• Experimental challenges to modeling prostate cancer heterogeneity

      Flores-Téllez, Teresita; Baena, Esther; Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Alderley Edge, Macclesfield, SK10 4TG (2022)
      Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a heterogeneous diversity at inter- and intra-tumor and inter-patient levels which are influenced by multiple intrinsic and/or extrinsic factors. Recent studies have started to characterize the complexity of prostate tumors and these different tiers of heterogeneity. In this review, we discuss the most common factors that contribute to tumoral diversity. Moreover, we focus on the description of the in vitro and in vivo approaches, as well as high-throughput technologies, that help to model intra-tumoral diversity. Further understanding tumor heterogeneities and the challenges they present will guide enhanced patient risk stratification, aid the design of more precise therapies, and ultimately help beat this chameleon-like disease.
    • Author Correction: QUAREP-LiMi: a community endeavor to advance quality assessment and reproducibility in light microscopy

      Boehm, U.; Nelson, G.; Brown, C. M.; Bagley, S.; Bajcsy, P.; Bischof, J.; Dauphin, A.; Dobbie, I. M.; Eriksson, J. E.; Faklaris, O.; et al. (2022)
    • Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?

      Gutierrez-Quintana, R.; Walker, D. J.; Williams, K. J.; Forster, D. M.; Chalmers, A. J.; Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Division of Pharmacy and Optometry, School of Health Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. Division of Informatics, Imaging and Data Sciences, Manchester Molecular Imaging Centre, The University of Manchester, Manchester, UK. (2022)
      Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.
    • MiR-378a inhibits glucose metabolism by suppressing GLUT1 in prostate cancer

      Cannistraci, A.; Hascoet, P.; Ali, A.; Mundra, P.; Clarke, N. W.; Pavet, V.; Marais, R.; Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Genito-Urinary Cancer Research Group and the FASTMAN Prostate Cancer Centre for Excellence, Division of Cancer Sciences, Manchester Cancer Research Centre, The University of Manchester, 555 Wilmslow Road, Manchester, M20 4GJ, UK. The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. valeria.pavet@cruk.manchester.ac.uk. Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. richard.marais@cruk.manchester.ac.uk. (2022)
      Prostate cancer (PCa) is the fifth leading cause of cancer related deaths worldwide, in part due to a lack of molecular stratification tools that can distinguish primary tumours that will remain indolent from those that will metastasise. Amongst potential molecular biomarkers, microRNAs (miRs) have attracted particular interest because of their high stability in body fluids and fixed tissues. These small non-coding RNAs modulate several physiological and pathological processes, including cancer progression. Herein we explore the prognostic potential and the functional role of miRs in localised PCa and their relation to nodal metastasis. We define a 7-miR signature that is associated with poor survival independently of age, Gleason score, pathological T state, N stage and surgical margin status and that is also prognostic for disease-free survival in patients with intermediate-risk localised disease. Within our 7-miR signature, we show that miR-378a-3p (hereafter miR-378a) levels are low in primary tumours compared to benign prostate tissue, and also lower in Gleason score 8–9 compared to Gleason 6–7 PCa. We demonstrate that miR-378a impairs glucose metabolism and reduces proliferation in PCa cells through independent mechanisms, and we identify glucose transporter 1 (GLUT1) messenger RNA as a direct target of miR-378a. We show that GLUT1 inhibition hampers glycolysis, leading to cell death. Our data provides a rational for a new PCa stratification strategy based on miR expression, and it reveals that miR-378a and GLUT1 are potential therapeutic targets in highly aggressive glycolytic PCa.
    • Defining the Validity of Skin Self-Examination as a Screening Test for the Detection of Suspicious Pigmented Lesions: A Meta-Analysis of Diagnostic Test Accuracy

