• Fanconi anaemia, childhood cancer and the BRCA genes

      Woodward, E. R.; Meyer, Stefan; Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester (2021)
      Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.
    • Health-related quality of life, symptoms, and tolerability of loncastuximab tesirine in patients with relapsed or refractory diffuse large B-cell lymphoma

      Spira, A.; Zhou, X.; Chen, L.; Gnanasakthy, A.; Wang, L.; Ungar, D.; Curiel, R.; Liao, L.; Radford, John A; Kahl, B.; et al. (2021)
      Background: Loncastuximab tesirine has shown antitumor activity with an acceptable toxicity profile in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who were relapsed or refractory after ≥2 prior therapies, including activity in patients with high-risk disease characteristics. This analysis examined health-related quality of life (HRQoL), symptoms, and tolerability in patients receiving loncastuximab tesirine for relapsed or refractory DLBCL. Patients and methods: The single-arm, open-label phase II LOTIS-2 study (ADCT-402-201; NCT03589469) enrolled 145 patients aged ≥18 years. Patients received loncastuximab tesirine as a 30-minute intravenous infusion on day 1 of each 3-week treatment cycle. Patient-reported outcomes were measured using EQ-5D and FACT-Lym at baseline, day 1 of each cycle, and the end-of-treatment visit. Results: During the course of treatment, EQ VAS overall health score was improved over time. The adjusted improvement was 0.65 per cycle (95% CI, 0.26-1.04; P = .001), and the adjusted mean change from baseline score was 5.00 (95% CI, 1.75-8.25; P = .003) at cycle 9, day 1. FACT-Lym total scores remained stable during treatment. More patients reported improvement compared to baseline in pain, lumps/swelling, and losing weight for a majority of visits. More than 60% of patients reported being "not at all" or "a little bit" bothered by treatment side effects for all treatment visits. Findings in elderly patients were similar to the population as whole. Conclusion: The findings on HRQoL, symptoms, and tolerability further support the clinical use of loncastuximab tesirine for the treatment of relapsed or refractory DLBCL.
    • Dual RAF/MEK inhibitor VS-6766 for treatment of KRAS mutant NSCLC: novel combinations targeting G12C or G12V variants

