Sir Peter MacCallum Department of Oncology - Research Publications

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    Tumour mutational burden: an overview for pathologists.
    Doig, KD ; Fellowes, A ; Scott, P ; Fox, SB (Elsevier BV, 2022-04)
    Cancer immunotherapy holds great promise and has shown durable responses in many patients; however, these responses are not uniform in all patients or all tumour streams. There is an ongoing clinical need for objective diagnostic biomarkers to identify patients that will respond to immunotherapies. Tumour mutational burden (TMB) is a diagnostic biomarker that can stratify cancer patients for response to immune checkpoint inhibitor therapies. It is commonly defined as the average number of somatic mutations per megabase in a tumour exome. Here we describe the TMB biomarker, how it is determined, its underlying molecular basis, the relationship to neoantigens and the issues around its clinical use. This overview is directed toward practising pathologists wishing to be informed of this predictive biomarker.
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    Findings from precision oncology in the clinic: rare, novel variants are a significant contributor to scaling molecular diagnostics
    Doig, KD ; Love, CG ; Conway, T ; Seleznev, A ; Ma, D ; Fellowes, A ; Blombery, P ; Fox, SB (BMC, 2022-03-26)
    BACKGROUND: Next generation sequencing for oncology patient management is now routine in clinical pathology laboratories. Although wet lab, sequencing and pipeline tasks are largely automated, the analysis of variants for clinical reporting remains largely a manual task. The increasing volume of sequencing data and the limited availability of genetic experts to analyse and report on variants in the data is a key scalability limit for molecular diagnostics. METHOD: To determine the impact and size of the issue, we examined the longitudinally compiled genetic variants from 48,036 cancer patients over a six year period in a large cancer hospital from ten targeted cancer panel tests in germline, solid tumour and haematology contexts using hybridization capture and amplicon assays. This testing generated 24,168,398 sequenced variants of which 23,255 (8214 unique) were clinically reported. RESULTS: Of the reported variants, 17,240 (74.1%) were identified in more than one assay which allowed curated variant data to be reused in later reports. The remainder, 6015 (25.9%) were not subsequently seen in later assays and did not provide any reuse benefit. The number of new variants requiring curation has significantly increased over time from 1.72 to 3.73 variants per sample (292 curated variants per month). Analysis of the 23,255 variants reported, showed 28.6% (n = 2356) were not present in common public variant resources and therefore required de novo curation. These in-house only variants were enriched for indels, tumour suppressor genes and from solid tumour assays. CONCLUSION: This analysis highlights the significant percentage of variants not present within common public variant resources and the level of non-recurrent variants that consequently require greater curation effort. Many of these variants are unique to a single patient and unlikely to appear in other patients reflecting the personalised nature of cancer genomics. This study depicts the real-world situation for pathology laboratories faced with curating increasing numbers of low-recurrence variants while needing to expedite the process of manual variant curation. In the absence of suitably accurate automated methods, new approaches are needed to scale oncology diagnostics for future genetic testing volumes.
