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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. An international multicenter study to evaluate reproducibility of automated scoring for assessment of Ki67 in breast cancer

Author

Rimm, David L., Leung, Samuel C.Y., McShane, Lisa M., Bai, Yalai, Bane, Anita L., Bartlett, John M.S., Bayani, Jane, Chang, Martin C., Dean, Michelle, Denkert, Carsten, Enwere, Emeka K., Galderisi, Chad, Gholap, Abhi, Hugh, Judith C., Jadhav, Anagha, Kornaga, Elizabeth N., Laurinavicius, Arvydas, Levenson, Richard, Lima, Joema, Miller, Keith, Pantanowitz, Liron, Piper, Tammy, Ruan, Jason, Srinivasan, Malini, Virk, Shakeel, Wu, Ying, Yang, Hua, Hayes, Daniel F., Nielsen, Torsten O., and Dowsett, Mitch

Published
2019
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3. 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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11. 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

14. 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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15. 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

16. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Spurdle, Amanda B., Couch, Fergus J., Parsons, Michael T., McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K., Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D. Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L., Domchek, Susan M., Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Ake, Andrulis, Irene L., Miron, Alexander, Hansen, Thomas V. O., Caldes, Trinidad, Neuhausen, Susan L., Toland, Amanda E., Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K., Osorio, Ana, Factor, Rachel E., Terry, Mary B., Rebbeck, Timothy R., Karlan, Beth Y., Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul D. P., Blows, Fiona M., Dunning, Alison M., Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Slamon, Dennis J., Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomaki, Kristiina, Muranen, Taru A., Heikkila, Paivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J., Brinton, Louise, Lissowska, Jolanta, Olson, Janet E., Pankratz, Vernon S., John, Esther M., Whittemore, Alice S., West, Dee W., Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rudiger, Thomas, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Van Asperen, Christi J., Eccles, Diana M., Tapper, William J., Durcan, Lorraine, Jones, Louise, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Dwek, Miriam, Swann, Ruth, Bane, Anita L., Glendon, Gord, Mulligan, Anna M., Giles, Graham G., Milne, Roger L., Baglietto, Laura, McLean, Catriona, Carpenter, Jane, Clarke, Christine, Scott, Rodney, Brauch, Hiltrud, Bruning, Thomas, Ko, Yon-Dschun, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Gronwald, Jacek, Dork, Thilo, Bogdanova, Natalia, Park-Simon, Tjoung-Won, Hillemanns, Peter, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Burwinkel, Barbara, Marme, Frederik, Surovy, Harald, Yang, Rongxi, Anton-Culver, Hoda, Ziogas, Argyrios, Hooning, Maartje J., Collee, J. Margriet, Martens, John W. M., Tilanus-Linthorst, Madeleine M. A., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volke, Stegmaier, Christa, Winqvist, Robert, Pylkas, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Lindblom, Annika, Margolin, Sara, Joseph, Vijai, Robson, Mark, Rau-Murthy, Rohini, Gonzalez-Neira, Anna, Arias, Jose Ignacio, Zamora, Pilar, Benitez, Javier, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Peterlongo, Paolo, Zaffaroni, Daniela, Barile, Monica, Capra, Fabio, Radice, Paolo, Teo, Soo H., Easton, Douglas F., Antoniou, Antonis C., Chenevix-Trench, Georgia, Goldgar, David E., Spurdle, Amanda B., Couch, Fergus J., Parsons, Michael T., McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K., Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D. Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L., Domchek, Susan M., Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Ake, Andrulis, Irene L., Miron, Alexander, Hansen, Thomas V. O., Caldes, Trinidad, Neuhausen, Susan L., Toland, Amanda E., Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K., Osorio, Ana, Factor, Rachel E., Terry, Mary B., Rebbeck, Timothy R., Karlan, Beth Y., Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul D. P., Blows, Fiona M., Dunning, Alison M., Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Slamon, Dennis J., Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomaki, Kristiina, Muranen, Taru A., Heikkila, Paivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J., Brinton, Louise, Lissowska, Jolanta, Olson, Janet E., Pankratz, Vernon S., John, Esther M., Whittemore, Alice S., West, Dee W., Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rudiger, Thomas, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Van Asperen, Christi J., Eccles, Diana M., Tapper, William J., Durcan, Lorraine, Jones, Louise, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Dwek, Miriam, Swann, Ruth, Bane, Anita L., Glendon, Gord, Mulligan, Anna M., Giles, Graham G., Milne, Roger L., Baglietto, Laura, McLean, Catriona, Carpenter, Jane, Clarke, Christine, Scott, Rodney, Brauch, Hiltrud, Bruning, Thomas, Ko, Yon-Dschun, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Gronwald, Jacek, Dork, Thilo, Bogdanova, Natalia, Park-Simon, Tjoung-Won, Hillemanns, Peter, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Burwinkel, Barbara, Marme, Frederik, Surovy, Harald, Yang, Rongxi, Anton-Culver, Hoda, Ziogas, Argyrios, Hooning, Maartje J., Collee, J. Margriet, Martens, John W. M., Tilanus-Linthorst, Madeleine M. A., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volke, Stegmaier, Christa, Winqvist, Robert, Pylkas, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Lindblom, Annika, Margolin, Sara, Joseph, Vijai, Robson, Mark, Rau-Murthy, Rohini, Gonzalez-Neira, Anna, Arias, Jose Ignacio, Zamora, Pilar, Benitez, Javier, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Peterlongo, Paolo, Zaffaroni, Daniela, Barile, Monica, Capra, Fabio, Radice, Paolo, Teo, Soo H., Easton, Douglas F., Antoniou, Antonis C., Chenevix-Trench, Georgia, and Goldgar, David E.

