Sir Peter MacCallum Department of Oncology - Research Publications

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    Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival
    Morra, A ; Schreurs, MAC ; Andrulis, IL ; Anton-Culver, H ; Augustinsson, A ; Beckmann, MW ; Behrens, S ; Bojesen, SE ; Bolla, MK ; Brauch, H ; Broeks, A ; Buys, SS ; Camp, NJ ; Castelao, JE ; Cessna, MH ; Chang-Claude, J ; Chung, WK ; Colonna, S ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Daly, MB ; Dennis, J ; Devilee, P ; Doerk, T ; Dunning, AM ; Dwek, M ; Easton, DF ; Eccles, DM ; Eriksson, M ; Evans, DG ; Fasching, PA ; Fehm, TN ; Figueroa, JD ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Closas, M ; Garcia-Saenz, JA ; Genkinger, JA ; Grassmann, F ; Guendert, M ; Hahnen, E ; Haiman, C ; Hamann, U ; Harrington, PA ; Hartikainen, JM ; Hoppe, R ; Hopper, JL ; Houlston, RS ; Howell, A ; Jakubowska, A ; Janni, W ; Jernstroem, H ; John, EM ; Johnson, N ; Jones, ME ; Kristensen, VN ; Kurian, AW ; Lambrechts, D ; Le Marchand, L ; Lindblom, A ; Lubinski, J ; Lux, MP ; Mannermaa, A ; Mavroudis, D ; Mulligan, AM ; Muranen, TA ; Nevanlinna, H ; Nevelsteen, I ; Neven, P ; Newman, WG ; Obi, N ; Offit, K ; Olshan, AF ; Park-Simon, T-W ; Patel, A ; Peterlongo, P ; Phillips, K-A ; Plaseska-Karanfilska, D ; Polley, EC ; Presneau, N ; Pylkas, K ; Rack, B ; Radice, P ; Rashid, MU ; Rhenius, V ; Robson, M ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schmutzler, RK ; Schuetze, S ; Scott, C ; Shah, MT ; Smichkoska, S ; Southey, MC ; Tapper, WJ ; Teras, LR ; Tollenaar, RAEM ; Tomczyk, K ; Tomlinson, I ; Troester, M ; Vachon, C ; van Veen, E ; Wang, Q ; Wendt, C ; Wildiers, H ; Winqvist, RA ; Ziogas, A ; Hall, P ; Pharoah, PDP ; Adank, M ; Hollestelle, A ; Schmidt, MK ; Hooning, MJ (WILEY, 2023-08)
    BACKGROUND: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. AIM: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. METHODS: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. RESULTS: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. CONCLUSION: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
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    Tumor P70S6K hyperactivation is inversely associated with tumor-infiltrating lymphocytes in triple-negative breast cancer
    Jimeno, R ; Mouron, S ; Salgado, R ; Loi, S ; Perez-Mies, B ; Sanchez-Bayona, R ; Manso, L ; Martinez, M ; Garrido-Garcia, A ; Serrano-Pardo, R ; Colomer, R ; Quintela-Fandino, M (SPRINGER INT PUBL AG, 2023-04)
    PURPOSE: Triple-negative breast cancer (TNBC) is characterized by large heterogeneity and relative lack of available targeted therapies. To find therapeutic strategies for distinct patients with TNBC, several approaches have been used for TNBC clustering, including recently immune and phosphoproteomic patterns. Based on 70-kDa ribosomal protein S6 kinase (P70S6K)-TNBC clustering, the current study explores the immune profiling in TNBC tumors. METHODS: Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated in human TNBC tumor samples. Furthermore, immunohistochemistry staining for CD8, CD4, Foxp3, and CD20 was performed in tissue microarrays (TMA) sections. RESULTS: Histological analysis showed decreased sTILs, CD20+ cells, and CD8+/CD4+ ratio in high phosphorylated P70S6K (p-P70S6K) tumors. Moreover, p-P70S6K score was directly correlated with CD4+ and Foxp3+ T cells, while it was inversely correlated with CD8+/CD4+ and CD8+/Foxp3+ ratios. CONCLUSION: sTIL infiltration and lymphocyte profiling vary in the context of hyperactivation of P70S6K in TNBC tumors.
