Author: "Pusztai, Lajos" / Database: OAIster - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Pusztai, Lajos"' showing total 125 results

Start Over Author "Pusztai, Lajos" Database OAIster

125 results on '"Pusztai, Lajos"'

1. Image-based multiplex immune profiling of cancer tissues: translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Author: Pathologie, Cancer, Jahangir, Chowdhury Arif, Page, David B., Broeckx, Glenn, Gonzalez, Claudia A., Burke, Caoimbhe, Murphy, Clodagh, Reis-Filho, Jorge S., Ly, Amy, Harms, Paul W., Gupta, Rajarsi R., Vieth, Michael, Hida, Akira I., Kahila, Mohamed, Kos, Zuzana, van Diest, Paul J., Verbandt, Sara, Thagaard, Jeppe, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Adams, Sylvia, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Burgues, Octavio, Chardas, Alexandros, Cheang, Maggie Chon U., Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Dudgeon, Sarah N., Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fineberg, Susan, Fox, Stephen B., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hewitt, Stephen, Horlings, Hugo M., Husain, Zaheed, Irshad, Sheeba, Janssen, Emiel A.M., Kataoka, Tatsuki R., Kawaguchi, Kosuke, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Akturk, Guray, Scott, Ely, Kovács, Anikó, Lænkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Kharidehal, Durga, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Ribeiro, Joana M., Rimm, David, Vincent-Salomon, Anne, Saltz, Joel, Sayed, Shahin, Hytopoulos, Evangelos, Mahon, Sarah, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, Verghese, Gregory E., Viale, Giuseppe, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Specht Stovgaard, Elisabeth, Salgado, Roberto, Gallagher, William M., Rahman, Arman, Pathologie, Cancer, Jahangir, Chowdhury Arif, Page, David B., Broeckx, Glenn, Gonzalez, Claudia A., Burke, Caoimbhe, Murphy, Clodagh, Reis-Filho, Jorge S., Ly, Amy, Harms, Paul W., Gupta, Rajarsi R., Vieth, Michael, Hida, Akira I., Kahila, Mohamed, Kos, Zuzana, van Diest, Paul J., Verbandt, Sara, Thagaard, Jeppe, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Adams, Sylvia, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Burgues, Octavio, Chardas, Alexandros, Cheang, Maggie Chon U., Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Dudgeon, Sarah N., Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fineberg, Susan, Fox, Stephen B., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hewitt, Stephen, Horlings, Hugo M., Husain, Zaheed, Irshad, Sheeba, Janssen, Emiel A.M., Kataoka, Tatsuki R., Kawaguchi, Kosuke, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Akturk, Guray, Scott, Ely, Kovács, Anikó, Lænkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Kharidehal, Durga, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Ribeiro, Joana M., Rimm, David, Vincent-Salomon, Anne, Saltz, Joel, Sayed, Shahin, Hytopoulos, Evangelos, Mahon, Sarah, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, Verghese, Gregory E., Viale, Giuseppe, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Specht Stovgaard, Elisabeth, Salgado, Roberto, Gallagher, William M., and Rahman, Arman
Published: 2024

2. Image-based multiplex immune profiling of cancer tissues:translational implications. A report of the International Immuno-oncology Biomarker Working Group on Breast Cancer

Author: Jahangir, Chowdhury Arif, Page, David B., Broeckx, Glenn, Gonzalez, Claudia A., Burke, Caoimbhe, Murphy, Clodagh, Reis-Filho, Jorge S., Ly, Amy, Harms, Paul W., Gupta, Rajarsi R., Vieth, Michael, Hida, Akira I., Kahila, Mohamed, Kos, Zuzana, van Diest, Paul J., Verbandt, Sara, Thagaard, Jeppe, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Adams, Sylvia, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Burgues, Octavio, Chardas, Alexandros, Cheang, Maggie Chon U., Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Dudgeon, Sarah N., Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fineberg, Susan, Fox, Stephen B., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hewitt, Stephen, Horlings, Hugo M., Husain, Zaheed, Irshad, Sheeba, Janssen, Emiel A.M., Kataoka, Tatsuki R., Kawaguchi, Kosuke, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Akturk, Guray, Scott, Ely, Kovács, Anikó, Lænkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Kharidehal, Durga, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Ribeiro, Joana M., Rimm, David, Vincent-Salomon, Anne, Saltz, Joel, Sayed, Shahin, Hytopoulos, Evangelos, Mahon, Sarah, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, Verghese, Gregory E., Viale, Giuseppe, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Specht Stovgaard, Elisabeth, Salgado, Roberto, Gallagher, William M., Rahman, Arman, Jahangir, Chowdhury Arif, Page, David B., Broeckx, Glenn, Gonzalez, Claudia A., Burke, Caoimbhe, Murphy, Clodagh, Reis-Filho, Jorge S., Ly, Amy, Harms, Paul W., Gupta, Rajarsi R., Vieth, Michael, Hida, Akira I., Kahila, Mohamed, Kos, Zuzana, van Diest, Paul J., Verbandt, Sara, Thagaard, Jeppe, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Adams, Sylvia, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Burgues, Octavio, Chardas, Alexandros, Cheang, Maggie Chon U., Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Dudgeon, Sarah N., Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fineberg, Susan, Fox, Stephen B., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hewitt, Stephen, Horlings, Hugo M., Husain, Zaheed, Irshad, Sheeba, Janssen, Emiel A.M., Kataoka, Tatsuki R., Kawaguchi, Kosuke, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Akturk, Guray, Scott, Ely, Kovács, Anikó, Lænkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Kharidehal, Durga, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Ribeiro, Joana M., Rimm, David, Vincent-Salomon, Anne, Saltz, Joel, Sayed, Shahin, Hytopoulos, Evangelos, Mahon, Sarah, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, Verghese, Gregory E., Viale, Giuseppe, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Specht Stovgaard, Elisabeth, Salgado, Roberto, Gallagher, William M., and Rahman, Arman
Abstract: Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer.
Published: 2024

3. Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.

Author: Tolaney, Sara, Tolaney, Sara, Garrett-Mayer, Elizabeth, Amiri-Kordestani, Laleh, Basho, Reva, Best, Ana, Boileau, Jean-Francois, Denkert, Carsten, Foster, Jared, Harbeck, Nadia, Jacene, Heather, King, Tari, Mason, Ginny, OSullivan, Ciara, Prowell, Tatiana, Richardson, Andrea, Sepulveda, Karla, Smith, Mary, Tjoe, Judy, Turashvili, Gulisa, Woodward, Wendy, Butler, Lynn, Schwartz, Elena, Korde, Larissa, Litton, Jennifer, Regan, Meredith, Pusztai, Lajos, Rugo, Hope, Tolaney, Sara, Tolaney, Sara, Garrett-Mayer, Elizabeth, Amiri-Kordestani, Laleh, Basho, Reva, Best, Ana, Boileau, Jean-Francois, Denkert, Carsten, Foster, Jared, Harbeck, Nadia, Jacene, Heather, King, Tari, Mason, Ginny, OSullivan, Ciara, Prowell, Tatiana, Richardson, Andrea, Sepulveda, Karla, Smith, Mary, Tjoe, Judy, Turashvili, Gulisa, Woodward, Wendy, Butler, Lynn, Schwartz, Elena, Korde, Larissa, Litton, Jennifer, Regan, Meredith, Pusztai, Lajos, and Rugo, Hope
Abstract: PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeut
Published: 2023

4. Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer:A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Author: Thagaard, Jeppe, Broeckx, Glenn, Page, David B, Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S, Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R, Bheemaraju, Vydehi, Blenman, Kim Rm, Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee Ad, Coosemans, An, Corredor, Germán, Dahl, Anders B, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N, Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B, Gallagher, William M, Giltnane, Jennifer M, Gnjatic, Sacha, Gonzalez-Ericsson, Paula I, Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G, Harbhajanka, Aparna, Hart, Steven N, Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I, Horlings, Hugo M, Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel Am, Kahila, Mohamed, Kataoka, Tatsuki R, Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I, Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L, Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne-Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K, Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K, Manur Narasimhamurthy, Vidya, Marks, Douglas K, McDonald, Elizabeth S, Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz Ul Amir Afsar, Mittal, Shachi, Moore, David A, Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D, Pinard, Christopher J, Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T, Reis-Filho, Jorge S, Ribeiro, Joana M, Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P, Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A, Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E Aubrey, Tramm, Trine, Tran, William T, van der Laak, Jeroen, van Diest, Paul J, Verghese, Gregory E, Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y, Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, Specht Stovgaard, Elisabeth, Thagaard, Jeppe, Broeckx, Glenn, Page, David B, Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S, Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R, Bheemaraju, Vydehi, Blenman, Kim Rm, Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee Ad, Coosemans, An, Corredor, Germán, Dahl, Anders B, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N, Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B, Gallagher, William M, Giltnane, Jennifer M, Gnjatic, Sacha, Gonzalez-Ericsson, Paula I, Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G, Harbhajanka, Aparna, Hart, Steven N, Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I, Horlings, Hugo M, Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel Am, Kahila, Mohamed, Kataoka, Tatsuki R, Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I, Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L, Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne-Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K, Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K, Manur Narasimhamurthy, Vidya, Marks, Douglas K, McDonald, Elizabeth S, Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz Ul Amir Afsar, Mittal, Shachi, Moore, David A, Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D, Pinard, Christopher J, Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T, Reis-Filho, Jorge S, Ribeiro, Joana M, Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P, Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A, Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E Aubrey, Tramm, Trine, Tran, William T, van der Laak, Jeroen, van Diest, Paul J, Verghese, Gregory E, Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y, Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, and Specht Stovgaard, Elisabeth
Abstract: The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer.
Published: 2023

5. Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials.

Author: Rediti, Mattia, Fernandez-Martinez, Aranzazu, Venet, David, Rothé, Françoise, Hoadley, Katherine A, Parker, Joel S, Singh, Baljit, Campbell, Jordan D, Ballman, Karla V, Hillman, David W, Winer, Eric P, El-Abed, Sarra, Piccart, Martine, Di Cosimo, Serena, Symmans, William Fraser, Krop, Ian, Salgado, Roberto, Loi, Sherene, Pusztai, Lajos, Perou, Charles M, Carey, Lisa A, Sotiriou, Christos, Rediti, Mattia, Fernandez-Martinez, Aranzazu, Venet, David, Rothé, Françoise, Hoadley, Katherine A, Parker, Joel S, Singh, Baljit, Campbell, Jordan D, Ballman, Karla V, Hillman, David W, Winer, Eric P, El-Abed, Sarra, Piccart, Martine, Di Cosimo, Serena, Symmans, William Fraser, Krop, Ian, Salgado, Roberto, Loi, Sherene, Pusztai, Lajos, Perou, Charles M, Carey, Lisa A, and Sotiriou, Christos
Abstract: The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2023

6. Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer

Author: Lambertini, Matteo, Ceppi, Marcello, Anderson, Richard A, Cameron, David A, Bruzzone, Marco, Franzoi, Maria Alice, Massarotti, Claudia, El-Abed, Sarra, Wang, Yingbo, Lecocq, Christophe, Nuciforo, Paolo, Rolyance, Rebecca, Pusztai, Lajos, Sohn, Joohyuk, Latocca, Maria Maddalena, Arecco, Luca, Pistilli, Barbara, Ruddy, Kathryn J, Ballestrero, Alberto, Del Mastro, Lucia, Peccatori, Fedro Alessandro, Partridge, Ann H, Saura, Cristina, Untch, Michael, Piccart, Martine, Di Cosimo, Serena, de Azambuja, Evandro, Demeestere, Isabelle, Lambertini, Matteo, Ceppi, Marcello, Anderson, Richard A, Cameron, David A, Bruzzone, Marco, Franzoi, Maria Alice, Massarotti, Claudia, El-Abed, Sarra, Wang, Yingbo, Lecocq, Christophe, Nuciforo, Paolo, Rolyance, Rebecca, Pusztai, Lajos, Sohn, Joohyuk, Latocca, Maria Maddalena, Arecco, Luca, Pistilli, Barbara, Ruddy, Kathryn J, Ballestrero, Alberto, Del Mastro, Lucia, Peccatori, Fedro Alessandro, Partridge, Ann H, Saura, Cristina, Untch, Michael, Piccart, Martine, Di Cosimo, Serena, de Azambuja, Evandro, and Demeestere, Isabelle
Abstract: info:eu-repo/semantics/published
Published: 2023

7. Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Author: Pathologie, Cancer, Thagaard, Jeppe, Broeckx, Glenn, Page, David B, Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S, Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R, Bheemaraju, Vydehi, Blenman, Kim Rm, Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee Ad, Coosemans, An, Corredor, Germán, Dahl, Anders B, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N, Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B, Gallagher, William M, Giltnane, Jennifer M, Gnjatic, Sacha, Gonzalez-Ericsson, Paula I, Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G, Harbhajanka, Aparna, Hart, Steven N, Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I, Horlings, Hugo M, Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel Am, Kahila, Mohamed, Kataoka, Tatsuki R, Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I, Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L, Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne-Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K, Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K, Manur Narasimhamurthy, Vidya, Marks, Douglas K, McDonald, Elizabeth S, Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz Ul Amir Afsar, Mittal, Shachi, Moore, David A, Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D, Pinard, Christopher J, Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T, Reis-Filho, Jorge S, Ribeiro, Joana M, Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P, Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A, Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E Aubrey, Tramm, Trine, Tran, William T, van der Laak, Jeroen, van Diest, Paul J, Verghese, Gregory E, Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y, Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, Specht Stovgaard, Elisabeth, Pathologie, Cancer, Thagaard, Jeppe, Broeckx, Glenn, Page, David B, Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S, Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R, Bheemaraju, Vydehi, Blenman, Kim Rm, Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee Ad, Coosemans, An, Corredor, Germán, Dahl, Anders B, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N, Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B, Gallagher, William M, Giltnane, Jennifer M, Gnjatic, Sacha, Gonzalez-Ericsson, Paula I, Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G, Harbhajanka, Aparna, Hart, Steven N, Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I, Horlings, Hugo M, Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel Am, Kahila, Mohamed, Kataoka, Tatsuki R, Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I, Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L, Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne-Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K, Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K, Manur Narasimhamurthy, Vidya, Marks, Douglas K, McDonald, Elizabeth S, Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz Ul Amir Afsar, Mittal, Shachi, Moore, David A, Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D, Pinard, Christopher J, Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T, Reis-Filho, Jorge S, Ribeiro, Joana M, Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P, Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A, Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E Aubrey, Tramm, Trine, Tran, William T, van der Laak, Jeroen, van Diest, Paul J, Verghese, Gregory E, Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y, Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, and Specht Stovgaard, Elisabeth
Published: 2023

8. Spatial analyses of immune cell infiltration in cancer: current methods and future directions. A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