      Coma, S.; Chowdhury, S.; Musteanu, M.; Stewart, A.; Pickard, L.; Krebs, Matthew G; Minchom, A.; Banerji, U.; Barbacid, M.; Pachter, J.; et al. (2021)
      Introduction:KRAS is mutated in 25% of non-small cell lung cancer(NSCLC) adenocarcinoma, with KRAS G12C and G12V mutationsoccurring inw13% andw7% of patients, respectively. Whereas G12Cinhibitors (G12Ci) sotorasib (AMG 510) and adagrasib (MRTX849) havedemonstrated promising antitumor activity in patients with KRAS G12Cmutant (mt) NSCLC, KRAS G12V mt NSCLC remains an unmet need. VS-6766 is a unique dual RAF/MEK inhibitor which has shown singleagent activity against KRAS G12V mt NSCLC (Guo Lancet Oncology2020).Methods:We assessed synergistic antitumor effects of VS-6766with G12C or focal adhesion kinase (FAK) inhibitors in KRAS G12C orG12V NSCLC preclinical models, respectively.Results:In KRAS G12Cmt NSCLC, emerging data suggest that G12Ci monotherapy may beinsufficient for maximal depth or duration of response, and combina-tions with agents that target additional nodes in the RAS pathway(vertical blockade) may be necessary. In 3D proliferation assays, VS-6766 was synergistic with both sotorasib and adagrasib in reducingviability of a panel of KRAS G12C mt NSCLC cell lines. Accordingly, VS-6766 effectively suppressed pERK across KRAS G12C mt NSCLC celllines as a single agent, and the combination of VS-6766 + G12Ci showedimproved depth and duration of inhibition relative to G12Ci alone. InKRAS G12C mt NSCLC xenograft models (H2122, H358), combinationwith VS-6766 (0.3 mg/kg QD) augmented tumor growth inhibition bysotorasib, whereas trametinib (0.3 mg/kg QD) was much less effectivein augmenting sotorasib efficacy. Strikingly, triple combination of VS-6766, sotorasib and FAK inhibitor conferred tumor reductions of 35% in all mice in both models. In KRAS G12V mt NSCLC, CRAFsignaling was essential for tumor progression in a genetically engi-neered mouse tumor model (Sanclemente Cancer Cell 2018), providingrationale for testing the RAF/MEK inhibitor VS-6766 in KRAS G12V mtNSCLC. As RAF and MEK inhibition have been reported to activate FAKas a potential resistance mechanism, the combination of VS-6766 withthe FAK inhibitor defactinib has been studied. In 3D proliferation as-says in vitro, VS-6766 was synergistic with defactinib in reducingviability of KRAS mt cell lines with the broadest synergy observed inKRAS G12V mt cell lines, as compared with G12C and G12D cell lines. Ina KRAS G12V mt/TP53 null NSCLC model, which has previously beenshown to be CRAF dependent, VS-6766 monotherapy induced statisti-cally significant tumor regression, while trametinib at the same dosedid not. FAK inhibition further augmented the tumor regressioninduced by VS-6766. These preclinical data correlate well with theclinical observation of partial responses in patients with KRAS G12V mtNSCLC treated with VS-6766 monotherapy (Guo Lancet Oncology2020) or in combination with defactinib. Furthermore, this combina-tion regimen of VS-6766 with defactinib exhibited a manageable safetyprofile with no patients discontinuing for adverse events (Krebs AACR2021).Conclusion:These results support the ongoing registration-directed study evaluating VS-6766±defactinib for treatment ofrecurrent KRAS G12V mt NSCLC (NCT04620330) and provide rationalefor the clinical evaluation of VS-6766 in combination with a G12C in-hibitor for treatment of KRAS G12C mt NSCLC.
    • Design and assessment of a penile fracture simulation model

      Kozan, A. A.; Logan, M.; Parnham, Arie S; Liew, M.; Barrass, B.; Venugopal, S.; Biyani, C. S.; Taylor, J.; Department of Urology, Hull University Teaching Hospital, Castle Hill Hospital, Cottingham, United Kingdom (2021)
      Objective: To design and assess a novel penile fracture simulation model for teaching penile fracture repair. Methods: We used a validated circumcision simulator to create a model. Foreskin for a circumcision was divided into two halves. A transverse slit ("simulated fracture") was created on one part of the first half of the foreskin (mimicking "tunica") and was applied over the penile model. A red jelly tablet ("clot") was placed underneath the cut. A second full-length of foreskin was applied over it to cover the defect. The model was assessed by participants and expert faculty at the Urology Simulation Boot Camp. Evaluation was performed using a 5-point Likert Scale questionnaire. Data was analysed using Microsoft Excel and IBM SPSS Statistics V25. The intra-class correlation was calculated using a "One-way random model". Results: Twenty-two urology trainees and four experts participated in the evaluation. The majority of trainees strongly agreed (59%, n = 13) the model is useful for training with experts similarly agreeing in 75% of cases. The appearance of penile fracture was considered good by both trainees (68%, n = 14) and faculty (75%). Overall, the ability of the model to represent a realistic simulation of the task was considered excellent by 23% of participants and good by 64%. Personal confidence after simulation in managing a similar situation was considered high among trainees. The main difficulties reported were related to fascial planes and urethra. Conclusion: This is the first simulation model for penile fracture repair and has demonstrated face validity at a national urology bootcamp.
    • Early-onset colorectal adenocarcinoma in the IDEA database: treatment adherence, toxicities, and outcomes with 3 and 6 months of adjuvant fluoropyrimidine and oxaliplatin

      Fontana, E.; Meyers, J.; Sobrero, A.; Iveson, T.; Shields, A. F.; Taieb, J.; Yoshino, T.; Souglakos, I.; Smyth, E. C.; Lordick, F.; et al. (2021)
      Purpose: Early-onset (EO) colorectal cancer (CRC, age < 50 years) incidence is increasing. Decisions on optimal adjuvant therapy should consider treatment adherence, adverse events, and expected outcomes in a population with life expectancy longer than later-onset (LO) CRC (age ≥ 50 years). Materials and methods: Individual patient data from six trials in the International Duration Evaluation of Adjuvant Chemotherapy database were analyzed. Characteristics, treatment adherence, and adverse events in stage II or III EO-CRC and LO-CRC were compared. To reduce confounders of non-cancer-related deaths because of age or comorbidities, time to recurrence (3-year relapse-free rate) and cancer-specific survival (5-year cancer-specific mortality rate) were considered. Results: Out of 16,349 patients, 1,564 (9.6%) had EO-CRC. Compared with LO-CRC, EO-CRC had better performance status (86% v 80%, P < .01), similar T stage (% T1-3/T4: 76/24 v 77/23, P = .97), higher N2 disease rate (24% v 22%, P < .01), more likely to complete the planned treatment duration (83.2% v 78.2%, P < .01), and received a higher treatment dose intensity, especially with 6-month regimens. Gastrointestinal toxicity was more common in EO-CRC; hematologic toxicity was more frequent in LO-CRC. Compared with LO-CRC, significantly worse cancer-specific outcomes were demonstrated especially in high-risk stage III EO-CRC: lower 3-year relapse-free rate (54% v 65%; hazard ratio [HR] 1.33; 95% CI, 1.14 to 1.55; P value < .001) and higher 5-year cancer-specific mortality rate (24% v 20%; HR 1.21; 95% CI, 1.00 to 1.47; P value < .06). In this subgroup, no difference was observed with 3 or 6 months of therapy, with equally poor disease-free survival rates (57% v 56%; HR 0.97; 95% CI, 0.73 to 1.29; P value = .85). Conclusion: Young age is negatively prognostic in high-risk stage III CRC and associated with significantly higher relapse rate; this is despite better treatment adherence and higher administered treatment intensity, suggesting more aggressive disease biology.
    • Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab in patients with advanced melanoma: analysis from KEYNOTE-006

      Long, G. V.; Arance, A.; Mortier, L.; Lorigan, Paul C; Blank, C.; Mohr, P.; Schachter, J.; Grob, J. J.; Lotem, M.; Middleton, M. R.; et al. (2021)
      Background: Antitumor activity of ipilimumab or BRAF ± MEK inhibition (BRAFi ± MEKi) following pembrolizumab in melanoma is poorly characterized. Patients and methods: In the phase 3 KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab 10 mg/kg once every 2 or 3 weeks (Q3W) or ipilimumab 3 mg/kg Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab and includes patients who completed or discontinued pembrolizumab after ≥1 dose. Pembrolizumab arms were pooled. Results: At data cutoff (December 4, 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) (33 received BRAFi + MEKi, 26 BRAFi alone; 37 [62.7%] were BRAFi ± MEKi-naïve). In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% (1 complete response [CR]; 17 partial response [PR]); 79.6% had discontinued pembrolizumab due to progressive disease (PD); median OS was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8 PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). Conclusions: Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.
    • Amivantamab in non-small cell lung cancer (NSCLC) with MET Exon 14 skipping (METex14) mutation: initial results from CHRYSALIS