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    BRINGING THE BENCH TO THE BEDSIDE: UPDATES ON THE MIND STUDY AND WHAT A ROUTINELY AVAILABLE SIMPLE BLOOD TEST FOR NEUROFILAMENT LIGHT WOULD MEAN AT THE CLINICAL COAL FACE FOR PATIENTS AND FAMILIES, PSYCHIATRISTS, NEUROLOGISTS, GERIATRICIANS AND GENERAL PRACTITIONERS
    Eratne, D ; Lewis, C ; Cadwallader, C ; Kang, M ; Keem, M ; Santillo, A ; Li, QX ; Stehmann, C ; Loi, SM ; Walterfang, M ; Watson, R ; Yassi, N ; Blennow, K ; Zetterberg, H ; Janelidze, S ; Hansson, O ; Berry-Kravitz, E ; Brodtmann, A ; Darby, D ; Walker, A ; Dean, O ; Masters, CL ; Collins, S ; Berkovic, SF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2022-05)
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    Ethnicity, Immunity, and Outcomes: Biology versus Socioeconomic Status
    Bergin, ART ; Salgado, R ; Loi, S (AMER ASSOC CANCER RESEARCH, 2023-06-02)
    Substantial advances in our understanding of breast cancer disease biology have led to marked improvements in cancer outcomes over the past two decades. These advances have largely focused on women from developed, high-income countries and as a result, significant disparities exist. In this issue, Bauer and colleagues provide new insight into the breast cancer immune microenvironment from women across geographic regions in sub-Saharan Africa, despite inherent infrastructure limitations. The study amassed data from 1,497 women from sub-Saharan Africa, and 117 women from Germany with breast cancer, suggesting regional variation in immune composition but with no significant prognostic impact. These important findings require validation in large, codesigned prospective studies to fully understand the impact of biology, ethnicity, and socioeconomic status on breast cancer outcomes. See related article by Bauer and colleagues (2) .
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    Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer
    Li, R ; Sant, S ; Brown, E ; Caramia, F ; Nikolic, B ; Clarke, K ; Byrne, A ; Gonzalez, LEL ; Savas, P ; Luen, SJ ; Teo, ZL ; Virassamy, B ; Neeson, PJ ; Darcy, PK ; Loi, S (OXFORD UNIV PRESS INC, 2023-07-06)
    BACKGROUND: Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. METHODS: We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. RESULTS: In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. CONCLUSION: Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.
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    Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
    Teo, ZL ; O'Connor, MJ ; Versaci, S ; Clarke, KA ; Brown, ER ; Percy, LW ; Kuykhoven, K ; Mintoff, CP ; Savas, P ; Virassamy, B ; Luen, SJ ; Byrne, A ; Sant, S ; Lindeman, GJ ; Darcy, PK ; Loi, S (NATURE PORTFOLIO, 2023-08-15)
    Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation. Combinations with a STING agonist resulted in further improved durable tumour regression and significant improvements in survival outcomes in murine tumour models of BRCA1/2 wild-type TNBC. In addition, we have identified baseline tumour-infiltrating lymphocyte (TIL) levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapies in BRCA1/2 wild-type TNBC.
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    CRISPR-Cas9 screening identifies an IRF1-SOCS1-mediated negative feedback loop that limits CXCL9 expression and antitumor immunity
    House, IG ; Derrick, EB ; Sek, K ; Chen, AXY ; Li, J ; Lai, J ; Todd, KL ; Munoz, I ; Michie, J ; Chan, CW ; Huang, Y-K ; Chan, JD ; Petley, E ; Tong, J ; Nguyen, D ; Engel, S ; Savas, P ; Hogg, SJ ; Vervoort, SJ ; Kearney, CJ ; Burr, ML ; Lam, EYN ; Gilan, O ; Bedoui, S ; Johnstone, RW ; Dawson, MA ; Loi, S ; Darcy, PK ; Beavis, PA (CELL PRESS, 2023-08-29)
    CXCL9 expression is a strong predictor of response to immune checkpoint blockade therapy. Accordingly, we sought to develop therapeutic strategies to enhance the expression of CXCL9 and augment antitumor immunity. To perform whole-genome CRISPR-Cas9 screening for regulators of CXCL9 expression, a CXCL9-GFP reporter line is generated using a CRISPR knockin strategy. This approach finds that IRF1 limits CXCL9 expression in both tumor cells and primary myeloid cells through induction of SOCS1, which subsequently limits STAT1 signaling. Thus, we identify a subset of STAT1-dependent genes that do not require IRF1 for their transcription, including CXCL9. Targeting of either IRF1 or SOCS1 potently enhances CXCL9 expression by intratumoral macrophages, which is further enhanced in the context of immune checkpoint blockade therapy. We hence show a non-canonical role for IRF1 in limiting the expression of a subset of STAT1-dependent genes through induction of SOCS1.
