sum test and Fisher's exact test were used to analyse differences in means and proportions. Multiple linear regression was used to evaluate the effect of variables on psychological/mental well-being outcomes. Outcomes included clinical practice, medical education, anxiety and depression, distress, and mental well-being. Results: A total of 127 trainees from 34 countries responded. Of these, 52% (66/127) were from countries with national training programs (UK/USA/Netherlands/Canada/Australia) and 48% (61/127) from countries with no national training programs. Altogether, 28% (35/125) had suspected/confirmed COVID-19, 28% (35/125) experienced a fall in household income, 20% (18/90) were self-isolated from households, 45% (57/126) had to re-use personal protective equipment, and 22% (28/126) purchased their own. In total, 32.3% (41/127) of trainees (16.6% (11/66) from countries with a national training program vs 49.1% (30/61) from countries with no national training program, p=0.02) perceived they would require additional time to complete their training fellowship. The additional training time anticipated did not differ between trainees from countries with or without national training programs (p=0.11) or trainees at the beginning or end of their fellowship (p=0.12). Surgical exposure was reduced for 50% of trainees. Departmental teaching continued throughout the pandemic for 69% (87/126) of trainees, although at reduced frequency for 16.1% (14/87), and virtually for 88.5% (77/87). Trainees reporting adequate pastoral support (defined as allocation of a dedicated mentor/access to occupational health support services) had better mental well-being with lower levels of anxiety/depression (p=0.02) and distress (p<0.001). Trainees from countries with a national training program experienced higher levels of distress (p=0.01). Mean (SD) pre-pandemic mental well-being scores were significantly higher than post-pandemic scores (8.3 (1.6) vs 7 (1.8); p<0.01). Conclusion: SARS-CoV-2 has negatively impacted the surgical training, household income, and psychological/mental well-being of surgical gynecological oncology trainees. The overall clinical impact was worse for trainees in countries with no national training program than for those in countries with a national training program, although national training program trainees reported greater distress. COVID-19 sickness increased anxiety/depression. The recovery phase must focus on improving mental well-being and addressing lost training opportunities.
  • Comprehensive library generation for identification and quantification of endometrial cancer protein biomarkers in cervico-vaginal fluid

    Njoku, Kelechi; Chiasserini, D.; Geary, Bethany; Pierce, Andrew; Jones, E. R.; Whetton, Andrew D; Crosbie, Emma J; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 5th Floor Research, St Mary's Hospital, Oxford Road, Manchester M13 9WL (2021)
    Endometrial cancer is the most common gynaecological malignancy in high-income countries and its incidence is rising. Early detection, aided by highly sensitive and specific biomarkers, has the potential to improve outcomes as treatment can be provided when it is most likely to effect a cure. Sequential window acquisition of all theoretical mass spectra (SWATH-MS), an accurate and reproducible platform for analysing biological samples, offers a technological advance for biomarker discovery due to its reproducibility, sensitivity and potential for data re-interrogation. SWATH-MS requires a spectral library in order to identify and quantify peptides from multiplexed mass spectrometry data. Here we present a bespoke spectral library of 154,206 transitions identifying 19,394 peptides and 2425 proteins in the cervico-vaginal fluid of postmenopausal women with, or at risk of, endometrial cancer. We have combined these data with a library of over 6000 proteins generated based on mass spectrometric analysis of two endometrial cancer cell lines. This unique resource enables the study of protein biomarkers for endometrial cancer detection in cervico-vaginal fluid. Data are available via ProteomeXchange with unique identifier PXD025925.
  • Biguanides drugs: Past success stories and promising future for drug discovery

    Grytsai, Oleksandr; Myrgorodska, I.; Rocchi, S.; Ronco, C; Benhida, R.; Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR 7272, 28 Avenue Valrose, 06108, Nice, France; Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, SK10 4TG, (2021)
    Biguanides have attracted much attention a century ago and showed resurgent interest in recent years after a long period of dormancy. They constitute an important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Therapeutic indications of biguanides include antidiabetic, antimalarial, antiviral, antiplaque, and bactericidal applications. This review presents an extensive overview of the biological activity of biguanides and different mechanisms of action of currently marketed biguanide-containing drugs, as well as their pharmacological properties when applicable. We highlight the recent developments in research on biguanide compounds, with a primary focus on studies on metformin in the field of oncology. We aim to provide a critical overview of all main bioactive biguanide compounds and discuss future perspectives for the design of new drugs based on the biguanide fragment.
  • Definition of biologically distinct groups of conjunctival melanomas according to etiological factors and implications for precision medicine