Author: Pathologie, Cancer, Page, David B, Broeckx, Glenn, Jahangir, Chowdhury Arif, Verbandt, Sara, Gupta, Rajarsi R, Thagaard, Jeppe, Khiroya, Reena, Kos, Zuzana, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Almeida, Jonas S, Alvarado-Cabrero, Isabel, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Bellolio, Enrique R, Bheemaraju, Vydehi, Blenman, Kim Rm, Botinelly Mendonça Fujimoto, Luciana, Burgues, Octavio, Cheang, Maggie Chon U, Ciompi, Francesco, Cooper, Lee Ad, Coosemans, An, Corredor, Germán, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Dudgeon, Sarah N, Elghazawy, Mahmoud, Ely, Scott, Fernandez-Martín, Claudio, Fineberg, Susan, Fox, Stephen B, Gallagher, William M, Giltnane, Jennifer M, Gnjatic, Sacha, Gonzalez-Ericsson, Paula I, Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G, Harbhajanka, Aparna, Hardas, Alexandros, Hart, Steven N, Hartman, Johan, Hewitt, Stephen, Hida, Akira I, Horlings, Hugo M, Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel Am, Kahila, Mohamed, Kataoka, Tatsuki R, Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I, Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L, Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne-Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K, Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K, Manur Narasimhamurthy, Vidya, Marks, Douglas K, McDonald, Elizabeth S, Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz Ul Amir Afsar, Mittal, Shachi, Moore, David A, Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D, Pinard, Christopher J, Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T, Reis-Filho, Jorge S, Ribeiro, Joana M, Rimm, David, Salomon, Anne-Vincent, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Siziopikou, Kalliopi P, Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A, Sur, Daniel, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E Aubrey, Tramm, Trine, Tran, William T, van der Laak, Jeroen, van Diest, Paul J, Verghese, Gregory E, Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y, Yang, Wentao, Yuan, Yinyin, Adams, Sylvia, Bartlett, John Mark Seaverns, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, Specht Stovgaard, Elisabeth, Akturk, Guray, Bouchmaa, Najat, Pathologie, Cancer, Page, David B, Broeckx, Glenn, Jahangir, Chowdhury Arif, Verbandt, Sara, Gupta, Rajarsi R, Thagaard, Jeppe, Khiroya, Reena, Kos, Zuzana, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Almeida, Jonas S, Alvarado-Cabrero, Isabel, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Bellolio, Enrique R, Bheemaraju, Vydehi, Blenman, Kim Rm, Botinelly Mendonça Fujimoto, Luciana, Burgues, Octavio, Cheang, Maggie Chon U, Ciompi, Francesco, Cooper, Lee Ad, Coosemans, An, Corredor, Germán, Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Dudgeon, Sarah N, Elghazawy, Mahmoud, Ely, Scott, Fernandez-Martín, Claudio, Fineberg, Susan, Fox, Stephen B, Gallagher, William M, Giltnane, Jennifer M, Gnjatic, Sacha, Gonzalez-Ericsson, Paula I, Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G, Harbhajanka, Aparna, Hardas, Alexandros, Hart, Steven N, Hartman, Johan, Hewitt, Stephen, Hida, Akira I, Horlings, Hugo M, Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel Am, Kahila, Mohamed, Kataoka, Tatsuki R, Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I, Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L, Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne-Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K, Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K, Manur Narasimhamurthy, Vidya, Marks, Douglas K, McDonald, Elizabeth S, Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz Ul Amir Afsar, Mittal, Shachi, Moore, David A, Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D, Pinard, Christopher J, Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T, Reis-Filho, Jorge S, Ribeiro, Joana M, Rimm, David, Salomon, Anne-Vincent, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Siziopikou, Kalliopi P, Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A, Sur, Daniel, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E Aubrey, Tramm, Trine, Tran, William T, van der Laak, Jeroen, van Diest, Paul J, Verghese, Gregory E, Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y, Yang, Wentao, Yuan, Yinyin, Adams, Sylvia, Bartlett, John Mark Seaverns, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, Specht Stovgaard, Elisabeth, Akturk, Guray, and Bouchmaa, Najat
Published: 2023

9. Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer:a report of the international immuno-oncology biomarker working group

Author: Thagaard, Jeppe, Broeckx, Glenn, Page, David B., Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dahl, Anders B., Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N., Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B., Gallagher, William M., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I., Horlings, Hugo M., Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel A.M., Kahila, Mohamed, Kataoka, Tatsuki R., Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Reis-Filho, Jorge S., Ribeiro, Joana M., Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, van Diest, Paul J., Verghese, Gregory E., Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, Specht Stovgaard, Elisabeth, Thagaard, Jeppe, Broeckx, Glenn, Page, David B., Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dahl, Anders B., Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N., Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B., Gallagher, William M., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I., Horlings, Hugo M., Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel A.M., Kahila, Mohamed, Kataoka, Tatsuki R., Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Reis-Filho, Jorge S., Ribeiro, Joana M., Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, van Diest, Paul J., Verghese, Gregory E., Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, and Specht Stovgaard, Elisabeth
Abstract: The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer.
Published: 2023

10. Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer:a report of the international immuno-oncology biomarker working group

Author: Thagaard, Jeppe, Broeckx, Glenn, Page, David B., Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dahl, Anders B., Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N., Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B., Gallagher, William M., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I., Horlings, Hugo M., Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel A.M., Kahila, Mohamed, Kataoka, Tatsuki R., Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Reis-Filho, Jorge S., Ribeiro, Joana M., Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, van Diest, Paul J., Verghese, Gregory E., Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, Specht Stovgaard, Elisabeth, Thagaard, Jeppe, Broeckx, Glenn, Page, David B., Jahangir, Chowdhury Arif, Verbandt, Sara, Kos, Zuzana, Gupta, Rajarsi, Khiroya, Reena, Abduljabbar, Khalid, Acosta Haab, Gabriela, Acs, Balazs, Akturk, Guray, Almeida, Jonas S., Alvarado-Cabrero, Isabel, Amgad, Mohamed, Azmoudeh-Ardalan, Farid, Badve, Sunil, Baharun, Nurkhairul Bariyah, Balslev, Eva, Bellolio, Enrique R., Bheemaraju, Vydehi, Blenman, Kim R.M., Botinelly Mendonça Fujimoto, Luciana, Bouchmaa, Najat, Burgues, Octavio, Chardas, Alexandros, Chon U Cheang, Maggie, Ciompi, Francesco, Cooper, Lee A.D., Coosemans, An, Corredor, Germán, Dahl, Anders B., Dantas Portela, Flavio Luis, Deman, Frederik, Demaria, Sandra, Doré Hansen, Johan, Dudgeon, Sarah N., Ebstrup, Thomas, Elghazawy, Mahmoud, Fernandez-Martín, Claudio, Fox, Stephen B., Gallagher, William M., Giltnane, Jennifer M., Gnjatic, Sacha, Gonzalez-Ericsson, Paula I., Grigoriadis, Anita, Halama, Niels, Hanna, Matthew G., Harbhajanka, Aparna, Hart, Steven N., Hartman, Johan, Hauberg, Søren, Hewitt, Stephen, Hida, Akira I., Horlings, Hugo M., Husain, Zaheed, Hytopoulos, Evangelos, Irshad, Sheeba, Janssen, Emiel A.M., Kahila, Mohamed, Kataoka, Tatsuki R., Kawaguchi, Kosuke, Kharidehal, Durga, Khramtsov, Andrey I., Kiraz, Umay, Kirtani, Pawan, Kodach, Liudmila L., Korski, Konstanty, Kovács, Anikó, Laenkholm, Anne Vibeke, Lang-Schwarz, Corinna, Larsimont, Denis, Lennerz, Jochen K., Lerousseau, Marvin, Li, Xiaoxian, Ly, Amy, Madabhushi, Anant, Maley, Sai K., Manur Narasimhamurthy, Vidya, Marks, Douglas K., McDonald, Elizabeth S., Mehrotra, Ravi, Michiels, Stefan, Minhas, Fayyaz ul Amir Afsar, Mittal, Shachi, Moore, David A., Mushtaq, Shamim, Nighat, Hussain, Papathomas, Thomas, Penault-Llorca, Frederique, Perera, Rashindrie D., Pinard, Christopher J., Pinto-Cardenas, Juan Carlos, Pruneri, Giancarlo, Pusztai, Lajos, Rahman, Arman, Rajpoot, Nasir Mahmood, Rapoport, Bernardo Leon, Rau, Tilman T., Reis-Filho, Jorge S., Ribeiro, Joana M., Rimm, David, Roslind, Anne, Vincent-Salomon, Anne, Salto-Tellez, Manuel, Saltz, Joel, Sayed, Shahin, Scott, Ely, Siziopikou, Kalliopi P., Sotiriou, Christos, Stenzinger, Albrecht, Sughayer, Maher A., Sur, Daniel, Fineberg, Susan, Symmans, Fraser, Tanaka, Sunao, Taxter, Timothy, Tejpar, Sabine, Teuwen, Jonas, Thompson, E. Aubrey, Tramm, Trine, Tran, William T., van der Laak, Jeroen, van Diest, Paul J., Verghese, Gregory E., Viale, Giuseppe, Vieth, Michael, Wahab, Noorul, Walter, Thomas, Waumans, Yannick, Wen, Hannah Y., Yang, Wentao, Yuan, Yinyin, Zin, Reena Md, Adams, Sylvia, Bartlett, John, Loibl, Sibylle, Denkert, Carsten, Savas, Peter, Loi, Sherene, Salgado, Roberto, and Specht Stovgaard, Elisabeth
Abstract: The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer.
Published: 2023

11. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial.