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    Spatial analyses of immune cell infiltration in cancer: current methods and future directions. A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer
    Page, DB ; Broeckx, G ; Jahangir, CA ; Jahangir, C ; Verbandt, S ; Gupta, RR ; Thagaard, J ; Khiroya, R ; Kos, Z ; Abduljabbar, K ; Acosta Haab, G ; Acs, B ; Almeida, JS ; Alvarado-Cabrero, I ; Azmoudeh-Ardalan, F ; Badve, S ; Baharun, NB ; Bellolio, ER ; Bheemaraju, V ; Blenman, KRM ; Botinelly Mendonca Fujimoto, L ; Burgues, O ; Cheang, MCU ; Ciompi, F ; Cooper, LAD ; Coosemans, A ; Corredor, G ; Dantas Portela, FL ; Deman, F ; Demaria, S ; Dudgeon, SN ; Elghazawy, M ; Ely, S ; Fernandez-Martin, C ; Fineberg, S ; Fox, SB ; Gallagher, WM ; Giltnane, JM ; Gnjatic, S ; Gonzalez-Ericsson, P ; Grigoriadis, A ; Halama, N ; Hanna, MG ; Harbhajanka, A ; Hardas, A ; Hart, SN ; Hartman, J ; Hewitt, S ; Hida, A ; Horlings, HM ; Husain, Z ; Hytopoulos, E ; Irshad, S ; Janssen, EAM ; Kahila, M ; Kataoka, TR ; Kawaguchi, K ; Kharidehal, D ; Khramtsov, A ; Kiraz, U ; Kirtani, P ; Kodach, LL ; Korski, K ; Kovacs, A ; Laenkholm, A-V ; Lang-Schwarz, C ; Larsimont, D ; Lennerz, JK ; Lerousseau, M ; Li, X ; Ly, A ; Madabhushi, A ; Maley, SK ; Manur Narasimhamurthy, V ; Marks, DK ; McDonald, ES ; Mehrotra, R ; Michiels, S ; Minhas, FUAA ; Mittal, S ; Moore, DA ; Mushtaq, S ; Nighat, H ; Papathomas, T ; Penault-Llorca, F ; Perera, RD ; Pinard, CJ ; Pinto-Cardenas, JC ; Pruneri, G ; Pusztai, L ; Rahman, A ; Rajpoot, NM ; Rapoport, BL ; Rau, TT ; Reis-Filho, JS ; Ribeiro, JM ; Rimm, D ; Salomon, A-V ; Salto-Tellez, M ; Saltz, J ; Sayed, S ; Siziopikou, KP ; Sotiriou, C ; Stenzinger, A ; Sughayer, MA ; Sur, D ; Symmans, F ; Tanaka, S ; Taxter, T ; Tejpar, S ; Teuwen, J ; Thompson, EA ; Tramm, T ; Tran, WT ; van Der Laak, J ; van Diest, PJ ; Verghese, GE ; Viale, G ; Vieth, M ; Wahab, N ; Walter, T ; Waumans, Y ; Wen, HY ; Yang, W ; Yuan, Y ; Adams, S ; Bartlett, JMS ; Loibl, S ; Denkert, C ; Savas, P ; Loi, S ; Salgado, R ; Specht Stovgaard, E ; Akturk, G ; Bouchmaa, N (WILEY, 2023-08)
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    Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: a report of the international immuno-oncology biomarker working group