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    Common variants in breast cancer risk loci predispose to distinct tumor subtypes
    Ahearn, TU ; Zhang, H ; Michailidou, K ; Milne, RL ; Bolla, MK ; Dennis, J ; Dunning, AM ; Lush, M ; Wang, Q ; Andrulis, IL ; Anton-Culver, H ; Arndt, V ; Aronson, KJ ; Auer, PL ; Augustinsson, A ; Baten, A ; Becher, H ; Behrens, S ; Benitez, J ; Bermisheva, M ; Blomqvist, C ; Bojesen, SE ; Bonanni, B ; Borresen-Dale, A-L ; Brauch, H ; Brenner, H ; Brooks-Wilson, A ; Bruening, T ; Burwinkel, B ; Buys, SS ; Canzian, F ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Devilee, P ; Dork, T ; Dwek, M ; Eccles, DM ; Evans, DG ; Fasching, PA ; Figueroa, J ; Floris, G ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Goldberg, MS ; Gonzalez-Neira, A ; Alnaes, GIG ; Grip, M ; Guenel, P ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Heemskerk-Gerritsen, BAM ; Holleczek, B ; Hollestelle, A ; Hooning, MJ ; Hoover, RN ; Hopper, JL ; Howell, A ; Jakimovska, M ; Jakubowska, A ; John, EM ; Jones, ME ; Jung, A ; Kaaks, R ; Kauppila, S ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Koutros, S ; Kristensen, VN ; Kruger, U ; Kubelka-Sabit, K ; Kurian, AW ; Kyriacou, K ; Lambrechts, D ; Lee, DG ; Lindblom, A ; Linet, M ; Lissowska, J ; Llaneza, A ; Lo, W-Y ; MacInnis, RJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Martinez, ME ; McLean, C ; Meindl, A ; Menon, U ; Nevanlinna, H ; Newman, WG ; Nodora, J ; Offit, K ; Olsson, H ; Orr, N ; Park-Simon, T-W ; Patel, A ; Peto, J ; Pita, G ; Plaseska-Karanfilska, D ; Prentice, R ; Punie, K ; Pylkas, K ; Radice, P ; Rennert, G ; Romero, A ; Ruediger, T ; Saloustros, E ; Sampson, S ; Sandler, DP ; Sawyer, EJ ; Schmutzler, RK ; Schoemaker, MJ ; Schottker, B ; Sherman, ME ; Shu, X-O ; Smichkoska, S ; Southey, MC ; Spinelli, JJ ; Swerdlow, AJ ; Tamimi, RM ; Tapper, WJ ; Taylor, JA ; Teras, LR ; Terry, MB ; Torres, D ; Troester, MA ; Vachon, CM ; van Deurzen, CHM ; van Veen, EM ; Wagner, P ; Weinberg, CR ; Wendt, C ; Wesseling, J ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Couch, FJ ; Simard, J ; Kraft, P ; Easton, DF ; Pharoah, PDP ; Schmidt, MK ; Garcia-Closas, M ; Chatterjee, N (BMC, 2022-01-04)
    BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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    In vitro and in vivo drug screens of tumor cells identify novel therapies for high-risk child cancer
    Lau, LMS ; Mayoh, C ; Xie, J ; Barahona, P ; MacKenzie, KL ; Wong, M ; Kamili, A ; Tsoli, M ; Failes, TW ; Kumar, A ; Mould, EVA ; Gifford, A ; Chow, S-O ; Pinese, M ; Fletcher, J ; Arndt, GM ; Khuong-Quang, D-A ; Wadham, C ; Eden, G ; Trebilcock, P ; Joshi, S ; Alfred, S ; Gopalakrishnan, A ; Khan, A ; Wade, DG ; Strong, PA ; Manouvrier, E ; Morgan, LT ; Cadiz, R ; Ung, C ; Thomas, DM ; Tucker, KM ; Warby, M ; McCowage, GB ; Dalla-Pozza, L ; Byrne, JA ; Saletta, F ; Fellowes, A ; Fox, SB ; Norris, MD ; Tyrrell, V ; Trahair, TN ; Lock, RB ; Cowley, MJ ; Ekert, PG ; Haber, M ; Ziegler, DS ; Marshall, GM (WILEY, 2021-12-20)
    Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.
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    BRAF Signaling Inhibition in Glioblastoma: Which Clinical Perspectives?
    Bouche, V ; Aldegheri, G ; Donofrio, CA ; Fioravanti, A ; Roberts-Thomson, S ; Fox, SB ; Schettini, F ; Generali, D (FRONTIERS MEDIA SA, 2021-11-03)
    IDH-wild type (wt) glioblastoma (GB) accounts for approximately 90% of all GB and has a poor outcome. Surgery and adjuvant therapy with temozolomide and radiotherapy is the main therapeutic approach. Unfortunately, after relapse and progression, which occurs in most cases, there are very limited therapeutic options available. BRAF which plays a role in the oncogenesis of several malignant tumors, is also involved in a small proportion of IDH-wt GB. Previous successes with anti-B-Raf targeted therapy in tumors with V600E BRAF mutation like melanoma, combined with the poor prognosis and paucity of therapeutic options for GB patients is leading to a growing interest in the potential efficacy of this approach. This review is thus focused on dissecting the state of the art and future perspectives on BRAF pathway inhibition in IDH-wt GB. Overall, clinical efficacy is mostly described within case reports and umbrella trials, with promising but still insufficient results to draw more definitive conclusions. Further studies are needed to better define the molecular and phenotypic features that predict for a favorable response to treatment. In addition, limitations of B-Raf-inhibitors, in monotherapy or in combination with other therapeutic partners, to penetrate the blood-brain barrier and the development of acquired resistance mechanisms responsible for tumor progression need to be addressed.
