Sir Peter MacCallum Department of Oncology - Research Publications

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    SP142 PD-L1 Scoring Shows High Interobserver and Intraobserver Agreement in Triple-negative Breast Carcinoma But Overall Low Percentage Agreement With Other PD-L1 Clones SP263 and 22C3
    Pang, J-MB ; Castles, B ; Byrne, DJ ; Button, P ; Hendry, S ; Lakhani, SR ; Sivasubramaniam, V ; Cooper, WA ; Armes, J ; Millar, EKA ; Raymond, W ; Roberts-Thomson, S ; Kumar, B ; Burr, M ; Selinger, C ; Harvey, K ; Chan, C ; Beith, J ; Clouston, D ; O'Toole, SA ; Fox, SB (LIPPINCOTT WILLIAMS & WILKINS, 2021-08-01)
    SP142 programmed cell death ligand 1 (PD-L1) status predicts response to atezolizumab in triple-negative breast carcinoma (TNBC). Prevalence of VENTANA PD-L1 (SP142) Assay positivity, concordance with the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay, and association with clinicopathologic features were assessed in 447 TNBCs. SP142 PD-L1 intraobserver and interobserver agreement was investigated in a subset of 60 TNBCs, with scores enriched around the 1% cutoff. The effect of a 1-hour training video on pretraining and posttraining scores was ascertained. At a 1% cutoff, 34.2% of tumors were SP142 PD-L1 positive. SP142 PD-L1 positivity was significantly associated with tumor-infiltrating lymphocytes (P <0.01), and node negativity (P=0.02), but not with tumor grade (P=0.35), tumor size (P=0.58), or BRCA mutation (P=0.53). Overall percentage agreement (OPA) for intraobserver and interobserver agreement was 95.0% and 93.7%, respectively, among 5 pathologists trained in TNBC SP142 PD-L1 scoring. In 5 TNBC SP142 PD-L1-naive pathologists, significantly higher OPA to the reference score was achieved after video training (posttraining OPA 85.7%, pretraining OPA 81.5%, P<0.05). PD-L1 status at a 1% cutoff was assessed by SP142 and SP263 in 420 cases, and by SP142 and 22C3 in 423 cases, with OPA of 88.1% and 85.8%, respectively. The VENTANA PD-L1 (SP142) Assay is reproducible for classifying TNBC PD-L1 status by trained observers; however, it is not analytically equivalent to the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay.
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    Adequate tumour cellularity is essential for accurate PD-L1 immunohistochemistry assessment on cytology cell-block specimens
    Hendry, S ; Byrne, DJ ; Christie, M ; Steinfort, DP ; Irving, LB ; Wagner, C-A ; Ellwood, T ; Cooper, WA ; Fox, SB (WILEY, 2020-01-11)
    OBJECTIVES: PD-L1 immunohistochemistry (IHC) is an essential predictive biomarker for patients with non-small cell lung cancer (NSCLC), required to inform treatment decisions regarding anti-PD-1 immune checkpoint inhibitor therapy. This study aims to investigate the concordance between PD-L1 IHC assessed on NSCLC cytology and histology specimens and to determine the impactce of tumour cellularity. METHODS: Matched cytology and histology NSCLC specimens were retrieved from the archives of the Royal Melbourne Hospital and the Royal Prince Alfred Hospital. PD-L1 IHC was performed concurrently on both specimens at the Peter MacCallum Cancer Centre using the SP263 assay kit on the Ventana Benchmark Ultra staining platform and scored by two experienced pathologists. RESULTS: Overall agreement between matched cytology and histology specimens was good (intraclass correlation coefficient = 0.653, n = 58); however, markedly increased when the analysis was limited to cell-blocks with >100 tumour cells (intraclass correlation coefficient = 0.957, n = 29). Specificity at both 1% and 50% cut-offs was high regardless of cellularity; however, sensitivity decreased in samples with <100 tumour cells. CONCLUSIONS: PD-L1 IHC on cytology cell-block specimens in NSCLC is an acceptable alternative to histological specimens, provided adequate tumour cells are present. Clinicians and pathologists should be mindful of the risk of false negative PD-L1 IHC in samples with low tumour cellularity, to avoid excluding patients from potentially beneficial treatment.
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    CD8(+) tumor-infiltrating lymphocytes within the primary tumor of patients with synchronous de novo metastatic colorectal carcinoma do not track with survival
    Millen, R ; Hendry, S ; Narasimhan, V ; Abbott, R ; Croxford, M ; Gibbs, P ; Tie, J ; Wong, H-L ; Jones, I ; Kosmider, S ; Byrne, D ; Zalcberg, J ; Fox, S ; Desai, J ; Visvanathan, K ; Ramsay, RG ; Tran, B (WILEY, 2020-01-01)
    OBJECTIVES: Tumor-infiltrating lymphocytes (TIL), particularly CD8+ TILs in patients with colorectal cancer (CRC), are highly prognostic in the early-disease stages (I-II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented de novo with mCRC. METHODS: Treatment-naïve patients (109) with mCRC were assessed for CD8+ TILs and PD-L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel. RESULTS: Microsatellite instability-high tumors had significantly more CD8+ TILs, with no significant survival advantage observed between MSI-H and microsatellite stable (MSS) tumors (12 vs 19 months, P = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months, P = 0.426), while PD-L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months; P = 0.038). MSI-H tumors and associated immune cells had higher PD-L1 expression than in MSS cases. A positive correlation between PD-L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI-H tumors. CONCLUSION: In contrast to early-stage CRC, the immune response in primary tumors of patients with de novo mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD-L1 comparable to MSI-H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.