    Thagaard, J ; Broeckx, G ; Page, DB ; Jahangir, CA ; Verbandt, S ; Kos, Z ; Gupta, R ; Khiroya, R ; Abduljabbar, K ; Acosta Haab, G ; Acs, B ; Akturk, G ; Almeida, JS ; Alvarado-Cabrero, I ; Amgad, M ; Azmoudeh-Ardalan, F ; Badve, S ; Baharun, NB ; Balslev, E ; Bellolio, ER ; Bheemaraju, V ; Blenman, KRM ; Botinelly Mendonca Fujimoto, L ; Bouchmaa, N ; Burgues, O ; Chardas, A ; Cheang, MU ; Ciompi, F ; Cooper, LAD ; Coosemans, A ; Corredor, G ; Dahl, AB ; Dantas Portela, FL ; Deman, F ; Demaria, S ; Dore Hansen, J ; Dudgeon, SN ; Ebstrup, T ; Elghazawy, M ; Fernandez-Martin, C ; Fox, SB ; Gallagher, WM ; Giltnane, JM ; Gnjatic, S ; Gonzalez-Ericsson, P ; Grigoriadis, A ; Halama, N ; Hanna, MG ; Harbhajanka, A ; Hart, SN ; Hartman, J ; Hauberg, S ; Hewitt, S ; Hida, A ; Horlings, HM ; Husain, Z ; Hytopoulos, E ; Irshad, S ; Janssen, EAM ; Kahila, M ; Kataoka, TR ; Kawaguchi, K ; Kharidehal, D ; Khramtsov, A ; Kiraz, U ; Kirtani, P ; Kodach, LL ; Korski, K ; Kovacs, A ; Laenkholm, A-V ; Lang-Schwarz, C ; Larsimont, D ; Lennerz, JK ; Lerousseau, M ; Li, X ; Ly, A ; Madabhushi, A ; Maley, SK ; Manur Narasimhamurthy, V ; Marks, DK ; McDonald, ES ; Mehrotra, R ; Michiels, S ; Minhas, FUAA ; Mittal, S ; Moore, DA ; Mushtaq, S ; Nighat, H ; Papathomas, T ; Penault-Llorca, F ; Perera, RD ; Pinard, CJ ; Pinto-Cardenas, JC ; Pruneri, G ; Pusztai, L ; Rahman, A ; Rajpoot, NM ; Rapoport, BL ; Rau, TT ; Reis-Filho, JS ; Ribeiro, JM ; Rimm, D ; Roslind, A ; Vincent-Salomon, A ; Salto-Tellez, M ; Saltz, J ; Sayed, S ; Scott, E ; Siziopikou, KP ; Sotiriou, C ; Stenzinger, A ; Sughayer, MA ; Sur, D ; Fineberg, S ; Symmans, F ; Tanaka, S ; Taxter, T ; Tejpar, S ; Teuwen, J ; Thompson, EA ; Tramm, T ; Tran, WT ; van Der Laak, J ; van Diest, PJ ; Verghese, GE ; Viale, G ; Vieth, M ; Wahab, N ; Walter, T ; Waumans, Y ; Wen, HY ; Yang, W ; Yuan, Y ; Zin, RM ; Adams, S ; Bartlett, J ; Loibl, S ; Denkert, C ; Savas, P ; Loi, S ; Salgado, R ; Specht Stovgaard, E (WILEY, 2023-08)
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    Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial.
    Jhaveri, K ; Eli, LD ; Wildiers, H ; Hurvitz, SA ; Guerrero-Zotano, A ; Unni, N ; Brufsky, A ; Park, H ; Waisman, J ; Yang, ES ; Spanggaard, I ; Reid, S ; Burkard, ME ; Vinayak, S ; Prat, A ; Arnedos, M ; Bidard, F-C ; Loi, S ; Crown, J ; Bhave, M ; Piha-Paul, SA ; Suga, JM ; Chia, S ; Saura, C ; Garcia-Saenz, JÁ ; Gambardella, V ; de Miguel, MJ ; Gal-Yam, EN ; Rapael, A ; Stemmer, SM ; Ma, C ; Hanker, AB ; Ye, D ; Goldman, JW ; Bose, R ; Peterson, L ; Bell, JSK ; Frazier, A ; DiPrimeo, D ; Wong, A ; Arteaga, CL ; Solit, DB (Elsevier BV, 2023-10)
    BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.