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    TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members
    Delahunty, R ; Nguyen, L ; Craig, S ; Creighton, B ; Ariyaratne, D ; Garsed, DW ; Christie, E ; Fereday, S ; Andrews, L ; Lewis, A ; Limb, S ; Pandey, A ; Hendley, J ; Traficante, N ; Carvajal, N ; Spurdle, AB ; Thompson, B ; Parsons, MT ; Beshay, V ; Volcheck, M ; Semple, T ; Lupat, R ; Doig, K ; Yu, J ; Chen, XQ ; Marsh, A ; Love, C ; Bilic, S ; Beilin, M ; Nichols, CB ; Greer, C ; Lee, YC ; Gerty, S ; Gill, L ; Newton, E ; Howard, J ; Williams, R ; Norris, C ; Stephens, AN ; Tutty, E ; Smyth, C ; O'Connell, S ; Jobling, T ; Stewart, CJR ; Tan, A ; Fox, SB ; Pachter, N ; Li, J ; Ellul, J ; Mir Arnau, G ; Young, M-A ; Gordon, L ; Forrest, L ; Harris, M ; Livingstone, K ; Hill, J ; Chenevix-Trench, G ; Cohen, PA ; Webb, PM ; Friedlander, M ; James, P ; Bowtell, D ; Alsop, K (LIPPINCOTT WILLIAMS & WILKINS, 2022-06-20)
    PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.
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    Rare germline copy number variants (CNVs) and breast cancer risk
    Dennis, J ; Tyrer, JP ; Walker, LC ; Michailidou, K ; Dorling, L ; Bolla, MK ; Wang, Q ; Ahearn, TU ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Arndt, V ; Aronson, KJ ; Freeman, LEB ; Beckmann, MW ; Behrens, S ; Benitez, J ; Bermisheva, M ; Bogdanova, N ; Bojesen, SE ; Brenner, H ; Castelao, JE ; Chang-Claude, J ; Chenevix-Trench, G ; Clarke, CL ; Collee, JM ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Devilee, P ; Dork, T ; Dossus, L ; Eliassen, AH ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Fletcher, O ; Flyger, H ; Fritschi, L ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Closas, M ; Giles, GG ; Gonzalez-Neira, A ; Guenel, P ; Hahnen, E ; Haiman, CA ; Hall, P ; Hollestelle, A ; Hoppe, R ; Hopper, JL ; Howell, A ; Jager, A ; Jakubowska, A ; John, EM ; Johnson, N ; Jones, ME ; Jung, A ; Kaaks, R ; Keeman, R ; Khusnutdinova, E ; Kitahara, CM ; Ko, Y-D ; Kosma, V-M ; Koutros, S ; Kraft, P ; Kristensen, VN ; Kubelka-Sabit, K ; Kurian, AW ; Lacey, J ; Lambrechts, D ; Larson, NL ; Linet, M ; Ogrodniczak, A ; Mannermaa, A ; Manoukian, S ; Margolin, S ; Mavroudis, D ; Milne, RL ; Muranen, TA ; Murphy, RA ; Nevanlinna, H ; Olson, JE ; Olsson, H ; Park-Simon, T-W ; Perou, CM ; Peterlongo, P ; Plaseska-Karanfilska, D ; Pylkas, K ; Rennert, G ; Saloustros, E ; Sandler, DP ; Sawyer, EJ ; Schmidt, MK ; Schmutzler, RK ; Shibli, R ; Smeets, A ; Soucy, P ; Southey, MC ; Swerdlow, AJ ; Tamimi, RM ; Taylor, JA ; Teras, LR ; Terry, MB ; Tomlinson, I ; Troester, MA ; Truong, T ; Vachon, CM ; Wendt, C ; Winqvist, R ; Wolk, A ; Yang, XR ; Zheng, W ; Ziogas, A ; Simard, J ; Dunning, AM ; Pharoah, PDP ; Easton, DF (NATURE PORTFOLIO, 2022-01-18)
    Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
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    Precision oncology using a clinician-directed, tailored approach to molecular profiling
    Lam, M ; Tran, B ; Beck, S ; Tie, J ; Herath, D ; Whittle, J ; Kwan, EM ; Fox, SB ; Fellowes, A ; Ananda, S ; Lipton, L ; Gibbs, P ; Rosenthal, MA ; Desai, J (WILEY, 2018-02-01)