      Spira, A.; Krebs, Matthew G; Cho, B. C.; Besse, B.; Goldman, J.; Janne, P.; Lee, C. K.; Ma, Z.; Mansfield, A.; Minchom, A.; et al. (2021)
      Introduction:Amivantamab, a novel, fully human bispecific antibodytargeting both the epidermal growth factor receptor (EGFR) and MET,is being explored as a monotherapy in non-small cell lung cancer(NSCLC) within the CHRYSALIS study (NCT02609776), and hasreceived Breakthrough Therapy Designation for the treatment of patients with EGFR exon 20 insertion disease, after prior treatmentwith platinum chemotherapy. Given the bispecific nature of amivanta-mab, its role in patients with MET exon 14 skipping (METex14) mu-tations is being explored (MET-2 cohort) in patients both naïve to andrefractory to other available MET therapy. We present early resultsdemonstrating amivantamab activity in MET-driven NSCLC.Methods:CHRYSALIS is an ongoing phase 1 dose escalation/dose expansionstudy of amivantamab in patients with advanced NSCLC. Patients withMETex14 NSCLC whose disease progressed on or who declined currentstandard of care were treated at the recommended phase 2 dose(RP2D) of 1050 mg (1400 mg 80 kg) weekly in cycle 1 and biweeklythereafter. Response was assessed by the investigator using RECISTv1.1.Results:As of 29 Mar 2021, 16 patients with METex14 NSCLChad received amivantamab at the RP2D. Median age was 70 (range,55e75), 69% were women, and median prior lines of therapy were 2(range, 0e10), including prior treatment with crizotinib (n¼3), cap-matinib (n¼1), tepotinib (n¼2), and anti-MET antibody (n¼1). Ninepatients had at least 1 postbaseline disease assessment, 7 are pendingfirst disease assessment; 13 remain on treatment. Antitumor activitywas observed in each of the 9 response-evaluable patients, with 4confirmed partial responses, including patients with prior anti-METtherapy (Figure). Three of the 4 responders remain on treatment(6.0e6.6+ months) with ongoing responses, and 1 discontinued after12 months. The safety profile was consistent with previously reportedexperience of amivantamab at the RP2D (Sabari 2021JTO16(3):S108-109). Treatment-related adverse events leading to dose reduction ordiscontinuation occurred in 6% of patients, each. Among 7 patientswho received prior MET tyrosine kinase inhibitor (TKI), baseline ctDNAdemonstrated 2 patients with potential resistance mechanisms: PIK3CAmutation in one, and CDK4 and EGFR amplifications and a possiblesecondary MET mutation (A1251V) in the other. Five patients had noidentified MET TKI resistance alteration.Conclusion:This reportprovidesfirst evidence of amivantamab activity in MET-driven NSCLC,in addition to its previously reported anti-EGFR activity, consistentwith its bispecific mechanism of action. Enrollment into MET-2 cohortis ongoing, and presentation will include updated data.
    • Avelumab in combination regimens for relapsed/refractory DLBCL: results from the Phase Ib JAVELIN DLBCL study

      Hawkes, E. A.; Phillips, T.; Budde, L. E.; Santoro, A.; Saba, N. S.; Roncolato, F.; Gregory, G. P.; Verhoef, G.; Offner, F.; Quero, C.; et al. (2021)
      Background: Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. Objective: The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. Methods: This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. Results: Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. Conclusions: The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. CLINICALTRIALS.
    • Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma

      Eggermont, A. M.; Meshcheryakov, A.; Atkinson, V.; Blank, C. U.; Mandala, M.; Long, G. V.; Barrow, C.; Di Giacomo, A. M.; Fisher, R.; Sandhu, S.; et al. (2021)
      Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively. Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes. Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE. Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.
    • The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer

      Murphy, Alexander D; Morgan, Robert D; Clamp, Andrew R; Jayson, Gordon C; The Christie NHS Foundation Trust, Manchester, M20 4BX, UK (2021)
      Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.
    • A novel 5x multiplex immunohistochemical staining reveals PSMA as a helpful marker in prostate cancer with low p504s expression