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    Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer
    Kos, Z ; Roblin, E ; Kim, RS ; Michiels, S ; Gallas, BD ; Chen, W ; van de Vijver, KK ; Goel, S ; Adams, S ; Demaria, S ; Viale, G ; Nielsen, TO ; Badve, SS ; Symmans, WF ; Sotiriou, C ; Rimm, DL ; Hewitt, S ; Denkert, C ; Loibl, S ; Luen, SJ ; Bartlett, JMS ; Savas, P ; Pruneri, G ; Dillon, DA ; Cheang, MCU ; Tutt, A ; Hall, JA ; Kok, M ; Horlings, HM ; Madabhushi, A ; van der Laak, J ; Ciompi, F ; Laenkholm, A-V ; Bellolio, E ; Gruosso, T ; Fox, SB ; Araya, JC ; Floris, G ; Hudecek, J ; Voorwerk, L ; Beck, AH ; Kerner, J ; Larsimont, D ; Declercq, S ; Van den Eynden, G ; Pusztai, L ; Ehinger, A ; Yang, W ; AbdulJabbar, K ; Yuan, Y ; Singh, R ; Hiley, C ; al Bakir, M ; Lazar, AJ ; Naber, S ; Wienert, S ; Castillo, M ; Curigliano, G ; Dieci, M-V ; Andre, F ; Swanton, C ; Reis-Filho, J ; Sparano, J ; Balslev, E ; Chen, I-C ; Stovgaard, EIS ; Pogue-Geile, K ; Blenman, KRM ; Penault-Llorca, F ; Schnitt, S ; Lakhani, SR ; Vincent-Salomon, A ; Rojo, F ; Braybrooke, JP ; Hanna, MG ; Soler-Monso, MT ; Bethmann, D ; Castaneda, CA ; Willard-Gallo, K ; Sharma, A ; Lien, H-C ; Fineberg, S ; Thagaard, J ; Comerma, L ; Gonzalez-Ericsson, P ; Brogi, E ; Loi, S ; Saltz, J ; Klaushen, F ; Cooper, L ; Amgad, M ; Moore, DA ; Salgado, R (NATURE RESEARCH, 2020-05-12)
    Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.
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    Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group
    Amgad, M ; Stovgaard, ES ; Balslev, E ; Thagaard, J ; Chen, W ; Dudgeon, S ; Sharma, A ; Kerner, JK ; Denkert, C ; Yuan, Y ; AbdulJabbar, K ; Wienert, S ; Savas, P ; Voorwerk, L ; Beck, AH ; Madabhushi, A ; Hartman, J ; Sebastian, MM ; Horlings, HM ; Hudecek, J ; Ciompi, F ; Moore, DA ; Singh, R ; Roblin, E ; Balancin, ML ; Mathieu, M-C ; Lennerz, JK ; Kirtani, P ; Chen, I-C ; Braybrooke, JP ; Pruneri, G ; Demaria, S ; Adams, S ; Schnitt, SJ ; Lakhani, SR ; Rojo, F ; Comerma, L ; Badve, SS ; Khojasteh, M ; Symmans, WF ; Sotiriou, C ; Gonzalez-Ericsson, P ; Pogue-Geile, KL ; Kim, RS ; Rimm, DL ; Viale, G ; Hewitt, SM ; Bartlett, JMS ; Penault-Llorca, F ; Goel, S ; Lien, H-C ; Loibl, S ; Kos, Z ; Loi, S ; Hanna, MG ; Michiels, S ; Kok, M ; Nielsen, TO ; Lazar, AJ ; Bago-Horvath, Z ; Kooreman, LFS ; van der Laak, JAWM ; Saltz, J ; Gallas, BD ; Kurkure, U ; Barnes, M ; Salgado, R ; Cooper, LAD (NATURE RESEARCH, 2020-05-12)
    Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.
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    Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials
    Hudecek, J ; Voorwerk, L ; van Seijen, M ; Nederlof, I ; de Maaker, M ; van den Berg, J ; van de Vijver, KK ; Sikorska, K ; Adams, S ; Demaria, S ; Viale, G ; Nielsen, TO ; Badve, SS ; Michiels, S ; Symmans, WF ; Sotiriou, C ; Rimm, DL ; Hewitt, SM ; Denkert, C ; Loibl, S ; Loi, S ; Bartlett, JMS ; Pruneri, G ; Dillon, DA ; Cheang, MCU ; Tutt, A ; Hall, JA ; Kos, Z ; Salgado, R ; Kok, M ; Horlings, HM (NATURE RESEARCH, 2020-05-12)
    Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting.