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119 results on '"Zabaglo, Lila A."'

1. Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study

Author

Acs, Balazs, Leung, Samuel CY, Kidwell, Kelley M, Arun, Indu, Augulis, Renaldas, Badve, Sunil S, Bai, Yalai, Bane, Anita L, Bartlett, John MS, Bayani, Jane, Bigras, Gilbert, Blank, Annika, Buikema, Henk, Chang, Martin C, Dietz, Robin L, Dodson, Andrew, Fineberg, Susan, Focke, Cornelia M, Gao, Dongxia, Gown, Allen M, Gutierrez, Carolina, Hartman, Johan, Kos, Zuzana, Lænkholm, Anne-Vibeke, Laurinavicius, Arvydas, Levenson, Richard M, Mahboubi-Ardakani, Rustin, Mastropasqua, Mauro G, Nofech-Mozes, Sharon, Osborne, C Kent, Penault-Llorca, Frédérique M, Piper, Tammy, Quintayo, Mary Anne, Rau, Tilman T, Reinhard, Stefan, Robertson, Stephanie, Salgado, Roberto, Sugie, Tomoharu, van der Vegt, Bert, Viale, Giuseppe, Zabaglo, Lila A, Hayes, Daniel F, Dowsett, Mitch, Nielsen, Torsten O, and Rimm, David L

Subjects
Cancer, Clinical Research, Breast Cancer, Biomarkers, Tumor, Biopsy, Breast Neoplasms, Female, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Ki-67 Antigen, Receptors, Estrogen, International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, Medical and Health Sciences, Pathology
Abstract

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error (p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections (p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.

Published
2022

2. Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015)

Author

Bliss, Judith M., Tovey, Holly, Evans, Abigail, Holcombe, Chris, Horgan, Kieran, Mallon, Elizabeth, Vidya, Raghavan, Skene, Anthony, Dodson, Andrew, Hills, Margaret, Detre, Simone, Zabaglo, Lila, Banerji, Jane, Kilburn, Lucy, Morden, James P., Robertson, John F. R., Smith, Ian, and Dowsett, Mitch

Published
2023
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3. Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study

Author

Lundgren, Katja, Brown, Matthew, Pineda Sanjuan, Silvia, Cuzick, Jack, Salter, Janine, Zabaglo, Lila, Howell, Anthony, Dowsett, Mitch, Landberg, Göran, TransATAC investigators, Lundgren, Katja, Brown, Matthew, Pineda Sanjuan, Silvia, Cuzick, Jack, Salter, Janine, Zabaglo, Lila, Howell, Anthony, Dowsett, Mitch, Landberg, Göran, and TransATAC investigators

Abstract

Introduction: Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D 1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen.Methods: To clarify these challenging and partly contrasting treatment predictive and prognostic links for cyclin D 1 we analysed a large cohort of postmenopausal breast cancer patients randomised to receive either adjuvant anastrozole or tamoxifen, as part of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The CCND1 amplification status and protein expression of cyclin D 1 were assessed by chromogenic in situ hybridisation and immunohistochemistry, respectively, in 1,155 postmenopausal, oestrogen-receptor-positive breast cancer patients included in the TransATAC substudy.Results: Amplification of CCND1 was observed in 8.7% of the tumours and was associated with increased risk of disease recurrence (hazard ratio = 1.61; 95% confidence interval, 1.08 to 2.41) after adjustment for other clinicopathological parameters. In contrast, nuclear expression of cyclin D 1 protein was associated with decreased recurrence rate (hazard ratio = 0.6; 95% confidence interval, 0.39 to 0.92). The intensity of nuclear or cytoplasmic expression was not of prognostic value. There was no significant interaction between cyclin D 1 status and treatment efficacy, ruling out any major detrimental effect of tamoxifen in CCND1-amplified postmenopausal breast cancer.Conclusions: In summary, CCND1 amplification and low nuclear expression of cyclin D 1 predicted poor clinical outcome in postmenopausal breast cancer patients treated with either anastrozole or tamoxifen., Lund University Research Funds, Malmö University Hospital, South Swedish and South-East Swedish Breast Cancer groups and Breakthrough Breast Cancer Unit, AstraZeneca, Roche, Cancerfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Depto. de Estadística y Ciencia de los Datos, Fac. de Estudios Estadísticos, TRUE, pub

Published
2024

4. Predictive algorithms for adjuvant therapy: TransATAC

Author

Penning, T.M., Dowsett, Mitch, Salter, Janine, Zabaglo, Lila, Mallon, Elizabeth, Howell, Antony, Buzdar, Aman U, Forbes, John, Pineda Sanjuan, Silvia, Cuzick, Jack, Penning, T.M., Dowsett, Mitch, Salter, Janine, Zabaglo, Lila, Mallon, Elizabeth, Howell, Antony, Buzdar, Aman U, Forbes, John, Pineda Sanjuan, Silvia, and Cuzick, Jack

Abstract

Estrogen receptor (ER) positive primary breast cancers have a wide range of clinical outcomes. Prediction of the likely course of the disease aids treatment decision-making. In the translational arm of the ATAC (anastrozole or tamoxifen alone or combined) trial (TransATAC) we have assessed individual and multiparameter biomarkers for their prediction of overall and distant recurrence. None of the biomarkers identified differential benefit for anastrozole versus tamoxifen. Each of ER, PgR, HER2 and Ki67 was associated with risk of recurrence. A combination of these to create a single predictor IHC4 was as informative as the 21-gene recurrence score (RS). Integration of each of these molecular profiles with classical clinicopathologic variables provided the most accurate prediction of outcome, Breakthrough Breast Cancer, AstraZeneca, Depto. de Estadística y Ciencia de los Datos, Fac. de Estudios Estadísticos, TRUE, pub

Published
2024

5. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer

Author

Jack Cuzick, Dowsett, Mitch, Pineda Sanjuan, Silvia, Wale, Christopher, Salter, Janine, Quinn, Emma, Zabaglo, Lila, Mallon, Elizabeth, R Green, Andrew, Ellis, Ian O, Howell, Anthony, Buzdar, Aman U, Forbes, John F, Jack Cuzick, Dowsett, Mitch, Pineda Sanjuan, Silvia, Wale, Christopher, Salter, Janine, Quinn, Emma, Zabaglo, Lila, Mallon, Elizabeth, R Green, Andrew, Ellis, Ian O, Howell, Anthony, Buzdar, Aman U, and Forbes, John F

Abstract

Purpose We recently reported that the mRNA-based, 21-gene Genomic Health recurrence score (GHI-RS) provided additional prognostic information regarding distant recurrence beyond that obtained from classical clinicopathologic factors (age, nodal status, tumor size, grade, endocrine treatment) in women with early breast cancer, confirming earlier reports. The aim of this article is to determine how much of this information is contained in standard immunohistochemical (IHC) markers. Patients and Methods The primary cohort comprised 1,125 estrogen receptor–positive (ER-positive) patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial who did not receive adjuvant chemotherapy, had the GHI-RS computed, and had adequate tissue for the four IHC measurements: ER, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67. Distant recurrence was the primary end point, and proportional hazards models were used with sample splitting to control for overfitting. A prognostic model that used classical variables and the four IHC markers (IHC4 score) was created and assessed in a separate cohort of 786 patients. Results All four IHC markers provided independent prognostic information in the presence of classical variables. In sample-splitting analyses, the information in the IHC4 score was found to be similar to that in the GHI-RS, and little additional prognostic value was seen in the combined use of both scores. The prognostic value of the IHC4 score was further validated in the second separate cohort. Conclusion This study suggests that the amount of prognostic information contained in four widely performed IHC assays is similar to that in the GHI-RS. Additional studies are needed to determine the general applicability of the IHC4 score., Royal Marsden National Institute for Health Research Biomedical Research Centre, Cancer Research United Kingdom Program Grant, Breakthrough Breast Cancer, AstraZeneca, Depto. de Estadística y Ciencia de los Datos, Fac. de Estudios Estadísticos, TRUE, pub

Published
2024

6. Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers

Author

Schuster, Eugene F., primary, Lopez-Knowles, Elena, additional, Alataki, Anastasia, additional, Zabaglo, Lila, additional, Folkerd, Elizabeth, additional, Evans, David, additional, Sidhu, Kally, additional, Cheang, Maggie Chon U., additional, Tovey, Holly, additional, Salto-Tellez, Manuel, additional, Maxwell, Perry, additional, Robertson, John, additional, Smith, Ian, additional, Bliss, Judith M., additional, and Dowsett, Mitch, additional

Published
2023
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7. Correction to: Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer

Author

Pancholi, Sunil, Leal, Mariana Ferreira, Ribas, Ricardo, Simigdala, Nikiana, Schuster, Eugene, Chateau-Joubert, Sophie, Zabaglo, Lila, Hills, Margaret, Dodson, Andrew, Gao, Qiong, Johnston, Stephen R., Dowsett, Mitch, Cosulich, Sabina C., Marangoni, Elisabetta, and Martin, Lesley-Ann

Published
2020
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9. The relationship between hypoxia, proliferation and apoptosis in murine CaNT tumours and human HT29 xenografts

Author

Zabaglo, Lila

Subjects
616.994
Abstract

Tumour hypoxia and cell proliferation are two factors which greatly influence cancer therapy. In this thesis the cell biology of tumours whose internal micro-environment was perturbed by therapeutically-relevant radiation doses or an oxygenation modifier (carbogen) was investigated. A well-defined murine experimental tumour, CaNT, and a widely used human tumour xenograft, HT29 were used in vivo and in vitro to study the relationship between hypoxia, proliferation and apoptosis. Hypoxia was assessed by measuring the incorporation of 7-(4'-(2-nitroimidazole-1-yl)-butyl)-theophylline (NITP), an immunologically identifiable hypoxia marker that binds bioreductively to cells under low-oxygen conditions. Experiments investigating the influence of various oxygen levels on NITP binding in separate phases of the cell cycle showed that aneuploid G2 cells disaggregated from CaNT tumours bind more NITP at all oxygen tensions than cells in other phases. The NITP binding in G1 and S phase cells was similar which could suggest that this phenomenon may be independent of cell size. HT29 xenografts showed a similar pattern of NITP binding, but with a lower overall nitroreductase activity compared with that seen in the murine tumours. CaNT and HT29 cells grown in vitro for several cell generations showed a different pattern of NITP binding. Simultaneous fluorescent staining of cells for hypoxia (NITP), proliferation (BrdUrd) and DNA content showed that treatment with a single fraction of carbogen induced a G2 phase delay in CaNT tumours. A 2-hour exposure of CaNT tumours to carbogen induced apoptosis, measured with the TdT assay, which could reflect re-perfusion injury to previously hypoxic cells. The experiments exploring the influence of carbogen breathing on proliferation in HT29 xenografts showed marked changes to the cell cycle. In HT29 xenografts carbogen treatment did not alter the cell cycle progression of oxic cells, whereas hypoxic cells completely halted progression through the cell cycle. The apoptotic response of CaNT and HT29 cell lines to radiation-induced DNA damage was investigated both in vivo and in vitro. CaNT and HT29 cell lines showed little or no radiation-induced apoptosis in vitro respectively. In contrast, in vivo doses as small as 0.5 Gy caused marked apoptosis. In CaNT tumours, the number of apoptotic cells increased from 10% in the controls to 33% 2 hours post treatment with 0.5 Gy. The percentage of apoptosis remained at an elevated level (22%) even 24 hours after irradiation. HT29 xenografts treated with 0.5 and 5 Gy X-rays showed 24 and 26% apoptosis respectively. The influence of micro-environmental factors such as hypoxia, nutrient deprivation and cell density on the induction of apoptosis was tested in vitro. However none of these factors could explain the differences between the apoptotic response to ionising radiation in vivo and in vitro.

Published
2000

10. Copy number calls from The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer

Author

Barry, Peter, primary, Vatsiou, Alexandra, primary, Spiteri, Inmaculada, primary, Nichol, Daniel, primary, Cresswell, George D., primary, Acar, Ahmet, primary, Trahearn, Nicholas, primary, Hrebien, Sarah, primary, Garcia-Murillas, Isaac, primary, Chkhaidze, Kate, primary, Ermini, Luca, primary, Huntingford, Ian Said, primary, Cottom, Hannah, primary, Zabaglo, Lila, primary, Koelble, Konrad, primary, Khalique, Saira, primary, Rusby, Jennifer E., primary, Muscara, Francesca, primary, Dowsett, Mitch, primary, Maley, Carlo C., primary, Natrajan, Rachael, primary, Yuan, Yinyin, primary, Schiavon, Gaia, primary, Turner, Nicholas, primary, and Sottoriva, Andrea, primary

Published
2023
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11. Table S2 from The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer

Author

Barry, Peter, primary, Vatsiou, Alexandra, primary, Spiteri, Inmaculada, primary, Nichol, Daniel, primary, Cresswell, George D., primary, Acar, Ahmet, primary, Trahearn, Nicholas, primary, Hrebien, Sarah, primary, Garcia-Murillas, Isaac, primary, Chkhaidze, Kate, primary, Ermini, Luca, primary, Huntingford, Ian Said, primary, Cottom, Hannah, primary, Zabaglo, Lila, primary, Koelble, Konrad, primary, Khalique, Saira, primary, Rusby, Jennifer E., primary, Muscara, Francesca, primary, Dowsett, Mitch, primary, Maley, Carlo C., primary, Natrajan, Rachael, primary, Yuan, Yinyin, primary, Schiavon, Gaia, primary, Turner, Nicholas, primary, and Sottoriva, Andrea, primary

Published
2023
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12. Supplementary methods from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Author

Leal, Mariana Ferreira, primary, Haynes, Ben P., primary, Schuster, Eugene, primary, Yeo, Belinda, primary, Afentakis, Maria, primary, Zabaglo, Lila, primary, Martins, Vera, primary, Buus, Richard, primary, Dodson, Andrew, primary, Cheang, Maggie C.U., primary, Smith, Ian E., primary, Martin, Lesley-Ann, primary, and Dowsett, Mitch, primary

Published
2023
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13. Supplementary Figures from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Author

Leal, Mariana Ferreira, primary, Haynes, Ben P., primary, Schuster, Eugene, primary, Yeo, Belinda, primary, Afentakis, Maria, primary, Zabaglo, Lila, primary, Martins, Vera, primary, Buus, Richard, primary, Dodson, Andrew, primary, Cheang, Maggie C.U., primary, Smith, Ian E., primary, Martin, Lesley-Ann, primary, and Dowsett, Mitch, primary

Published
2023
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14. Supplementary Figure 3 from The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer

Author

Barry, Peter, primary, Vatsiou, Alexandra, primary, Spiteri, Inmaculada, primary, Nichol, Daniel, primary, Cresswell, George D., primary, Acar, Ahmet, primary, Trahearn, Nicholas, primary, Hrebien, Sarah, primary, Garcia-Murillas, Isaac, primary, Chkhaidze, Kate, primary, Ermini, Luca, primary, Huntingford, Ian Said, primary, Cottom, Hannah, primary, Zabaglo, Lila, primary, Koelble, Konrad, primary, Khalique, Saira, primary, Rusby, Jennifer E., primary, Muscara, Francesca, primary, Dowsett, Mitch, primary, Maley, Carlo C., primary, Natrajan, Rachael, primary, Yuan, Yinyin, primary, Schiavon, Gaia, primary, Turner, Nicholas, primary, and Sottoriva, Andrea, primary

Published
2023
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15. Supplementary Material and Methods from The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer

Author

Barry, Peter, primary, Vatsiou, Alexandra, primary, Spiteri, Inmaculada, primary, Nichol, Daniel, primary, Cresswell, George D., primary, Acar, Ahmet, primary, Trahearn, Nicholas, primary, Hrebien, Sarah, primary, Garcia-Murillas, Isaac, primary, Chkhaidze, Kate, primary, Ermini, Luca, primary, Huntingford, Ian Said, primary, Cottom, Hannah, primary, Zabaglo, Lila, primary, Koelble, Konrad, primary, Khalique, Saira, primary, Rusby, Jennifer E., primary, Muscara, Francesca, primary, Dowsett, Mitch, primary, Maley, Carlo C., primary, Natrajan, Rachael, primary, Yuan, Yinyin, primary, Schiavon, Gaia, primary, Turner, Nicholas, primary, and Sottoriva, Andrea, primary

Published
2023
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16. Supplementary Tables from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Author

Leal, Mariana Ferreira, primary, Haynes, Ben P., primary, Schuster, Eugene, primary, Yeo, Belinda, primary, Afentakis, Maria, primary, Zabaglo, Lila, primary, Martins, Vera, primary, Buus, Richard, primary, Dodson, Andrew, primary, Cheang, Maggie C.U., primary, Smith, Ian E., primary, Martin, Lesley-Ann, primary, and Dowsett, Mitch, primary

Published
2023
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17. Supplementary Figure 8 from The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer

Author

Barry, Peter, primary, Vatsiou, Alexandra, primary, Spiteri, Inmaculada, primary, Nichol, Daniel, primary, Cresswell, George D., primary, Acar, Ahmet, primary, Trahearn, Nicholas, primary, Hrebien, Sarah, primary, Garcia-Murillas, Isaac, primary, Chkhaidze, Kate, primary, Ermini, Luca, primary, Huntingford, Ian Said, primary, Cottom, Hannah, primary, Zabaglo, Lila, primary, Koelble, Konrad, primary, Khalique, Saira, primary, Rusby, Jennifer E., primary, Muscara, Francesca, primary, Dowsett, Mitch, primary, Maley, Carlo C., primary, Natrajan, Rachael, primary, Yuan, Yinyin, primary, Schiavon, Gaia, primary, Turner, Nicholas, primary, and Sottoriva, Andrea, primary

Published
2023
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18. SUPPLEMENTARY FIGURE AND TABLE LEGENDS from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Author

Leal, Mariana Ferreira, primary, Haynes, Ben P., primary, Schuster, Eugene, primary, Yeo, Belinda, primary, Afentakis, Maria, primary, Zabaglo, Lila, primary, Martins, Vera, primary, Buus, Richard, primary, Dodson, Andrew, primary, Cheang, Maggie C.U., primary, Smith, Ian E., primary, Martin, Lesley-Ann, primary, and Dowsett, Mitch, primary

Published
2023
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19. Abstract P2-03-07: Multi-parametric algorithm integrating on-treatment Ki67 value and standard clinicopathological variables to predict risk of recurrences for women > 70 years old with early ER+HER2- tumours in POETIC trial

Author

Cheang, Maggie Chon U, primary, Dewan, Monisha, additional, Kilburn, Lucy, additional, Morani, Gabriele, additional, Zabaglo, Lila, additional, Sidhu, Kally, additional, Tovey, Holly, additional, Zhu, Xixuan, additional, Holcombe, Chris, additional, Skene, Anthony, additional, Smith, Ian, additional, Robertson, John, additional, Ring, Alistair, additional, Turner, Nicholas, additional, Bliss, Judith, additional, and Dowsett, Mitch, additional

Published
2023
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20. Abstract PD10-07: PD10-07 Low plasma estradiol, low expression of estrogen responsive genes and TP53 mutations are associated with poor anti-proliferative response to aromatase inhibitors

Author

Schuster, Eugene F., primary, López-Knowles, Elena, additional, Alataki, Anastasia, additional, Zabaglo, Lila, additional, Folkerd, Elizabeth, additional, Evans, David, additional, Sidhu, Kally, additional, Tovey, Holly, additional, Maxwell, Perry, additional, Turner, Nicholas, additional, Johnston, Stephen, additional, Salto-Tellez, Manuel, additional, Cheang, Maggie Chon U, additional, Robertson, John, additional, Smith, Ian, additional, Bliss, Judith, additional, and Dowsett, Mitch, additional

Published
2023
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21. Abstract PD10-08: PD10-08 Immune cell infiltration associated with poor anti-proliferative response to aromatase inhibitors in postmenopausal women with primary ER-positive HER2-negative breast cancer

Author

Alataki, Anastasia, primary, Schuster, Gene, additional, Zabaglo, Lila, additional, Maxwell, Perry, additional, López-Knowles, Elena, additional, Folkerd, Elizabeth, additional, Evans, David, additional, Sidhu, Kally, additional, Tovey, Holly, additional, Turner, Nicholas, additional, Johnston, Stephen, additional, Cheang, Maggie Chon U, additional, Robertson, John, additional, Salto-Tellez, Manuel, additional, Smith, Ian, additional, Bliss, Judith, additional, and Dowsett, Mitch, additional

Published
2023
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23. An international study to increase concordance in Ki67 scoring

Author

Polley, Mei-Yin C, Leung, Samuel C Y, Gao, Dongxia, Mastropasqua, Mauro G, Zabaglo, Lila A, Bartlett, John M S, McShane, Lisa M, Enos, Rebecca A, Badve, Sunil S, Bane, Anita L, Borgquist, Signe, Fineberg, Susan, Lin, Ming-Gang, Gown, Allen M, Grabau, Dorthe, Gutierrez, Carolina, Hugh, Judith C, Moriya, Takuya, Ohi, Yasuyo, Osborne, C Kent, Penault-Llorca, Frédérique M, Piper, Tammy, Porter, Peggy L, Sakatani, Takashi, Salgado, Roberto, Starczynski, Jane, Lænkholm, Anne-Vibeke, Viale, Giuseppe, Dowsett, Mitch, Hayes, Daniel F, and Nielsen, Torsten O

Published
2015
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24. Additional file 3 of Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015)

Author

Bliss, Judith M., Tovey, Holly, Evans, Abigail, Holcombe, Chris, Horgan, Kieran, Mallon, Elizabeth, Vidya, Raghavan, Skene, Anthony, Dodson, Andrew, Hills, Margaret, Detre, Simone, Zabaglo, Lila, Banerji, Jane, Kilburn, Lucy, Morden, James P., Robertson, John F. R., Smith, Ian, and Dowsett, Mitch

Abstract

Additional file 3: Fig. S3. Log fold change in Ki67 A. for patients allocated control by sample. type, B. for patients allocated AI by sample type and choice of AI. Presented separately for HER2- and HER2- patients.

Published
2023
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25. Additional file 1 of Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015)

Author

Bliss, Judith M., Tovey, Holly, Evans, Abigail, Holcombe, Chris, Horgan, Kieran, Mallon, Elizabeth, Vidya, Raghavan, Skene, Anthony, Dodson, Andrew, Hills, Margaret, Detre, Simone, Zabaglo, Lila, Banerji, Jane, Kilburn, Lucy, Morden, James P., Robertson, John F. R., Smith, Ian, and Dowsett, Mitch

Abstract

Additional file 1: Fig. S1. Distribution of Ki67Baseline a. Distribution of Ki67 % positive cells b. Distribution of ln(Ki67+0.1) c. Distribution of Ki67Baseline by HER2 status

Published
2023
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26. Additional file 2 of Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015)

Author

Bliss, Judith M., Tovey, Holly, Evans, Abigail, Holcombe, Chris, Horgan, Kieran, Mallon, Elizabeth, Vidya, Raghavan, Skene, Anthony, Dodson, Andrew, Hills, Margaret, Detre, Simone, Zabaglo, Lila, Banerji, Jane, Kilburn, Lucy, Morden, James P., Robertson, John F. R., Smith, Ian, and Dowsett, Mitch

Abstract

Additional file 2: Fig. S2. Distribution of A. log(Ki67Baseline +0.1) for all patients, B. log(Ki672week +0.1) in patients allocated control, C. log fold. change Ki67 in patients allocated control, D. log(Ki672week +0.1) in patients allocated AI and E. log fold change Ki67 in patients allocated AI. Presented separately for HER2- and HER2+ patients.

Published
2023
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27. Additional file 4 of Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015)

Author

Bliss, Judith M., Tovey, Holly, Evans, Abigail, Holcombe, Chris, Horgan, Kieran, Mallon, Elizabeth, Vidya, Raghavan, Skene, Anthony, Dodson, Andrew, Hills, Margaret, Detre, Simone, Zabaglo, Lila, Banerji, Jane, Kilburn, Lucy, Morden, James P., Robertson, John F. R., Smith, Ian, and Dowsett, Mitch

Abstract

Additional file 4: Table S1. Univariable and multivariable linear regression results for change in Ki67 in patients allocated to control by HER2 status. Table S2. Multivariable linear regression results for change in Ki67 in patients allocated to control by HER2 status showing adjustment for sample type. Table S3. Multivariable linear regression results for change in Ki67 in patients allocated to AI by HER2 status showing adjustment for sample type and AI choice. Table S4. CCCA by AI and sample type in patients allocated AI.

Published
2023
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31. An International Ki67 Reproducibility Study

Author

Polley, Mei-Yin C., Leung, Samuel C. Y., McShane, Lisa M., Gao, Dongxia, Hugh, Judith C., Mastropasqua, Mauro G., Viale, Giuseppe, Zabaglo, Lila A., Penault-Llorca, Frédérique, Bartlett, John M.S., Gown, Allen M., Symmans, W. Fraser, Piper, Tammy, Mehl, Erika, Enos, Rebecca A., Hayes, Daniel F., Dowsett, Mitch, and Nielsen, Torsten O.

Published
2013
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35. Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

Author

Leal, Mariana Ferreira, primary, Haynes, Ben P., additional, Schuster, Eugene, additional, Yeo, Belinda, additional, Afentakis, Maria, additional, Zabaglo, Lila, additional, Martins, Vera, additional, Buus, Richard, additional, Dodson, Andrew, additional, Cheang, Maggie C.U., additional, Smith, Ian E., additional, Martin, Lesley-Ann, additional, and Dowsett, Mitch, additional

Published
2019
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36. MOESM3 of Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in vitro and in vivo targets oestrogen receptor-positive endocrine-resistant breast cancer

Author

Pancholi, Sunil, Leal, Mariana, Ribas, Ricardo, Nikiana Simigdala, Schuster, Eugene, Chateau-Joubert, Sophie, Zabaglo, Lila, Hills, Margaret, Dodson, Andrew, Gao, Qiong, Johnston, Stephen, Dowsett, Mitch, Cosulich, Sabina, Maragoni, Elisabetta, and Lesley-Ann Martin

Abstract

Additional file 3: Figure S2. Effect of vistusertib on RTKs and downstream signalling pathways over a time course of 96 hours. MCF7 LTEDwt were treated for a time-course period of 24, 48, 72 and 96 hours with or without vistusertib (100 nM) in the presence or absence of E2 (0.01 nM).

Published
2019
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37. Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections:an international multicentre collaboration

Author

Leung, Samuel C.Y., Nielsen, Torsten O., Zabaglo, Lila A., Arun, Indu, Badve, Sunil S., Bane, Anita L., Bartlett, John M.S., Borgquist, Signe, Chang, Martin C., Dodson, Andrew, Ehinger, Anna, Fineberg, Susan, Focke, Cornelia M., Gao, Dongxia, Gown, Allen M., Gutierrez, Carolina, Hugh, Judith C., Kos, Zuzana, Lænkholm, Anne Vibeke, Mastropasqua, Mauro G., Moriya, Takuya, Nofech-Mozes, Sharon, Osborne, C. Kent, Penault-Llorca, Frédérique M., Piper, Tammy, Sakatani, Takashi, Salgado, Roberto, Starczynski, Jane, Sugie, Tomoharu, van der Vegt, Bert, Viale, Giuseppe, Hayes, Daniel F., McShane, Lisa M., Dowsett, Mitch, Leung, Samuel C.Y., Nielsen, Torsten O., Zabaglo, Lila A., Arun, Indu, Badve, Sunil S., Bane, Anita L., Bartlett, John M.S., Borgquist, Signe, Chang, Martin C., Dodson, Andrew, Ehinger, Anna, Fineberg, Susan, Focke, Cornelia M., Gao, Dongxia, Gown, Allen M., Gutierrez, Carolina, Hugh, Judith C., Kos, Zuzana, Lænkholm, Anne Vibeke, Mastropasqua, Mauro G., Moriya, Takuya, Nofech-Mozes, Sharon, Osborne, C. Kent, Penault-Llorca, Frédérique M., Piper, Tammy, Sakatani, Takashi, Salgado, Roberto, Starczynski, Jane, Sugie, Tomoharu, van der Vegt, Bert, Viale, Giuseppe, Hayes, Daniel F., McShane, Lisa M., and Dowsett, Mitch

Abstract

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further.