      Rüschoff, J. H.; Stratton, S.; Roberts, E.; Clark, S.; Sebastiao, N.; Fankhauser, Christian D; Eberli, D.; Moch, H.; Wild, P. J.; Rupp, N. J.; et al. (2021)
      The ability to combine multiple immunohistochemical (IHC) markers within a single tissue section facilitates the evaluation and detection of co-expressions, while saving tissue. A newly developed 5x multiplex (MPX) IHC staining of five different IHC markers (Basal cell cocktail (34βE12 + p63), p504s (SP116), ERG (EPR3864), Ki-67 (30-9), PSMA (EP192)) was applied on whole sections of n = 37 radical prostatectomies (RPE) including normal and cancerous tissue. Four different colors including brown, magenta, yellow and teal coded for different stainings, whereas magenta was used twice for nuclear Ki-67 and cytosolic / membranous PSMA. The staining of multiplex IHC was compared to single stains of ERG, PSMA and p504s. The proper staining of the basal cell cocktail and Ki-67 could be assessed by internal positive controls in the multiplex staining. The proportion of PSMA and p504s expression revealed a significant correlation between multiplex and single stains (p < 0.01) as well as a concordant staining pattern for ERG (n = 14 prostate cancers were identified ERG positive with both methods). Our proof of concept study demonstrates a robust staining pattern of all five different antibodies with this newly developed 5x MPX IHC. This approach facilitates the recognition of prostate cancer, in particular by adding PSMA in cases with low p504s expression.
    • The perspectives of survivors of Hodgkin lymphoma on lung cancer screening: A qualitative study

      Broadbent, Rachel; Gorman, L.; Armitage, C. J.; Radford, John A; Linton, Kim M; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK (2021)
      Background: Hodgkin lymphoma survivors (HLS) are at excess risk of lung cancer as a consequence of HL treatment. HLS without a heavy smoking history are currently unable to access lung cancer screening (LCS) programmes aimed at ever smokers, and there is an unmet need to develop a targeted LCS programme. In this study we prospectively explored HLS perspectives on a future LCS programme, including motivating factors and potential barriers to participation, with the aim of identifying ways to optimise uptake in a future programme. Methods: Semistructured telephone interviews were conducted with HLS, aged 18-80 and lymphoma-free for ≥5 years, selected from a clinical database (ADAPT). Participants provided informed consent. Data were analysed using inductive thematic analysis. Results: Despite awareness of other late effects, most participants were unaware of their excess risk of lung cancer. Most were willing to participate in a future LCS programme, citing the potential curability of early-stage lung cancer and reassurance as motivating factors, whilst prior experience of healthcare was a facilitator. Whilst the screening test (a low dose CT scan) was considered acceptable, radiation risk was a concern for some and travel and time off work were potential barriers to participation. Conclusions: Our results suggest that most HLS would participate in a future LCS programme, motivated by perceived benefits. Their feedback identified a need to develop educational materials addressing lung cancer risk and concerns about screening, including radiation risk. Such materials could be provided upon an invitation to LCS. Uptake in a future programme may be further optimized by offering flexible screening appointments close to home.
    • TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change

      Payapilly, Aishwarya; Guilbert, Ryan; Descamps, Tine; White, Gavin R M; Magee, Peter; Zhou, Cong; Kerr, Alastair; Simpson, Kathryn L; Blackhall, Fiona H; Dive, Caroline; et al. (2021)
      Small-cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analyzing expression data from SCLC tumors, patient-derived models, and established cell lines, we show that the expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduces viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion is dependent upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promotes Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding fails to suppress apoptosis triggered by TIAM1 depletion. In conclusion, TIAM1-RAC1 signaling promotes SCLC cell survival via Nur77 nuclear sequestration.
    • Value of comprehensive genomic profiling in pre-screening patients for NTRK fusion in STARTRK2 trial: Single centre experience

      Ortega-Franco, Ana; Adamson-Raieste, A.; Rahman, Rozana A; Pihlak, Rille; Peters, N.; Scott, J. A.; Aruketty, Sreeja; Thomson, C.; Dransfield, Sarah; Henshaw, A.; et al. (2021)
      Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) is increasingly used as a pre-screening tool for clinical trials. The aim of this project was to retrospectively determine the scope of alterations identified by CGP that could render patients suitable for alternative early phase clinical trials of genomically-matched (GM) / immunotherapy (IO) or ‘off-label’ drug use. Methods: Patients were pre-screened for the STARTRK2 study (Roche sponsored study of Entrectinib, NCT02568267) at The Christie NHS foundation Trust using FoundatioCDx. Testing is validated for NTRK, ROS1 and ALK fusion testing but all pathogenic alterations are reported on a clinical trial specific Foundation Medicine (FM) report. Results were scrutinised for actionable alterations that could direct patients to alternative clinical trials or off label drug use. Results: A total of 269 patients with were consented since FM testing was introduced in the trial in Jan’2019. FM yielded results in 229 patients (85.2%), mean age was 54, 58.4% were male and 45.8% had 1-2 prior systemic lines. Most prevalent tumour subtypes were colorectal (26.4%), head and neck (21.6%) and sarcomas (7.1%). Most prevalent alterations occurred in: TP53 (12.6%), APC (8.4%) and KRAS (4.6%). MSI High was 1.5%. No patients had NTRK/ROS1 fusions, 1 non-small cell lung cancer patient had ALK fusion. 104 (45.4%) patients were potentially eligible for matched clinical trials (101 for GM and 3 for IO) and 61 (26.6%) patients could have been considered for off-label drug use. The most prevalent actionable alterations found across common and rare disease types were PI3KCA (10%), ERBB2 (6.1%), PTEN (3.1%), tumour mutation burden 10 mut/Mb (2.6%) and HRAS (1.7%). The following alterations occurred in <1%: AKT1, KRAS G12C, BRAF V600E, BRCA, FGFR3 and IDH1. Conclusions: Our results highlight the relevance of CGP in identifying patients for GM or IO within clinical trials or off-label drug use. The retrospective nature of this work and the fact that FM results provided within STARTRK2 are not intended for clinical use precluded implementing these recommendations. NTRK fusions were not detected in our cohort which highlights the rarity of this event in our population
    • The impact of gadolinium-based MR contrast on radiotherapy planning for oropharyngeal treatment on the MR Linac

      Hales, Rosie; Chuter, Robert; McWilliam, Alan; Salah, Amal; Dubec, Michael; Freear, Linnea; McDaid, Lisa; Aznar, Marianne Camille; van Herk, Marcel; McPartlin, Andrew J; et al. (2021)
      Purpose: Gadolinium-based contrast agents (GBCAs) may add value to Magnetic Resonance (MR)-only radiotherapy workflows including on hybrid machines such as the MR Linac. The impact of GBCAs on radiotherapy dose distributions however have not been well studied. This work used retrospective GBCA-enhanced datasets to assess the dosimetric effect of GBCAs on head and neck plans. Methods: Ten patients with oropharyngeal SCC receiving radiotherapy from November 2018-April 2020 were included in this study. Radiotherapy planning included contrast-enhanced CT and MR scans. A contrast agent 'contour' was defined by delineating GBCA-enhanced regions using an agreed window/level threshold, transferred to the planning CT and given a standardised electron density (ED) of 1.149 in the Monaco treatment planning system (Elekta AB). Four plans were per patient calculated and compared using two methods: (1) optimised without contrast (Plan A) then recalculated with ED (Plan B), and (2) optimised with contrast ED (Plan C) then without (Plan D). For target parameters minimum and maximum doses to 1cc of PTVs, D95 values, and percent dose differences were calculated. Dose differences for OARs were calculated as a percentage of the clinical tolerance value. For the purposes of this study, ±2% over the whole treatment course was considered to be a clinically acceptable dose deviation. Wilcoxon-signed rank tests were used to determine any dose differences within and between the two methods of optimisation and recalculation (p < 0.05). Pearson's correlations were used to establish the relationship between gadolinium uptake volume in a structure (i.e. proportion of structure covered by a density override) and the resulting dose difference. Results: The median percent dose differences for key reportable dosimetric parameters between non-contrast and simulated contrast plans were <1.2% over all fractions over all patients for reportable target parameters (mean 0.34%, range 0.22-1.02%). The percent dose differences for max dose to 1cc of both PTV1 and PTV2 were significantly different after application of density override (p < 0.05) but only in method 2 (Plan C vs Plan D). For D95 PTV1 there was a statistically significant effect of density override (p < 0.01), however only in method 1 (Plan A vs Plan B). There were no significant differences between calculation methods of the impact of contrast in most target parameters with the exception of D95 PTV1 (p < 0.01), and for D95 PTV2 (p < 0.05). The median percent dose differences for reportable OAR parameters as a percentage of clinical planning tolerances were <2.0% over a full treatment course (mean 0.65%, range 0.27-1.62%). There were no significant differences in dose to OARs within or between methods for contrast impact assessment. Conclusions: Dose differences to targets and OARs in oropharyngeal cancer treatment due to a presence of GBCA were minimal and this work suggests that prospective in vivo evaluations of impact may not be necessary in this clinical site. Accounting for GBCAs may not be needed in daily adaptive workflows on the MR Linac.
    • The need for tailored posttreatment surveillance for low-grade appendiceal mucinous neoplasms (LAMN)