    Gardrat, S.; Houy, A.; Brooks, Kelly; Cassoux, N.; Barnhill, R.; Dayot, S.; Bièche, I.; Raynal, V.; Baulande, S.; Marais, Richard; et al. (2021)
    Conjunctival melanoma (ConjMel) is a potentially deadly ocular melanoma, originating from partially sunlight-exposed mucosa. We explored the mutational landscape of ConjMel and studied the correlation with etiological factors. We collected 47 primary ConjMel samples and performed next-generation sequencing of 400 genes. Hotspot mutations in BRAF, NRAS, HRAS, and KIT were observed in 16 (34%), 5 (11%), 2, and 2 cases, respectively. Patients with BRAF and CDKN2A-mutated ConjMel tended to be younger while the NF1-mutated one tended to be older. The eight tumors arising from nevi were enriched in CTNNB1 mutations (63% vs. 8%; Fisher's exact p-test = 0.001) compared to non-nevi ConjMel and five were devoid of BRAF, RAS, NF1, or KIT mutations, suggesting a specific oncogenic process in these tumors. The two KIT-mutated cases carried SF3B1 mutations and were located on sun-protected mucosa, a genotype shared with genital and anorectal mucosal melanomas. Targetable mutations were observed in ERBB2, IDH1, MET, and MAP2K1 (one occurrence each). Mutational landscape of ConjMel characterizes distinct molecular subtypes with oncogenic drivers common with mucosal and skin melanomas. CTNNB1 mutations were associated with nevus-derived ConjMel. Concomitant KIT/SF3B1 mutations in sun-protected cases suggest a common tumorigenic process with genital and anorectal mucosal melanomas.
  • High versus low sun protection factor sunscreens and cutaneous squamous cell carcinoma risk: a population-based cohort study

    Lergenmuller, S.; Ghiasvand, R.; Robsahm, T. E.; Green, Adèle C; Lund, E.; Rueegg, C. S; Veierød, M. B.; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (2021)
    Evidence on sunscreen use and cutaneous squamous cell carcinoma (cSCC) risk is limited. Most studies did not take sun protection factor (SPF) into consideration, and used nonusers of sunscreen as the reference group. Nonusers are likely a priori at lower cSCC risk than users. No study has investigated the effect of high versus low SPF sunscreens on cSCC appropriately adjusting for time-varying confounding. Using data from the Norwegian Women and Cancer study (1991-2016), we investigated whether use of SPF≥15+ versus SPF<15+ sunscreens reduces cSCC risk. We used marginal structural Cox proportional hazards model with inverse probability of treatment and censoring weights to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During follow-up of 148,781 women (1991-2016, mean 14.3 years), 653 women were diagnosed with cSCC. The effect on cSCC risk of SPF≥15+ versus SPF<15+ sunscreens was close to the null when used at any latitudes (HR=1.02, 95% CI: 0.82, 1.27) and when used in lower latitude settings (HR=1.05, 95% CI: 0.84, 1.32). In conclusion, we found no indication that SPF≥15+ sunscreens reduced Norwegian women's cSCC risk more than SPF<15+ sunscreens, suggesting that either there is no difference in their effects long-term, or the difference is diluted by incorrect application.
  • TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target

    Kennedy, E.; Coulter, E.; Halliwell, E.; Profitos-Peleja, N.; Walsby, E.; Clark, B.; Phillips, Elizabeth H; Burley, T. A.; Mitchell, S.; Devereux, S.; et al. (2021)
    Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide-DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P < .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, β2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P < .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node-derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P < .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.
  • Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial

    Nutting, C. M.; Griffin, C. L.; Sanghera, P.; Foran, B.; Beasley, M.; Bernstein, D.; Cosgrove, V.; Fisher, S.; West, Catharine M L; Sibtain, A.; et al. (2021)
    Background: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. Methods: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Findings: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. Conclusion: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer.
  • Molecular characterization of fast-growing melanomas

    Gaudy-Marqueste, C.; Macagno, N.; Loundou, A.; Pellegrino, E.; Ouafik, L.; Budden, Timothy; Mundra, Piyashkumar A; Gremel, Gabriela; Akhras, V.; Lin, L.; et al. (2021)
    Background: The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM), and its potential to stratify patients at high risk of death, has not been comprehensively studied. Objective: To investigate the epidemiological, clinical and mutational profile of primary cutaneous melanomas with a thickness ≥ 1mm, stratified by rate of growth (ROG). Methods: Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin embedded primary melanoma samples. Comparison of FGMM (ROG >0.5mm/month) and non-FGMM (ROG≤0.5 mm/month). Results: Two hundred patients were enrolled among which 70 were FGMM. The relapse free survival was lower in the FGMM group (p=0.014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than non-FGMM (p=0.033). Ulceration (p=0.032), thickness (p=0.006), lower sun exposure (p=0.049), and FGFR2 mutations (p=0.037) were significantly associated with fast growth. Limitations: Single-center study, cohort size, potential memory bias, number of investigated genes. Conclusion: Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness and FGFR2 mutations associate with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM which are probably good candidates for adjuvant therapies.
  • Development of randomized trials in adults with medulloblastoma-the example of EORTC 1634-BTG/NOA-24