    AIM: Precision oncology involves molecularly matching patients to targeted agents usually in early drug development (EDD) programs. Molecular profiling (MP) identifies actionable targets. Comprehensive commercial MP platforms are costly and in resource limited environments, a more practical approach to MP is necessary to support EDD and precision oncology. We adopted a clinician-directed, tailored approach to MP to enrol patients onto molecularly targeted trials. We report the feasibility of this approach. METHODS: All patients referred to the Royal Melbourne Hospital (RMH) EDD between September 2013 and September 2015 were identified in a prospective database. Key captured data included clinicopathological data, MP platform ordered (if any), molecular targets identified and subsequent enrolment onto clinical trials. EDD-clinician decisions to order MP and the platform utilized was guided by patient consultation, tumor type, trial availability and requirement for molecular information. RESULTS: We identified 377 patients referred to RMH EDD. A total of 216 (57%) had MP ordered. The remainder had known actionable targets (19%), or were inappropriate for clinical trials (24%). In those undergoing MP, 187 genetic aberrations were found in 113 patients with 98 considered actionable targets in 86 patients. Ninety-eight (25%) patients were enrolled onto a clinical trial, including 40 (11%) receiving molecularly matched treatments. Median progression-free survival was improved in patients enrolled onto molecularly matched trials compared to those on unmatched trials (3.6 months vs 1.9 months, HR 0.58 [0.38-0.89], P  =  0.013). CONCLUSION: A clinician-directed, tailored approach to the use of MP is feasible, resulting in 11% of patients enrolled onto molecularly matched trials.
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    Australian recommendations for EGFR T790M testing in advanced non-small cell lung cancer
    John, T ; Bowden, JJ ; Clarke, S ; Fox, SB ; Garrett, K ; Horwood, K ; Karapetis, CS (WILEY, 2017-08-01)
    First-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as first-line therapy in patients with non-small cell lung cancer (NSCLC) harboring a sensitizing mutation in the EGFR gene. Unfortunately, resistance to these therapies often occurs within 10 months of commencing treatment and is mostly commonly due to the development of the EGFR T790M mutation. Treatment with the third-generation EGFR TKI, osimertinib can prolong progression free survival in patients with the T790M mutation, so it is important to determine the resistance mechanism in order to plan ongoing therapeutic strategies. Here we review the evidence and make recommendations for the timing of T790M mutation testing, the most appropriate specimens to test and the available testing methods in patients progressing during treatment with first line EGFR TKIs for NSCLC.
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    Cousins not twins: intratumoural and intertumoural heterogeneity in syndromic neuroendocrine tumours
    Flynn, A ; Dwight, T ; Benn, D ; Deb, S ; Colebatch, AJ ; Fox, S ; Harris, J ; Duncan, EL ; Robinson, B ; Hogg, A ; Ellul, J ; To, H ; Cuong, D ; Miller, JA ; Yates, C ; James, P ; Trainer, A ; Gill, AJ ; Clifton-Bligh, R ; Hicks, RJ ; Tothill, RW (WILEY, 2017-07-01)