Published
2019

38. Additional file 2: of Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer

Author

Bianchini, Giampaolo, Kiermaier, Astrid, Bianchi, Giulia, Young-Hyuck Im, Pienkowski, Tadeusz, Mei-Ching Liu, Ling-Ming Tseng, Dowsett, Mitch, Zabaglo, Lila, Kirk, Sarah, Szado, Tania, Eng-Wong, Jennifer, Amler, Lukas, Valagussa, Pinuccia, and Gianni, Luca

Abstract

Figure S1. Relationship between biomarkers and pCR by treatment group and estrogen receptor status. CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase, catalytic subunit; PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, TGF transforming growth factor; WT wild-type. (PDF 836Â kb)

Published
2017
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39. Additional file 1: Table S1. of Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer

Author

Bianchini, Giampaolo, Kiermaier, Astrid, Bianchi, Giulia, Young-Hyuck Im, Pienkowski, Tadeusz, Mei-Ching Liu, Ling-Ming Tseng, Dowsett, Mitch, Zabaglo, Lila, Kirk, Sarah, Szado, Tania, Eng-Wong, Jennifer, Amler, Lukas, Valagussa, Pinuccia, and Gianni, Luca

Abstract

Biomarker analyses on the intent-to-treat population: sample sizes and technical success rates. *As a percentage of the ITT population (N = 417). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, SNP single nucleotide polymorphism, TGF transforming growth factor. Table S2. Baseline levels of all biomarkers in all four treatment groups (biomarker population, based on the intent-to-treat population). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, SNP single nucleotide polymorphism, TGF transforming growth factor. Table S3. Relationship between biomarkers and pCR, adjusted for hormone receptor status and breast cancer type (biomarker population, based on the intent-to-treat population). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Mut mutant , Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, SNP single nucleotide polymorphism, TGF transforming growth factor, WT wild-type. Cochran–Mantel–Haenszel Chi-square test based on biomarker subgroup x pCR status (2 × 2) stratified by hormone receptor status and breast cancer type. Table S4. Treatment and biomarker interaction tests comparing groups A (trastuzumab plus docetaxel) and B (pertuzumab, trastuzumab, and docetaxel) (median cut-point; biomarker population, based on the intent-to-treat population). *Subgroup defined by using a cutoff for target:centromere ratio of 2. †Subgroup defined using mutation versus no mutation. CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, SNP single nucleotide polymorphism, TGF transforming growth factor. Table S5. Relationship between biomarkers and pCR by hormone receptor status (biomarker population, based on the intent-to-treat population). CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase catalytic subunit, PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, TGF transforming growth factor. Table S6. Detailed analyses of biomarker levels by ER status. CR concentration ratio, Cyt cytoplasmic, EGF epidermal growth factor, EGFR epidermal growth factor receptor, ELISA enzyme-linked immunosorbent assay, FISH fluorescence in situ hybridization, IGF1R insulin-like growth factor 1 receptor, IHC immunohistochemistry, Mem membranous, Nuc nuclear, pCR pathologic complete response, PIK3CA gene encoding phosphoinositide 3-kinase, catalytic subunit; PTEN phosphatase and tensin homolog, qRT-PCR quantitative reverse transcription PCR, sHER2 serum HER2 extracellular domain, TGF transforming growth factor; WT wild-type. Cochran–Mantel–Haenszel Chi-square test based on biomarker subgroup × pCR status (2 × 2) stratified by breast cancer type. (DOCX 59 kb)

Published
2017
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40. The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer

Author

Barry, Peter, primary, Vatsiou, Alexandra, additional, Spiteri, Inmaculada, additional, Nichol, Daniel, additional, Cresswell, George D., additional, Acar, Ahmet, additional, Trahearn, Nicholas, additional, Hrebien, Sarah, additional, Garcia-Murillas, Isaac, additional, Chkhaidze, Kate, additional, Ermini, Luca, additional, Huntingford, Ian Said, additional, Cottom, Hannah, additional, Zabaglo, Lila, additional, Koelble, Konrad, additional, Khalique, Saira, additional, Rusby, Jennifer E., additional, Muscara, Francesca, additional, Dowsett, Mitch, additional, Maley, Carlo C., additional, Natrajan, Rachael, additional, Yuan, Yinyin, additional, Schiavon, Gaia, additional, Turner, Nicholas, additional, and Sottoriva, Andrea, additional

Published
2018
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41. Additional file 3: Figure S1. of Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas

Author

Lรณpez-Knowles, Elena, Gao, Qiong, Cheang, Maggie, Morden, James, Parker, Joel, Lesley-Ann Martin, Pinhel, Isabel, McNeill, Fiona, Hills, Margaret, Detre, Simone, Afentakis, Maria, Zabaglo, Lila, Dodson, Andrew, Skene, Anthony, Holcombe, Chris, Robertson, John, Smith, Ian, Bliss, Judith, and Dowsett, Mitch

Abstract

Paired correlations in study I. Correlation of detectable probes by Pearson correlation in 23 pairs of samples. Figure S2. Examples of paired correlations in study I. Correlation of detectable probes by Pearson correlation: the three samples with the highest correlations, median correlation and the lowest correlations. Figure S3. Correlation of 18 genes in study I. Pearson correlation of 18 genes commonly studied in breast cancer in 23 pairs of samples. Figure S4. Scatterplots of numeric differences between correlation coefficients to average gene expression profiles of intrinsic subtypes for each tumor in study I (S4A and B) and study II (S4C and D). Difference between luminal A and luminal B centroids (A and C), and luminal B and HER2-enriched centroids (C and D). Open circle: concordant subtype assignments between the two time points. Triangle: discordant subtype assignments between the two time points. Figure S5. Paired correlations in study II. Correlation of detectable probes by Pearson correlation in 56 pairs of samples. Figure S6. Correlations of 18 genes in study II. Pearson correlation of 18 genes commonly studied in breast cancer in 56 pairs of samples. (PDF 1479 kb)

Published
2016
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42. Additional file 1: of Heterogeneity in global gene expression profiles between biopsy specimens taken peri-surgically from primary ER-positive breast carcinomas

Author

LĂłpez-Knowles, Elena, Gao, Qiong, Cheang, Maggie, Morden, James, Parker, Joel, Lesley-Ann Martin, Pinhel, Isabel, McNeill, Fiona, Hills, Margaret, Detre, Simone, Afentakis, Maria, Zabaglo, Lila, Dodson, Andrew, Skene, Anthony, Holcombe, Chris, Robertson, John, Smith, Ian, Bliss, Judith, and Dowsett, Mitch

Abstract

Supplementary information. Additional description of the materials and methods. (DOCX 24 kb)

Published
2016
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43. Biomarker analysis of the NeoSphere study: pertuzumab, trastuzumab, and docetaxel versus trastuzumab plus docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel for the neoadjuvant treatment of HER2-positive breast cancer

Author

Bianchini, Giampaolo, primary, Kiermaier, Astrid, additional, Bianchi, Giulia Valeria, additional, Im, Young-Hyuck, additional, Pienkowski, Tadeusz, additional, Liu, Mei-Ching, additional, Tseng, Ling-Ming, additional, Dowsett, Mitch, additional, Zabaglo, Lila, additional, Kirk, Sarah, additional, Szado, Tania, additional, Eng-Wong, Jennifer, additional, Amler, Lukas C., additional, Valagussa, Pinuccia, additional, and Gianni, Luca, additional

Published
2017
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44. Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration.

Author

Leung, Samuel C Y, Nielsen, Torsten O, Zabaglo, Lila A, Arun, Indu, Badve, Sunil S, Bane, Anita L, Bartlett, John M S, Borgquist, Signe, Chang, Martin C, Dodson, Andrew, Ehinger, Anna, Fineberg, Susan, Focke, Cornelia M, Gao, Dongxia, Gown, Allen M, Gutierrez, Carolina, Hugh, Judith C, Kos, Zuzana, Lænkholm, Anne‐Vibeke, and Mastropasqua, Mauro G.

Subjects
ONCOLOGIC surgery, BREAST cancer, NUCLEAR nonproliferation, INTRACLASS correlation, IMMUNOHISTOCHEMISTRY
Abstract

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot‐spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot‐spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot‐spots varies between cases. The median times for scoring were 9 and 6 min for global and hot‐spot methods, respectively. Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further. [ABSTRACT FROM AUTHOR]

Published
2019
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45. Analytical validation of a standardized scoring protocol for Ki67:phase 3 of an international multicenter collaboration

Author

Leung, Samuel C Y, Nielsen, Torsten O, Zabaglo, Lila, Arun, Indu, Badve, Sunil S, Bane, Anita L, Bartlett, John M S, Borgquist, Signe, Chang, Martin C, Dodson, Andrew, Enos, Rebecca A, Fineberg, Susan, Focke, Cornelia M, Gao, Dongxia, Gown, Allen M, Grabau, Dorthe, Gutierrez, Carolina, Hugh, Judith C, Kos, Zuzana, Lænkholm, Anne-Vibeke, Lin, Ming-Gang, Mastropasqua, Mauro G, Moriya, Takuya, Nofech-Mozes, Sharon, Osborne, C Kent, Penault-Llorca, Frédérique M, Piper, Tammy, Sakatani, Takashi, Salgado, Roberto, Starczynski, Jane, Viale, Giuseppe, Hayes, Daniel F, McShane, Lisa M, Dowsett, Mitch, Leung, Samuel C Y, Nielsen, Torsten O, Zabaglo, Lila, Arun, Indu, Badve, Sunil S, Bane, Anita L, Bartlett, John M S, Borgquist, Signe, Chang, Martin C, Dodson, Andrew, Enos, Rebecca A, Fineberg, Susan, Focke, Cornelia M, Gao, Dongxia, Gown, Allen M, Grabau, Dorthe, Gutierrez, Carolina, Hugh, Judith C, Kos, Zuzana, Lænkholm, Anne-Vibeke, Lin, Ming-Gang, Mastropasqua, Mauro G, Moriya, Takuya, Nofech-Mozes, Sharon, Osborne, C Kent, Penault-Llorca, Frédérique M, Piper, Tammy, Sakatani, Takashi, Salgado, Roberto, Starczynski, Jane, Viale, Giuseppe, Hayes, Daniel F, McShane, Lisa M, and Dowsett, Mitch

Abstract

Pathological analysis of the nuclear proliferation biomarker Ki67 has multiple potential roles in breast and other cancers. However, clinical utility of the immunohistochemical (IHC) assay for Ki67 immunohistochemistry has been hampered by unacceptable between-laboratory analytical variability. The International Ki67 Working Group has conducted a series of studies aiming to decrease this variability and improve the evaluation of Ki67. This study tries to assess whether acceptable performance can be achieved on prestained core-cut biopsies using a standardized scoring method. Sections from 30 primary ER+ breast cancer core biopsies were centrally stained for Ki67 and circulated among 22 laboratories in 11 countries. Each laboratory scored Ki67 using three methods: (1) global (4 fields of 100 cells each); (2) weighted global (same as global but weighted by estimated percentages of total area); and (3) hot-spot (single field of 500 cells). The intraclass correlation coefficient (ICC), a measure of interlaboratory agreement, for the unweighted global method (0.87; 95% credible interval (CI): 0.81-0.93) met the prespecified success criterion for scoring reproducibility, whereas that for the weighted global (0.87; 95% CI: 0.7999-0.93) and hot-spot methods (0.84; 95% CI: 0.77-0.92) marginally failed to do so. The unweighted global assessment of Ki67 IHC analysis on core biopsies met the prespecified criterion of success for scoring reproducibility. A few cases still showed large scoring discrepancies. Establishment of external quality assessment schemes is likely to improve the agreement between laboratories further. Additional evaluations are needed to assess staining variability and clinical validity in appropriate cohorts of samples.