      Jiyad, Z.; Plasmeijer, E. I.; Keegan, S.; Samarasinghe, V.; Green, A. C.; Akhras, V.; Department of Dermatology, St. George’s Hospital, London, United Kingdom (2022)
      Background: Skin self-examination (SSE) is widely promoted for the detection of suspicious pigmented lesions. However, determining screening accuracy is essential to appraising the usefulness of SSE. Objectives: The aim of this work was to pool estimates from studies of SSE diagnostic accuracy in the detection of suspicious pigmented lesions. Methods: This study was registered with PROSPERO (CRD42021246356) and conducted in accordance with PRISMA-DTA guidelines. A systematic search of Medline (PubMed) EMBASE, CINAHL, and The Cochrane Library was conducted to identify relevant studies. We included studies that examined the accuracy of SSE, either whole-body or site-specific, for detecting change in individual pigmented lesions or detecting an atypical naevus. A univariate random-effects model, based on logit-transformed data, was used to calculate a summary diagnostic odds ratio (DOR) as well as pooled sensitivity and specificity. Cochran’s Q test and the I2 statistic were calculated to assess heterogeneity. A proportional hazards model was used to calculate the area under the curve (AUC) and plot the summary receiver operator characteristic curve. We used the Quality Assessment of Diagnostic Accuracy Studies-2 tool to grade study quality. Results: We identified 757 studies, of which 3 met inclusion criteria for quantitative synthesis. The pooled sensitivity and specificity based on 553 included participants was 59 and 82%, respectively. The summary DOR was 5.88 and the AUC was 0.71. There were some concerns regarding risk of bias in all 3 studies. Conclusions: SSE can detect suspicious pigmented lesions with reasonable sensitivity and relatively high specificity, with the AUC suggesting acceptable discriminatory ability.
    • Benchmarking small-variant genotyping in polyploids

      Cooke, D. P.; Wedge, D. C.; Lunter, G. (2022)
      Genotyping from sequencing is the basis of emerging strategies in the molecular breeding of polyploid plants. However, compared with the situation for diploids, in which genotyping accuracies are confidently determined with comprehensive benchmarks, polyploids have been neglected; there are no benchmarks measuring genotyping error rates for small variants using real sequencing reads. We previously introduced a variant calling method, Octopus, that accurately calls germline variants in diploids and somatic mutations in tumors. Here, we evaluate Octopus and other popular tools on whole-genome tetraploid and hexaploid data sets created using in silico mixtures of diploid Genome in a Bottle (GIAB) samples. We find that genotyping errors are abundant for typical sequencing depths but that Octopus makes 25% fewer errors than other methods on average. We supplement our benchmarks with concordance analysis in real autotriploid banana data sets.
    • Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer

      Nalio Ramos, R.; Missolo-Koussou, Y.; Gerber-Ferder, Y.; Bromley, C. P.; Bugatti, M.; Núñez, N. G.; Tosello Boari, J.; Richer, W.; Menger, L.; Denizeau, J.; et al. (2022)
      Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
    • VIOLETTE: Randomised phase II study of olaparib (ola) plus ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

      Tutt, A.; Nowecki, Z.; Szoszkiewicz, R.; Im, S. A.; Arkenau, H. T.; Armstrong, Anne C; Jacot, W.; Kim, J. H.; Webster, M.; Balmana, J.; et al. (2022)
      Background Combining DNA damage response (DDR) inhibitors to inhibit multiple DDR pathways may enhance tumour cell death. Preclinical models show synergistic antitumour effects of ola (PARP1 inhibitor) + cer (ATR inhibitor) or ada (WEE1 inhibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola ± cer or ada as 2nd–3rd line in pts with mTNBC. Methods Randomisation was stratified within each arm by mutation status (BRCAm, non-BRCAm homologous recombination repair pathway mutations [HRRm], or no HRRm [non-HRRm]) based on a prospective central tumour test and prior platinum therapy. Pts received ola 300 mg BID, 28-d cycle; cer 160 mg d 1–7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1–3, 8–10 + ola 200 mg BID (ada+ola), 21-d cycle. Primary study endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), safety, and tolerability. Ada+ola was discontinued early due to higher than expected grade ≥3 haematologic toxicity, which limited its interpretation. We focus on cer+ola vs ola. The sponsor stopped VIOLETTE after reviewing BRCAm stratum efficacy data. Results Of 273 pts (450 planned; median age: 53 y), 114 received ola, 112 cer+ola, and 47 ada+ola. Primary analyses showed no statistically significant difference in PFS for cer+ola vs ola (BRCAm: n=83; HR 1.02 [90% CI 0.63–1.66, P=0.94], HRRm: n=40; 0.54 [0.28–1.03, 0.13], non-HRRm: n=103; 0.76 [0.50–1.14, 0.30]). No statistically significant difference in ORR was seen for cer+ola vs ola in BRCAm (50% vs 44%) or HRRm (20% vs 15%). ORR was higher in non-HRRm for cer+ola (15%, n=8) vs ola (4%, n=2) (odds ratio 4.45; 90% CI 1.30–21.20, P=0.04). In all pts, nausea and anaemia were the most common adverse events (AEs). Grade ≥3 AEs: 36% ola, 47% cer+ola, 78% ada+ola. Details of exploratory and subgroup analyses will be presented. Conclusions Cer+ola did not improve PFS vs ola as 2nd–3rd line for mTNBC. Clinical significance of higher ORR with cer+ola in non-HRRm pts is unclear. Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment.
    • Biomarker and multivariate analyses results from AIPAC: A phase IIb study comparing eftilagimod alpha (a soluble LAG-3 protein) vs placebo in combination with weekly paclitaxel in HR+HER2-metastatic breast cancer