      Campana, Luca G; Wilson, Malcolm S; Halstead, Rebecca; Wild, Jonathan; O'Dwyer, Sarah T; Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, (2021)
    • Quality of life in men with prostate cancer randomly allocated to receive docetaxel or abiraterone in the STAMPEDE trial

      Rush, H. L.; Murphy, L.; Morgans, A. K.; Clarke, Noel W; Cook, A. D.; Attard, G.; Macnair, A.; Dearnaley, D. P.; Parker, C. C.; Russell, J. M.; et al. (2021)
      Purpose: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. Methods: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. Results: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). Conclusion: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.
    • Prospective observational study of prevalence, assessment and treatment of pancreatic exocrine insufficiency (PEI) in patients with advanced pancreatic cancer (aPC): PanDA

      Lamarca, Angela; Carnie, Lynsey; Shah, Dinakshi; Vaughan, Kate; Kapacee, Zainul Abedin; McCallum, Lynne; Abraham, Marc; Backen, Alison C; McNamara, Mairead G; Hubner, Richard A; et al. (2021)
      Background: PEI in patients with advanced pancreatic cancer is well documented, but there is a lack of consensus regarding optimal screening. Methods: Eligible patients for this observational study (NCT03616431) were those diagnosed with aPC referred for consideration of palliative therapy who consented to evaluation by a research dietitian. In addition to symptom and full dietetic assessment (including Mid-Upper Arm Circumference (MUAC), handgrip and stair climb test), full nutritional blood panel, faecal elastase (FE) and 13C mixed triglyceride breath test (for diagnostic cohort (DiC)) were performed. Primary objectives: prospective assessment of PEI prevalence (dietitian-assessed; demographic cohort (DeC)), and to design (using breath test as gold standard; DiC) and validate (follow-up cohort (FuC)) the most suitable screening tool for PEI in patients with aPC. Logistic and Cox regression were used for statistical analysis (Stat v.12). Results: Between 1st July 2018 and 30th October 2020, 112 eligible patients [50 (DeC), 25 (DiC), 37 (FuC)]. Prevalence of PEI in the DeC was 64.0% (PEI-related symptoms were flatus (84.0%), weight loss (84.0%), abdominal discomfort (50.0%) and steatorrhea (48.0%)); 70.0% of patients required pancreatic enzyme replacement therapy and 74.0% had anorexia (low appetite); 44.0% and 18.0% had low vitamin D and vitamin A levels, respectively. Designed PEI screening panel (DiC; 19 patients with breath test completed) included FE [normal/missing (0 points); low (1 point)] and MUAC [normal/missing ( > percentile 25 for age/gender) (0 points); low (2 points)] and identified patients at high-risk (2-3 total points) of PEI [vs. low-medium risk (0-1 total points)]. When patients from DeC and DiC) were analysed together, those classified as “high-risk of PEI” according to the screening panel had shorter overall survival (multivariable Hazard Ratio (mHR) 1.86 (95% CI 1.03-3.36); p-value 0.040) when adjusted for other prognostic factors, including presence of PEI symptoms (mHR 2.28 (95% CI 1.19-4.35); p-value 0.013). The screening panel was tested in the FuC; 78.38% were classified as patients at “high-risk of PEI”; of these, 89.6% were confirmed to have PEI by the dietitian. The panel was feasible for use in clinical practice, (64.8% of patients completed fully the assessments required) and acceptability was high (87.5% of patients would do it again). The majority of patients (91.3%) recommended that all future patients with aPC should have dietitian input. Conclusions: PEI is present in the majority of patients with aPC, and early dietetic input is important to provide a holistic nutritional overview, including, but not limited to, PEI. This proposed screening panel could be used to prioritise patients at higher risk of PEI requiring urgent dietitian input. Its prognostic role needs further validation.
    • Identification of modes of tumour regression in NSCLC patients during radiotherapy