Published
2016

46. High‐throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium

Author

Abubakar, Mustapha, primary, Howat, William J, additional, Daley, Frances, additional, Zabaglo, Lila, additional, McDuffus, Leigh‐Anne, additional, Blows, Fiona, additional, Coulson, Penny, additional, Raza Ali, H, additional, Benitez, Javier, additional, Milne, Roger, additional, Brenner, Herman, additional, Stegmaier, Christa, additional, Mannermaa, Arto, additional, Chang‐Claude, Jenny, additional, Rudolph, Anja, additional, Sinn, Peter, additional, Couch, Fergus J, additional, Tollenaar, Rob A.E.M., additional, Devilee, Peter, additional, Figueroa, Jonine, additional, Sherman, Mark E, additional, Lissowska, Jolanta, additional, Hewitt, Stephen, additional, Eccles, Diana, additional, Hooning, Maartje J, additional, Hollestelle, Antoinette, additional, WM Martens, John, additional, HM van Deurzen, Carolien, additional, Investigators, kConFab, additional, Bolla, Manjeet K, additional, Wang, Qin, additional, Jones, Michael, additional, Schoemaker, Minouk, additional, Broeks, Annegien, additional, van Leeuwen, Flora E, additional, Van't Veer, Laura, additional, Swerdlow, Anthony J, additional, Orr, Nick, additional, Dowsett, Mitch, additional, Easton, Douglas, additional, Schmidt, Marjanka K, additional, Pharoah, Paul D, additional, and Garcia‐Closas, Montserrat, additional

Published
2016
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49. HER2 staining intensity in HER2-positive disease: Relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab

Author

Zabaglo, Lila, Salter, Janine, Dowsett, Mitch, Stoss, Oliver, Rüschoff, Josef, Zielinski, Dirk, Arfi, Mounir, Bradbury, Ian, Procter, Marion, Dafni, Urania, Piccart-Gebhart, Martine, Zabaglo, Lila, Salter, Janine, Dowsett, Mitch, Stoss, Oliver, Rüschoff, Josef, Zielinski, Dirk, Arfi, Mounir, Bradbury, Ian, Procter, Marion, Dafni, Urania, and Piccart-Gebhart, Martine

Abstract

Background: Trastuzumab treatment improves survival of HER2-positive primary breast cancer. HER2 staining intensity varies widely in HER2-positive tumours. Patients and methods: We investigated whether differences in immunohistochemical (IHC) staining intensity for HER2 in HER2-positive tumors (IHC 3+ or FISH ratio ≥2.0) was associated with prognosis or benefit from trastuzumab treatment in patients randomized to 1 year or no trastuzumab in the HERceptin Adjuvant (HERA) trial. Median follow-up was 2 years. The nested case-control analysis, included 425 patients (cases) with a disease-free survival (DFS) event and two matched controls (no DFS event) per case. Tissue sections stained for HER2 were assessed for HER2 staining intensity by image analysis. Results: HER2 staining intensity varied widely and correlated with HER2 gene copy number (Spearman, r = 0.498, P < 0.001) or less closely with HER2/CEP17 FISH ratio (r = 0.396, P < 0.001). We found no significant difference in DFS in the observation arm according to staining intensity (odds ratio [OR] change per 10 unit change in intensity: 1.015, 95% confidence interval [CI] 0.930-1.108) and no impact of staining intensity on benefit derived from 1-year trastuzumab (OR: 1.017, 95% CI 0.925-1.120). Conclusions: Variability in HER2 staining in HER2-positive tumours has no role in clinical management with adjuvant trastuzumab. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology All rights reserved., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2013

50. Effects of cyclin D-1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study

Author

Lundgren, Katja, Brown, Matthew, Pineda, Silvia, Cuzick, Jack, Salter, Janine, Zabaglo, Lila, Howell, Anthony, Dowsett, Mitch, Landberg, Goeran, Lundgren, Katja, Brown, Matthew, Pineda, Silvia, Cuzick, Jack, Salter, Janine, Zabaglo, Lila, Howell, Anthony, Dowsett, Mitch, and Landberg, Goeran

Abstract

Introduction: Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D-1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen. Methods: To clarify these challenging and partly contrasting treatment predictive and prognostic links for cyclin D-1 we analysed a large cohort of postmenopausal breast cancer patients randomised to receive either adjuvant anastrozole or tamoxifen, as part of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The CCND1 amplification status and protein expression of cyclin D-1 were assessed by chromogenic in situ hybridisation and immunohistochemistry, respectively, in 1,155 postmenopausal, oestrogen-receptor-positive breast cancer patients included in the TransATAC substudy. Results: Amplification of CCND1 was observed in 8.7% of the tumours and was associated with increased risk of disease recurrence (hazard ratio = 1.61; 95% confidence interval, 1.08 to 2.41) after adjustment for other clinicopathological parameters. In contrast, nuclear expression of cyclin D-1 protein was associated with decreased recurrence rate (hazard ratio = 0.6; 95% confidence interval, 0.39 to 0.92). The intensity of nuclear or cytoplasmic expression was not of prognostic value. There was no significant interaction between cyclin D-1 status and treatment efficacy, ruling out any major detrimental effect of tamoxifen in CCND1-amplified postmenopausal breast cancer. Conclusions: In summary, CCND1 amplification and low nuclear expression of cyclin D-1 predicted poor clinical outcome in postmenopausal breast cancer patients treated with either anastrozole or tamoxifen.

Published
2012

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