      Marme, F.; Wildiers, H.; Dirix, L.; Armstrong, Anne C; De Cuypere, E.; Dalenc, F.; Schroder, C. P.; Vuylsteke, P.; Brain, E.; Kuemmel, S.; et al. (2022)
      Background Eftilagimod alpha (EF) is a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules and mediates activation of antigen-presenting cells followed by T-cells. AIPAC investigated EF + paclitaxel (PA). We hereby report exploratory biomarker and multivariate analyses. Methods This double-blinded, 1:1 randomized phase IIb trial enrolled pts with HR+ HER2- MBC. Pts received PA (80 mg/m2 IV on D1, D8, D15) + EF (30 mg) or placebo (PL) on D2, D16 per cycle (28 days) for 24 wks + EF/PL for 52 wks. Exploratory EPs were potential biomarkers and their correlation to efficacy. Multivariate analysis used backward selection p>0.15 (univariate cox model). Blood cell subsets (CD4; CD8, PBMCs, monocytes) & Th1 biomarker CXCL-10 were measured centrally. Comparison was done using 2-sided Wilcoxon test. Results 226 pts [efti n=114; placebo n=112] were included. Pts were endocrine resistant (84%), pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Safety/efficacy were reported at SABCS 2020 #132; SITC 2021 #948 In the multivariate predictive model 4 groups (high Neutrophil/Lymphocyte Ratio [NLR]; no prior taxanes; low monocytes and <5 yrs since diagnosis) were significant for OS (Table) On treatment mean fold-changes of monocytes (5.81 vs. 2.29; p=0.025), PBMCs (2.00 vs. 1.41; p=0.041), T cells (2.28 vs. 1.48; p=0.086), & CXCL10 (2.78 vs. 1.56; p=0.06) were significantly higher (EF vs PL) and linked to higher OS. Post baseline CD4 (median 896/μl vs. 736 μl; p=0.038) & CD8 (median 377/μl vs. 223 μl; p=0.005) T cell count increased significantly in pts with higher OS EF vs. PL. Conclusions EF + PA elicits significant effects on different immune cells which is significantly associated with higher OS. Multivariate analysis identified potential target populations for phase III.
    • Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers

      Marcinkute, R.; Woodward, E. R.; Gandhi, A.; Howell, S.; Crosbie, E. J.; Wissely, J.; Harvey, J.; Highton, L.; Murphy, J.; Holland, C.; et al. (2022)
      Background: Women testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer (OC). The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers. Methods: Women were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/OC cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk. Results: In total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range = 0.01-24.3; total = 4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO-10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of OC (RRSO versus non-RRSO) was 100%. Conclusion: Over a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.
    • Establishing metastatic prostate cancer quality indicators using a modified Delphi approach

      Zheng, J.; Sampurno, F.; George, D. J.; Morgans, A. K.; Nguyen, H.; Abrahm, J. L.; Bjartell, A.; Davis, I. D.; Fitch, M. I.; Gillessen, Silke; et al. (2022)
      Background There is variation in the care provided to men with metastatic prostate cancer (mPCa). There has been no previous set of quality indicators (QIs) regarding the management of men with mPCa. The objective of this study is to develop a set of international mPCa-specific QIs, which will enable global benchmarking of quality of care. Materials and methods Potential QIs were identified through a literature review. Fourteen multidisciplinary mPCa experts (representing medical and radiation oncology, nursing, psychology, palliative care and urology) from eight countries participated in a modified Delphi process, which consisted of two online surveys, one face-to-face meeting and two teleconferences. Panelists were asked to rate each indicator's importance and feasibility on a Likert scale from 1 to 9. Indicators that received median importance and median feasibility scores ≥ 7.5, and a disagreement index <1 for both measures, on the final round of voting were included in the final set. Results There was consensus on 23 QIs out of total of 662. Four regarding “general management”, 12 “therapies”, three “complications” and four “patient-reported quality of life”. One of the inherent limitations of the Delphi process is that there is a small expert panel involved. Conclusion The quality indicator set defined by our process for management of men with mPCa will enable greater understanding of the standard and variation of care globally and will promote consistency of good practice. Future directions will include retrospective evaluation for compliance with these indicators, as well as prospective monitoring.
    • Tissue-resident FOLR2(+) macrophages associate with CD8(+) T cell infiltration in human breast cancer

      Ramos, R. N.; Missolo-Koussou, Y.; Gerber-Ferder, Y.; Bromley, Christian P; Bugatti, M.; Nunez, N. G.; Boari, J. T.; Richer, W.; Menger, L.; Denizeau, J.; et al. (2022)
      Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
    • Prevalence of cataract among Australian commercial airline pilots

      Miura, K.; Coroneo, M.; Dusingize, J. C.; Olsen, C. M.; Tinker, R.; Karipidis, K.; Hosegood, I.; Green, A. C. (2022)
      Because little is known about cataract in pilots, we estimated prevalence by anonymously ascertaining all commercial airline pilots diagnosed with cataract 2011–2016 using the electronic Medical Records System of the Australian Civil Aviation Safety Authority. Of 14,163 Australian male commercial pilots licensed in 2011, 1286 aged ≥60 had biennial eye examinations showing a cataract prevalence of 11.6%. Among 12,877 pilots aged <60, based on compulsory eye examinations only when first licensed, prevalence was 0.5%. There was no significant difference by ambient ultraviolet (UV) radiation levels in state of residence though lowest prevalence was seen in the low-UV state of Victoria. Most cataract in pilots ≥60 years was bilateral and of mild severity, while cataract in pilots <60 were more likely to be unilateral and of greater severity.
    • Bariatric surgery-induced high-density lipoprotein functionality enhancement is associated with reduced inflammation

      Adam, Safwaan; Ho, J. H.; Liu, Y.; Siahmansur, T.; Siddals, K.; Iqbal, Z.; Azmi, S.; Senapati, S.; New, J.; Jeziorska, M.; et al. (2022)
      Background: Emerging evidence suggests an association between impaired high-density lipoprotein (HDL) functionality and cardiovascular disease (CVD). HDL is essential for reverse cholesterol transport (RCT) and reduces inflammation and oxidative stress principally via paraoxonase-1 (PON1). RCT depends on HDL's capacity to accept cholesterol (cholesterol efflux capacity [CEC]) and active transport through ATP-binding cassette (ABC) A1, G1, and scavenger receptor-B1 (SR-B1). We have studied the impact of Roux-en-Y gastric bypass (RYGB) in morbidly obese subjects on RCT and HDL functionality. Methods: Biomarkers associated with increased CVD risk including tumour necrosis factor-α (TNF-α), high-sensitivity C-reactive protein (hsCRP), myeloperoxidase mass (MPO), PON1 activity, and CEC in vitro were measured in 44 patients before and 6 and 12 months after RYGB. Overweight but otherwise healthy (mean body mass index [BMI] 28 kg/m2) subjects acted as controls. Twelve participants also underwent gluteal subcutaneous adipose tissue biopsies before and 6 months after RYGB for targeted gene expression (ABCA1, ABCG1, SR-B1, TNF-α) and histological analysis (adipocyte size, macrophage density, TNF-α immunostaining). Results: Significant (P < 0.05) improvements in BMI, HDL-cholesterol, hsCRP, TNF-α, MPO mass, PON1 activity, and CEC in vitro were observed after RYGB. ABCG1 (fold-change, 2.24; P = 0.005) and ABCA1 gene expression increased significantly (fold-change, 1.34; P = 0.05). Gluteal fat adipocyte size (P < 0.0001), macrophage density (P = 0.0067), and TNF-α immunostaining (P = 0.0425) were reduced after RYBG and ABCG1 expression correlated inversely with TNF-α immunostaining (r = -0.71; P = 0.03). Conclusion: RYGB enhances HDL functionality in association with a reduction in adipose tissue and systemic inflammation.
    • Highlights from the 2022 ASCO gastrointestinal cancer symposium: An overview by the EORTC gastrointestinal tract cancer group

      Sclafani, F.; Fontana, E.; Wyrwicz, L.; Wagner, A. D.; Valle, Juan W; Smyth, E.; Peeters, M.; Obermannova, R.; Neuzillet, C.; Lutz, M. P.; et al. (2022)
      Recently, we have witnessed impressive diagnostic and therapeutic changes for gastrointestinal cancer patients. New challenges brought by the COVID-19 pandemic have led us to re-evaluate our work priorities. Thanks to the commendable resilience of both investigators and patients, however, clinical research never stopped. In addition to conducting cutting-edge research and serving patients' needs, as EORTC Gastrointestinal Tract Cancer Group, we are committed to pursuing educational initiatives beneficial to the entire European oncology community and beyond. In this regard, we have been providing critical discussions of new data from major international meetings. In this article, we discuss results of important selected studies presented at the 2022 ASCO Gastrointestinal Cancer Symposium, putting them in perspectives and highlighting potential implications for routine practice. With the number of in-person attendees and practice-changing/informing trials presented, this meeting represented a milestone in the return to normality as well as in the fight against cancer.
    • Multi-institutional matched comparison of radical cystectomy to trimodality therapy for muscle-invasive bladder cancer

      Zlotta, A. R.; Ballas, L. K.; Niemierko, A.; Lajkosz, K.; Kuk, C.; Miranda, G.; Drumm, M.; Mari, A.; Fleshner, N. E.; Kulkarni, G. S.; et al. (2022)
      Background: Prior randomized controlled trials (RCT) comparing bladder preservation to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC) closed early due to lack of accrual. Given that no future RCTs are foreseen, and in the absence of level 1 data, we aimed to provide the best evidence possible on outcomes of matched cohorts comparing trimodality therapy (TMT, maximal transurethral resection of bladder tumor followed by concurrent chemoradiation) to RC in order to guide management. Methods: This retrospective analysis included 703 patients with MIBC clinical stage T2-T3/4aN0M0 MIBC urothelial carcinoma of the bladder, 421 RC and 282 TMT who would have been eligible for both TMT or RC, treated at the Massachusetts General Hospital, Boston; Princess Margaret Cancer Centre, Toronto; and University of Southern California, Los Angeles between 2005-2017. To compare homogeneous cohorts, all patients included in this analysis had solitary tumors < 7 cm, no or unilateral hydronephrosis, and no multifocal carcinoma in situ. Treatment propensity scores were estimated using logistic regression, and patients were matched 3:1 with replacement. Covariates included age, sex, clinical T stage, hydronephrosis, (neo)adjuvant chemotherapy, body mass index, smoking history, and ECOG status. Overall survival (OS) was estimated with adjusted Cox models; cancer-specific survival (CSS), distant failure-free survival, pelvic nodal failure-free survival and metastasis-free survival (combined distant and pelvic nodal failure) were estimated with adjusted competing risk models. Our primary endpoint of interest was metastasis-free survival. The analysis was performed as intent-to-treat. Results: The 3:1 matched cohort comprised of 1,116 patients (834 RC vs 282 TMT). After matching, age (71.3 vs 71.6), cT2 clinical stage (88 vs 90%), presence of hydronephrosis (12 vs 10%), and use of (neo)adjuvant chemotherapy (60 vs 65%) were similar between RC and TMT cohorts. Salvage cystectomy was performed in 38 patients (13%) treated by TMT. At 5 years, metastasis-free (73 vs 78%, p = 0.07), distant failure-free (78 vs 82%, p = 0.14), and pelvic nodal failure-free (96 vs 94%, p = 0.33) survival were not statistically different between RC and TMT, whereas CSS and OS favored TMT (78 vs 85%, p = 0.02; 70 vs 78%, p < 0.001). Outcomes for RC and TMT were not different among centers. Final pT stage in the RC patients was: pT0 14%, pT1 7%, pT2 29%, pT3/4 42% and N+ 24%. Peri RC mortality was 2.1% and median number of nodes removed was 40. NMIBC recurrence occurred in 57/278 (20.5%) TMT patients. Conclusions: This large multi-institutional contemporary study provides the best evidence to date, in the absence of randomized trials, supporting TMT for select patients with MIBC. Oncologic outcomes seem to be equivalent between TMT and RC, affirming the position that TMT should be offered as an effective alternative.
    • VIOLETTE: Randomised phase II study of olaparib (ola) plus ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC)

      Tutt, A.; Nowecki, Z.; Szoszkiewicz, R.; Im, S. A.; Arkenau, H. T.; Armstrong, Anne C; Jacot, W.; Kim, J. H.; Webster, M.; Balmana, J.; et al. (2022)
      Background: Combining DNA damage response (DDR) inhibitors to inhibit multiple DDR pathways may enhance tumour cell death. Preclinical models show synergistic antitumour effects of ola (PARP1 inhibitor) + cer (ATR inhibitor) or ada (WEE1 in- hibitor). VIOLETTE (NCT03330847), a phase 2 open-label study, evaluated ola cer or ada as 2nde3rd line in pts with mTNBC. Methods: Randomisation was stratified within each arm by mutation status (BRCAm, non-BRCAm homologous recombination repair pathway mutations [HRRm], or no HRRm [non-HRRm]) based on a prospective central tumour test and prior platinum therapy. Pts received ola 300 mg BID, 28-d cycle; cer 160 mg d 1e7 + ola 300 mg BID (cer+ola), 28-d cycle; or ada 150 mg BID d 1e3, 8e10 + ola 200 mg BID (ada+ola), 21- d cycle. Primary study endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), safety, and tolerability. Ada+ola was discontinued early due to higher than expected grade 3 haematologic toxicity, which limited its interpretation. We focus on cer+ola vs ola. The sponsor stopped VIOLETTE after reviewing BRCAm stratum efficacy data. Results: Of 273 pts (450 planned; median age: 53 y), 114 received ola, 112 cer+ola, and 47 ada+ola. Primary analyses showed no statistically significant difference in PFS for cer+ola vs ola (BRCAm: n¼83; HR 1.02 [90% CI 0.63e1.66, P¼0.94], HRRm: n¼40; 0.54 [0.28e1.03, 0.13], non-HRRm: n¼103; 0.76 [0.50e1.14, 0.30]). No statistically significant difference in ORR was seen for cer+ola vs ola in BRCAm (50% vs 44%) or HRRm (20% vs 15%). ORR was higher in non-HRRm for cer+ola (15%, n¼8) vs ola (4%, n¼2) (odds ratio 4.45; 90% CI 1.30e21.20, P¼0.04). In all pts, nausea and anaemia were the most common adverse events (AEs). Grade 3 AEs: 36% ola, 47% cer+ola, 78% ada+ola. Details of exploratory and subgroup analyses will be presented. Conclusions: Cer+ola did not improve PFS vs ola as 2nde3rd line for mTNBC. Clinical significance of higher ORR with cer+ola in non-HRRm pts is unclear. Cer+ola had a manageable safety profile consistent with known profiles of each. Further analyses may identify pts likely to benefit from each treatment.
    • Biomarker and multivariate analyses results from AIPAC: A phase IIb study comparing eftilagimod alpha (a soluble LAG-3 protein) vs placebo in combination with weekly paclitaxel in HR+HER2-metastatic breast cancer

      Marme, F.; Wildiers, H.; Dirix, L.; Armstrong, Anne C; De Cuypere, E.; Dalenc, F.; Schroder, C. P.; Vuylsteke, P.; Brain, E.; Kuemmel, S.; et al. (2022)
      Background: Eftilagimod alpha (EF) is a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules and mediates activation of antigen-presenting cells followed by T-cells. AIPAC investigated EF + paclitaxel (PA). We hereby report exploratory biomarker and multivariate analyses. Methods: This double-blinded, 1:1 randomized phase IIb trial enrolled pts with HR+ HER2- MBC. Pts received PA (80 mg/m2 IV on D1, D8, D15) + EF (30 mg) or placebo (PL) on D2, D16 per cycle (28 days) for 24 wks + EF/PL for 52 wks. Exploratory EPs were potential biomarkers and their correlation to efficacy. Multivariate analysis used backward selection p>0.15 (univariate cox model). Blood cell subsets (CD4; CD8, PBMCs, monocytes) & Th1 biomarker CXCL-10 were measured centrally. Comparison was done using 2-sided Wilcoxon test. Results: 226 pts [efti n¼114; placebo n¼112] were included. Pts were endocrine resistant (84%), pre-treated with CDK4/6 inhibitors (44.2%). Post-study treatment was similar. Safety/efficacy were reported at SABCS 2020 #132; SITC 2021 #948 In the multivariate predictive model 4 groups (high Neutrophil/Lymphocyte Ratio [NLR]; no prior taxanes; low monocytes and <5 yrs since diagnosis) were significant for OS (Table) On treatment mean fold-changes of monocytes (5.81 vs. 2.29; p¼0.025), PBMCs (2.00 vs. 1.41; p¼0.041), T cells (2.28 vs. 1.48; p¼0.086), & CXCL10 (2.78 vs. 1.56; p¼0.06) were significantly higher (EF vs PL) and linked to higher OS. Post baseline CD4 (median 896/ml vs. 736 ml; p¼0.038) & CD8 (median 377/ml vs. 223 ml; p¼0.005) T cell count increased significantly in pts with higher OS EF vs. PL. Conclusions: EF + PA elicits significant effects on different immune cells which is significantly associated with higher OS. Multivariate analysis identified potential traget populations for phase III.
    • Surgical outcome measures in a cohort of patients at high risk of breast cancer treated by bilateral risk reducing mastectomy and breast reconstruction

      Gandhi, A.; Duxbury, P.; Clancy, T.; Lalloo, F.; Wisely, J. A.; Kirwan, C. C.; Foden, P.; Stocking, K.; Howell, Anthony; Evans, D. G.; et al. (2022)
      Introduction: Women with breast cancer related genetic pathogenic variants (e.g. BRCA1, BRCA2) or with a strong family history carry lifetime risks of developing breast cancer of up to 80-90%. A significant proportion of these women proceed to bilateral risk reducing mastectomy (RRM). We aimed to document the surgical morbidity of RRM and establish whether a diagnosis of breast cancer at the time of surgery impacted on outcomes. Methods: Clinical details of 445 women identified as having >25% lifetime risk of developing breast cancer who underwent RRM and breast reconstruction were interrogated for surgical outcomes such as planned, unplanned and emergency procedures, complication rates, length of stay and longevity of breast reconstruction. These outcome measures were recorded in women diagnosed with breast cancer perioperatively (cancer group, CG) and those without malignancy (benign group, BG). Results: Median follow up was similar in both groups (BG, 70months; CG 73 months). Patients were older in the CG than BG (43y v 39y; p<0.001). Women in the CG required more planned procedures to complete reconstruction than those in the BG (4 v 2; p=0.002). Emergency procedures, unplanned surgical interventions (e.g. capsulectomy) and post reconstruction complication rates were similar between groups.One in five women overall required revisional surgery. Patients with autologous reconstructions had a revision rate of 1.24/1000 person years compared with 2.52 in the implant reconstruction group. Conclusion: Women contemplating RRM can be reassured that this a safe and effective procedure but will likely take multiple interventions. This knowledge should be integral to obtaining informed consent.
    • Contemporary breast cancer treatment-associated thrombosis

      Kirwan, Cliona C; Blower, Emma L; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Cancer Research Centre, University of Manchester, United Kingdom of Great Britain and Northern Ireland (2022)
      Although cancer-associated thrombosis (CAT) is relatively uncommon in breast cancer compared to other solid cancers, as breast cancer is the most commonly diagnosed cancer in women worldwide, the financial and per sonal cost of breast cancer associated thrombosis (BrCAT) is significant. This increasing risk of BrCAT over time parallels modern developments in breast cancer management. This review comprehensively reports the evidence for BrCAT in the context of modern breast cancer treatments. The risk of BrCAT is most pronounced within the first 3 months to year of diagnosis. The risk of BrCAT in creases with operating time, paralleling the increasing frequency of immediate breast reconstruction. Systemic therapies such as chemotherapy and tamoxifen have well recognised thrombogenic effects, that are exacerbated by surgery and supplementary treatments such as colony-stimulating factors, steroids, and bisphosphonates however risk assessment tools are not designed specifically for this lower-VTE risk cancer. Cyclin-dependent kinases 4 and 6 (CDK4/6) Inhibitors, used in metastatic breast cancer, with trials ongoing in early disease, appear to have a class thrombogenic effect, although there is no increase CAT risk with other breast cancer targeted therapies. Given the numerous prothrombotic treatments facing patients within the first year of diagnosis, from surgery, chemotherapy, targeted therapies and endocrine therapy, a more personalised approach considering the additive effects of each individual patient’s pathway, as well as their pre-existing risk factors, needs to be considered.