    Hau, P.; Frappaz, D.; Hovey, E.; McCabe, Martin G; Pajtler, K. W.; Wiestler, B.; Seidel, C.; Combs, S. E.; Dirven, L.; Klein, M.; et al. (2021)
    Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
  • COVID-19 in children with haematological malignancies

    Millen, G. C.; Arnold, R.; Cazier, J. B.; Curley, H.; Feltbower, R.; Gamble, A.; Glaser, A.; Grundy, R. G.; Kirton, L.; Lee, L. Y. W.; et al. (2021)
    Background: Children with cancer are not at increased risk of severe SARS-CoV-2 infection; however, adults with haematological malignancies have increased risk of severe infections compared with non-haematological malignancies. Methods: We compared patients with haematological and non-haematological malignancies enrolled in the UK Paediatric Coronavirus Cancer Monitoring Project between 12 March 2020 and 16 February 2021. Children who received stem cell transplantation were excluded. Results: Only 2/62 patients with haematological malignancy had severe/critical infections, with an OR of 0.5 for patients with haematological compared with non-haematological malignancies. Interpretation: Children with haematological malignancies are at no greater risk of severe SARS-CoV-2 infection than those with non-haematological malignancies.
  • Preservation of quality of life in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with tucatinib or placebo when added to trastuzumab and capecitabine (HER2CLIMB trial)

    Mueller, V.; Wardley, Andrew M; Paplomata, E.; Hamilton, E.; Zelnak, A.; Fehrenbacher, L.; Jakobsen, E.; Curtit, E.; Boyle, F.; Harder Brix, E.; et al. (2021)
    Aims: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. Methods: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3-9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. Results: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. Conclusions: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases.
  • Combined longitudinal clinical and autopsy phenomic assessment in lethal metastatic prostate cancer: recommendations for advancing precision medicine

    Jasu, J.; Tolonen, T.; Antonarakis, E. S.; Beltran, H.; Halabi, S.; Eisenberger, M. A.; Carducci, M. A.; Loriot, Y.; Van der Eecken, K.; Lolkema, M.; et al. (2021)
    Background: Systematic identification of data essential for outcome prediction in metastatic prostate cancer (mPC) would accelerate development of precision oncology. Objective: To identify novel phenotypes and features associated with mPC outcome, and to identify biomarker and data requirements to be tested in future precision oncology trials. Design setting and participants: We analyzed deep longitudinal clinical, neuroendocrine expression, and autopsy data of 33 men who died from mPC between 1995 and 2004 (PELICAN33), and related findings to mPC biomarkers reported in the literature. Intervention: Thirty-three men prospectively consented to participate in an integrated clinical-molecular rapid autopsy study of mPC. Outcome measurements and statistical analysis: Data exploration with correction for multiple testing and survival analysis from the time of diagnosis to time to death and time to first occurrence of severe pain as outcomes were carried out. The effect of seven complications on the modeled probability of dying within 2 yr after presenting with the complication was evaluated using logistic regression. Results and limitations: Feature exploration revealed novel phenotypes related to mPC outcome. Four complications (pleural effusion, severe anemia, severe or controlled pain, and bone fracture) predict the likelihood of death within 2 yr. Men with Gleason grade group 5 cancers developed severe pain sooner than those with lower-grade tumors. Surprisingly, neuroendocrine (NE) differentiation was frequently observed in the setting of high serum prostate-specific antigen (PSA) levels (≥30 ng/ml). In 4/33 patients, no controlled (requiring analgesics) or severe pain was detected, and strikingly, 14/15 metastatic sites studied in these men did not express NE markers, suggesting an inverse relationship between NE differentiation and pain in mPC. Intracranial subdural metastasis is common (36%) and is usually clinically undetected. Categorization of "skeletal-related events" complications used in recent studies likely obscures the understanding of spinal cord compression and fracture. Early death from prostate cancer was identified in a subgroup of men with a low longitudinal PSA bandwidth. Cachexia is common (body mass index <0.89 in 24/31 patients) but limited to the last year of life. Biomarker review identified 30 categories of mPC biomarkers in need of winnowing in future trials. All findings require validation in larger cohorts, preferably alongside data from this study. Conclusions: The study identified novel outcome subgroups for future validation and provides "vision for mPC precision oncology 2020-2050" draft recommendations for future data collection and biomarker studies.
  • No difference in penetrance between truncating and missense/aberrant splicing pathogenic variants in MLH1 and MSH2: a prospective Lynch syndrome database study

    Dominguez-Valentin, M.; Plazzer, J. P.; Sampson, J. R.; Engel, C.; Aretz, S.; Jenkins, M. A.; Sunde, L.; Bernstein, I.; Capella, G.; Balaguer, F.; et al. (2021)
    Background: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

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