Abstract

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)

Published
2014

20. BRCA2 Mutation-associated Breast Cancers Exhibit a Distinguishing Phenotype Based on Morphology and Molecular Profiles From Tissue Microarrays

Author

Bane, Anita L., primary, Beck, Jeanne C., additional, Bleiweiss, Ira, additional, Buys, Saundra S., additional, Catalano, Edison, additional, Daly, Mary B., additional, Giles, Graham, additional, Godwin, Andy K., additional, Hibshoosh, Hanina, additional, Hopper, John L., additional, John, Esther M., additional, Layfield, Lester, additional, Longacre, Teri, additional, Miron, Alexander, additional, Senie, Rubie, additional, Southey, Melissa C., additional, West, Dee W., additional, Whittemore, Alice S., additional, Wu, Hong, additional, Andrulis, Irene L., additional, and O'Malley, Frances P., additional

Published
2007
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21. A role for the TGFβ-Par6 polarity pathway in breast cancer progression.

Author

Alicia M. Viloria-Petit, Laurent David, Jun Yong Jia, Erdemir, Tuba, Bane, Anita L., Pinnaduwage, Dushanthi, Roncari, Luba, Narimatsu, Masahiro, Bose, Rohit, Moffat, Jason, Wong, John W., Kerbel, Robert S., O'MaIIey, Frances P., Andrulis, Irene L., and Wrana, Jeffrey L.

Subjects
DISEASE progression, BREAST cancer, CELL polarity, CANCER invasiveness, LUNG tumors, METASTASIS
Abstract