      Amugongo, Lameck M; Green, Andrew; Cobben, D.; van Herk, Marcel; McWilliam, Alan; Vasquez Osorio, Eliana; Division of Cancer Sciences, University of Manchester, Manchester (2021)
      Purpose: Observed gross tumour volume shrinkage during radiotherapy (RT) raises the question of whether to adapt treatment to changes observed on the acquired images. In the literature, two modes of tumour regression have been described: elastic and non-elastic. These modes of tumour regression will affect the safety of treatment adaptation. This study applies a novel approach, using routine cone-beam computed tomography (CBCT) and deformable image registration to automatically distinguish between elastic and non-elastic tumour regression. Methods: In this retrospective study, hundred and fifty (150) locally advanced non-small cell lung cancer patients treated with 55 Gray of radiotherapy were included. First, the two modes of tumour regression were simulated. For each mode of tumour regression, one timepoint was simulated. Based on the results of simulated data, the approach used for analysis in real patients was developed. CBCTs were non-rigidly registered to the baseline CBCT using a cubic B-spline algorithm, NiftyReg. Next, the Jacobian determinants were computed from the deformation vector fields. To capture local volume changes, ten Jacobian values were sampled perpendicular to the surface of the GTV, across the lung-tumour boundary. From the simulated data, we can distinguish elastic from non-elastic tumour regression by comparing the Jacobian values samples between 5-12.5 mm inside and 5-12.5 mm outside the planning GTV. Finally, morphometric results compared between tumours of different histology. Results: Most patients (92.3%) in our cohort showed stable disease in the first week of treatment and non-elastic shrinkage in the later weeks of treatment. At week 2, 125 patients (88%) showed stable disease, 3 patients (2.1%) disease progression and 11 patients (8%) regression. By treatment completion, 91 patients (64%) had stable disease, 1 patient (0.7%) progression and 46 patients (32%) regression. A slight difference in the mode of tumour change was observed between tumours of different histology. Conclusion: Our novel approach shows that it may be possible to automatically quantify and identify global changes in lung cancer patients during RT, using routine CBCT images. Our results show that different regions of the tumour changes in different ways. Therefore, careful consideration should be taken when adapting RT. This article is protected by copyright. All rights reserved.
    • Prostate zones and cancer: lost in transition?

      Ali, Amin; Du Feu, Alexander; Oliveira, Pedro; Choudhury, Ananya; Bristow, Robert G; Baena, Esther; Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester (2021)
      Localized prostate cancer shows great clinical, genetic and environmental heterogeneity; however, prostate cancer treatment is currently guided solely by clinical staging, serum PSA levels and histology. Increasingly, the roles of differential genomics, multifocality and spatial distribution in tumorigenesis are being considered to further personalize treatment. The human prostate is divided into three zones based on its histological features: the peripheral zone (PZ), the transition zone (TZ) and the central zone (CZ). Each zone has variable prostate cancer incidence, prognosis and outcomes, with TZ prostate tumours having better clinical outcomes than PZ and CZ tumours. Molecular and cell biological studies can improve understanding of the unique molecular, genomic and zonal cell type features that underlie the differences in tumour progression and aggression between the zones. The unique biology of each zonal tumour type could help to guide individualized treatment and patient risk stratification.