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithehal cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGFβ, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFβ-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithehium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA 1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Published
2009
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22. Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Spurdle, Amanda B., Couch, Fergus J., Parsons, Michael T., McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K., Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D Gareth, Davidson, Rosemarie, Izatt, Louise, Eeles, Ros, Adlard, Julian, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Nathanson, Katherine L., Varesco, Liliana, Balleine, Rosemary, Offit, Kenneth, Domchek, Susan M., Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Miron, Alexander, Borg, Åke, Andrulis, Irene L., Caldes, Trinidad, Hansen, Thomas V. O., Neuhausen, Susan L., Toland, Amanda E., Nevanlinna, Heli, Montagna, Marco, Godwin, Andrew K., Garber, Judy, Osorio, Ana, Factor, Rachel E., Terry, Mary Beth, Rebbeck, Timothy R., Karlan, Beth Y., Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul D. P., Blows, Fiona M., Provenzano, Elena, Dunning, Alison M., Hall, Per, Czene, Kamila, Schmidt, Marjanka K., Broeks, Annegien, Verhoef, Senno, Cornelissen, Sten, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Slamon, Dennis J., Nordestgaard, Børge G., Nielsen, Sune F., Bojesen, Stig E., Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A., Heikkilä, Päivi, Blomqvist, Carl, Chanock, Stephen J., Figueroa, Jonine, Brinton, Louise, Lissowska, Jolanta, Olson, Janet E., Pankratz, Vernon S., John, Esther M., West, Dee W., Whittemore, Alice S., Hamann, Ute, Torres, Diana, Ulmer, Hans Ulrich, Rüdiger, Thomas, Devilee, Peter, Tollenaar, Robert A. E. M., Seynaeve, Caroline, Asperen, Christi J. Van, Eccles, Diana M., Tapper, William J., Durcan, Lorraine, Jones, Louise, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Dwek, Miriam, Bane, Anita L., Swann, Ruth, Glendon, Gord, Mulligan, Anna M., Giles, Graham G., Milne, Roger L., Baglietto, Laura, McLean, Catriona, Carpenter, Jane, Clarke, Christine, Scott, Rodney, Brüning, Thomas, Brauch, Hiltrud, Ko, Yon-Dschun, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Jaworska-Bieniek, Katarzyna, Lubinski, Jan, Durda, Katarzyna, Gronwald, Jacek, Dörk, Thilo, Bogdanova, Natalia, Park-Simon, Tjoung-Won, Hillemanns, Peter, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Marme, Frederik, Burwinkel, Barbara, Yang, Rongxi, Surovy, Harald, Anton-Culver, Hoda, Ziogas, Argyrios, Hooning, Maartje J., Collée, Margriet, Martens, John W. M., Tilanus-Linthorst, Madeleine M. A., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volke, Stegmaier, Christa, Jukkola-Vuorinen, Arja, Pylkäs, Katri, Winqvist, Robert, Grip, Mervi, Lindblom, Annika, Margolin, Sara, Joseph, Vijai, González-Neira, Anna, Rau-Murthy, Rohini, Robson, Mark, Arias, José Ignacio, Zamora, Pilar, Benítez, Javier, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Peterlongo, Paolo, Zaffaroni, Daniela, Capra, Fabio, Barile, Monica, Radice, Paolo, Teo, Soo H., Easton, Douglas F., Chenevix-Trench, Georgia, Antoniou, Antonis C., and Goldgar, David E.

Subjects
endocrine system diseases, Oncology, Breast--Histopathology, Breast--Tumors, Genetics, Mutation (Biology), skin and connective tissue diseases, 10. No inequality, 3. Good health
Abstract

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

23. Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration

Author

Nielsen, Torsten O., Leung, Samuel C. Y., Zabaglo, Lila A., Arun, Indu, Badve, Sunil S., Bane, Anita L., Bartlet, 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, Laenkholm, Anne-Vibeke, Mastropasqua, Mauro G., Moriya, Takuya, Nofech-Mozes, Sharon, Osborne, C. Kent, Penault-Llorca, Frederique 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, and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

24. Refined histopathological predictors of BRCA1 and BRCA2 mutation status : a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author

Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Spurdle, Amanda B., Couch, Fergus J., Parsons, Michael T., McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K., Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D. Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L., Domchek, Susan M., Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Ake, Andrulis, Irene L., Miron, Alexander, Hansen, Thomas V. O., Caldes, Trinidad, Neuhausen, Susan L., Toland, Amanda E., Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K., Osorio, Ana, Factor, Rachel E., Terry, Mary B., Rebbeck, Timothy R., Karlan, Beth Y., Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul D. P., Blows, Fiona M., Dunning, Alison M., Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Slamon, Dennis J., Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A., Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J., Brinton, Louise, Lissowska, Jolanta, Olson, Janet E., Pankratz, Vernon S., John, Esther M., Whittemore, Alice S., West, Dee W., Hamann, Ute, Torres López, Diana María, Ulmer, Hans Ulrich, Rüdiger, Thomas, Devilee, Peter, Tollenaar, Robert A. E. M, Seynaeve, Caroline, Van Asperen, Christi J., Eccles, Diana M., Tapper, William J., Durcan, Lorraine, Jones, Louise, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Dwek, Miriam, Swann, Ruth, Bane, Anita L., Glendon, Gord, Mulligan, Anna M., Giles, Graham G., Milne, Roger L., Baglietto, Laura, McLean, Catriona, Carpenter, Jane, Clarke, Christine, Scott, Rodney, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Gronwald, Jacek, Dörk, Thilo, Bogdanova, Natalia, Park-Simon, Tjoung-Won, Hillemanns, Peter, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Burwinkel, Barbara, Marme, Frederik, Surovy, Harald, Yang, Rongxi, Anton-Culver, Hoda, Ziogas, Argyrios, Hooning, Maartje J., Collée, J. Margriet, Martens, John W. M., Tilanus-Linthorst, Madeleine M. A., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volke, Stegmaier, Christa, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Lindblom, Annika, Margolin, Sara, Joseph, Vijai, Robson, Mark, Rau-Murthy, Rohini, González Neira, Anna, Arias, Jose Ignacio, Zamora, Pilar, Benítez, Javier, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Peterlongo, Paolo, Zaffaroni, Daniela, Barile, Monica, Capra, Fabio, Radice, Paolo, Teo, Soo H., Easton, Douglas F., Antoniou, Antonis C., Chenevix-Trench, Georgia, Goldgar, David E., Pontificia Universidad Javeriana. Facultad de Medicina. Instituto de Genética Humana, Spurdle, Amanda B., Couch, Fergus J., Parsons, Michael T., McGuffog, Lesley, Barrowdale, Daniel, Bolla, Manjeet K., Wang, Qin, Healey, Sue, Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Hahnen, Eric, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Ellis, Steve, Frost, Debra, Platte, Radka, Perkins, Jo, Evans, D. Gareth, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Scuvera, Giulietta, Manoukian, Siranoush, Bonanni, Bernardo, Mariette, Frederique, Fortuzzi, Stefano, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Varesco, Liliana, Balleine, Rosemary, Nathanson, Katherine L., Domchek, Susan M., Offitt, Kenneth, Jakubowska, Anna, Lindor, Noralane, Thomassen, Mads, Jensen, Uffe Birk, Rantala, Johanna, Borg, Ake, Andrulis, Irene L., Miron, Alexander, Hansen, Thomas V. O., Caldes, Trinidad, Neuhausen, Susan L., Toland, Amanda E., Nevanlinna, Heli, Montagna, Marco, Garber, Judy, Godwin, Andrew K., Osorio, Ana, Factor, Rachel E., Terry, Mary B., Rebbeck, Timothy R., Karlan, Beth Y., Southey, Melissa, Rashid, Muhammad Usman, Tung, Nadine, Pharoah, Paul D. P., Blows, Fiona M., Dunning, Alison M., Provenzano, Elena, Hall, Per, Czene, Kamila, Schmidt, Marjanka K., Broeks, Annegien, Cornelissen, Sten, Verhoef, Senno, Fasching, Peter A., Beckmann, Matthias W., Ekici, Arif B., Slamon, Dennis J., Bojesen, Stig E., Nordestgaard, Borge G., Nielsen, Sune F., Flyger, Henrik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, Aittomäki, Kristiina, Muranen, Taru A., Heikkilä, Päivi, Blomqvist, Carl, Figueroa, Jonine, Chanock, Stephen J., Brinton, Louise, Lissowska, Jolanta, Olson, Janet E., Pankratz, Vernon S., John, Esther M., Whittemore, Alice S., West, Dee W., Hamann, Ute, Torres López, Diana María, Ulmer, Hans Ulrich, Rüdiger, Thomas, Devilee, Peter, Tollenaar, Robert A. E. M, Seynaeve, Caroline, Van Asperen, Christi J., Eccles, Diana M., Tapper, William J., Durcan, Lorraine, Jones, Louise, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Dwek, Miriam, Swann, Ruth, Bane, Anita L., Glendon, Gord, Mulligan, Anna M., Giles, Graham G., Milne, Roger L., Baglietto, Laura, McLean, Catriona, Carpenter, Jane, Clarke, Christine, Scott, Rodney, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Cox, Angela, Cross, Simon S., Reed, Malcolm W. R., Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Gronwald, Jacek, Dörk, Thilo, Bogdanova, Natalia, Park-Simon, Tjoung-Won, Hillemanns, Peter, Haiman, Christopher A., Henderson, Brian E., Schumacher, Fredrick, Le Marchand, Loic, Burwinkel, Barbara, Marme, Frederik, Surovy, Harald, Yang, Rongxi, Anton-Culver, Hoda, Ziogas, Argyrios, Hooning, Maartje J., Collée, J. Margriet, Martens, John W. M., Tilanus-Linthorst, Madeleine M. A., Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volke, Stegmaier, Christa, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Lindblom, Annika, Margolin, Sara, Joseph, Vijai, Robson, Mark, Rau-Murthy, Rohini, González Neira, Anna, Arias, Jose Ignacio, Zamora, Pilar, Benítez, Javier, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M., Peterlongo, Paolo, Zaffaroni, Daniela, Barile, Monica, Capra, Fabio, Radice, Paolo, Teo, Soo H., Easton, Douglas F., Antoniou, Antonis C., Chenevix-Trench, Georgia, and Goldgar, David E.

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

Author

Leung SCY, Nielsen TO, Zabaglo L, Arun I, Badve SS, Bane AL, Bartlett JMS, Borgquist S, Chang MC, Dodson A, Enos RA, Fineberg S, Focke CM, Gao D, Gown AM, Grabau D, Gutierrez C, Hugh JC, Kos Z, Lænkholm AV, Lin MG, Mastropasqua MG, Moriya T, Nofech-Mozes S, Osborne CK, Penault-Llorca FM, Piper T, Sakatani T, Salgado R, Starczynski J, Viale G, Hayes DF, McShane LM, and Dowsett M

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., Competing Interests: J.M.S.B. has consulted for Insight Genetics and BioNTech and received compensation. T.O.N. has consulted for Nanostring and received compensation. C.K.O. has consulted for Astra Zeneca, Genentech and NanoString and received compensation. The remaining authors declare no conflict of interest.

Published
2016
Full Text
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26. Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

Author

Spurdle AB, Couch FJ, Parsons MT, McGuffog L, Barrowdale D, Bolla MK, Wang Q, Healey S, Schmutzler R, Wappenschmidt B, Rhiem K, Hahnen E, Engel C, Meindl A, Ditsch N, Arnold N, Plendl H, Niederacher D, Sutter C, Wang-Gohrke S, Steinemann D, Preisler-Adams S, Kast K, Varon-Mateeva R, Ellis S, Frost D, Platte R, Perkins J, Evans DG, Izatt L, Eeles R, Adlard J, Davidson R, Cole T, Scuvera G, Manoukian S, Bonanni B, Mariette F, Fortuzzi S, Viel A, Pasini B, Papi L, Varesco L, Balleine R, Nathanson KL, Domchek SM, Offitt K, Jakubowska A, Lindor N, Thomassen M, Jensen UB, Rantala J, Borg Å, Andrulis IL, Miron A, Hansen TV, Caldes T, Neuhausen SL, Toland AE, Nevanlinna H, Montagna M, Garber J, Godwin AK, Osorio A, Factor RE, Terry MB, Rebbeck TR, Karlan BY, Southey M, Rashid MU, Tung N, Pharoah PD, Blows FM, Dunning AM, Provenzano E, Hall P, Czene K, Schmidt MK, Broeks A, Cornelissen S, Verhoef S, Fasching PA, Beckmann MW, Ekici AB, Slamon DJ, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Chang-Claude J, Flesch-Janys D, Rudolph A, Seibold P, Aittomäki K, Muranen TA, Heikkilä P, Blomqvist C, Figueroa J, Chanock SJ, Brinton L, Lissowska J, Olson JE, Pankratz VS, John EM, Whittemore AS, West DW, Hamann U, Torres D, Ulmer HU, Rüdiger T, Devilee P, Tollenaar RA, Seynaeve C, Van Asperen CJ, Eccles DM, Tapper WJ, Durcan L, Jones L, Peto J, dos-Santos-Silva I, Fletcher O, Johnson N, Dwek M, Swann R, Bane AL, Glendon G, Mulligan AM, Giles GG, Milne RL, Baglietto L, McLean C, Carpenter J, Clarke C, Scott R, Brauch H, Brüning T, Ko YD, Cox A, Cross SS, Reed MW, Lubinski J, Jaworska-Bieniek K, Durda K, Gronwald J, Dörk T, Bogdanova N, Park-Simon TW, Hillemanns P, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Burwinkel B, Marme F, Surovy H, Yang R, Anton-Culver H, Ziogas A, Hooning MJ, Collée JM, Martens JW, Tilanus-Linthorst MM, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Lindblom A, Margolin S, Joseph V, Robson M, Rau-Murthy R, González-Neira A, Arias JI, Zamora P, Benítez J, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Peterlongo P, Zaffaroni D, Barile M, Capra F, Radice P, Teo SH, Easton DF, Antoniou AC, Chenevix-Trench G, and Goldgar DE

Subjects
Adult, Age Factors, Aged, Breast Neoplasms metabolism, Breast Neoplasms pathology, Carcinoma metabolism, Carcinoma pathology, Female, Humans, Likelihood Functions, Middle Aged, Mutation, Neoplasm Grading, Neoplasm Staging, Receptor, ErbB-2 metabolism, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Breast Neoplasms genetics, Carcinoma genetics, Genes, BRCA1, Genes, BRCA2, Triple Negative Breast Neoplasms genetics
Abstract

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling., Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach., Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24))., Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Published
2014
Full Text
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