Author: Pusztai, Lajos, Pusztai, Lajos, Yau, Christina, Han, Hyo, Du, Lili, Wallace, Anne, String-Reasor, Erica, Boughey, Judy, Chien, A, Elias, Anthony, Beckwith, Heather, Nanda, Rita, Albain, Kathy, Clark, Amy, Kemmer, Kathleen, Kalinsky, Kevin, Isaacs, Claudine, Thomas, Alexandra, Helsten, Theresa, Forero-Torres, Andres, Liu, Minetta, Brown-Swigart, Lamorna, Petricoin, Emmanuel, Wulfkuhle, Julia, Asare, Smita, Wilson, Amy, Singhrao, Ruby, Sit, Laura, Berry, Scott, Sanil, Ashish, Asare, Adam, Matthews, Jeffrey, Perlmutter, Jane, Melisko, Michelle, Rugo, Hope, Schwab, Richard, Symmans, W, Yee, Doug, Vant Veer, Laura, DeMichele, Angela, Berry, Donald, Esserman, Laura, Hylton, Nola, Wolf, Denise, Shatsky, Rebecca, Hirst, Gillian, Pusztai, Lajos, Pusztai, Lajos, Yau, Christina, Han, Hyo, Du, Lili, Wallace, Anne, String-Reasor, Erica, Boughey, Judy, Chien, A, Elias, Anthony, Beckwith, Heather, Nanda, Rita, Albain, Kathy, Clark, Amy, Kemmer, Kathleen, Kalinsky, Kevin, Isaacs, Claudine, Thomas, Alexandra, Helsten, Theresa, Forero-Torres, Andres, Liu, Minetta, Brown-Swigart, Lamorna, Petricoin, Emmanuel, Wulfkuhle, Julia, Asare, Smita, Wilson, Amy, Singhrao, Ruby, Sit, Laura, Berry, Scott, Sanil, Ashish, Asare, Adam, Matthews, Jeffrey, Perlmutter, Jane, Melisko, Michelle, Rugo, Hope, Schwab, Richard, Symmans, W, Yee, Doug, Vant Veer, Laura, DeMichele, Angela, Berry, Donald, Esserman, Laura, Hylton, Nola, Wolf, Denise, Shatsky, Rebecca, and Hirst, Gillian
Abstract: The combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib added to standard paclitaxel neoadjuvant chemotherapy (durvalumab/olaparib/paclitaxel [DOP]) was investigated in the phase II I-SPY2 trial of stage II/III HER2-negative breast cancer. Seventy-three participants were randomized to DOP and 299 to standard of care (paclitaxel) control. DOP increased pathologic complete response (pCR) rates in all HER2-negative (20%-37%), hormone receptor (HR)-positive/HER2-negative (14%-28%), and triple-negative breast cancer (TNBC) (27%-47%). In HR-positive/HER2-negative cancers, MammaPrint ultra-high (MP2) cases benefited selectively from DOP (pCR 64% versus 22%), no benefit was seen in MP1 cancers (pCR 9% versus 10%). Overall, 12.3% of patients in the DOP arm experienced immune-related grade 3 adverse events versus 1.3% in control. Gene expression signatures associated with immune response were positively associated with pCR in both arms, while a mast cell signature was associated with non-pCR. DOP has superior efficacy over standard neoadjuvant chemotherapy in HER2-negative breast cancer, particularly in a highly sensitive subset of high-risk HR-positive/HER2-negative patients.
Published: 2021

12. Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients.

Author: Yau, Christina, Yau, Christina, Osdoit, Marie, van der Noordaa, Marieke, Shad, Sonal, Wei, Jane, de Croze, Diane, Hamy, Anne-Sophie, Laé, Marick, Reyal, Fabien, Sonke, Gabe S, Steenbruggen, Tessa G, van Seijen, Maartje, Wesseling, Jelle, Martín, Miguel, Del Monte-Millán, Maria, López-Tarruella, Sara, I-SPY 2 Trial Consortium, Boughey, Judy C, Goetz, Matthew P, Hoskin, Tanya, Gould, Rebekah, Valero, Vicente, Edge, Stephen B, Abraham, Jean E, Bartlett, John MS, Caldas, Carlos, Dunn, Janet, Earl, Helena, Hayward, Larry, Hiller, Louise, Provenzano, Elena, Sammut, Stephen-John, Thomas, Jeremy S, Cameron, David, Graham, Ashley, Hall, Peter, Mackintosh, Lorna, Fan, Fang, Godwin, Andrew K, Schwensen, Kelsey, Sharma, Priyanka, DeMichele, Angela M, Cole, Kimberly, Pusztai, Lajos, Kim, Mi-Ok, van 't Veer, Laura J, Esserman, Laura J, Symmans, W Fraser, Yau, Christina, Yau, Christina, Osdoit, Marie, van der Noordaa, Marieke, Shad, Sonal, Wei, Jane, de Croze, Diane, Hamy, Anne-Sophie, Laé, Marick, Reyal, Fabien, Sonke, Gabe S, Steenbruggen, Tessa G, van Seijen, Maartje, Wesseling, Jelle, Martín, Miguel, Del Monte-Millán, Maria, López-Tarruella, Sara, I-SPY 2 Trial Consortium, Boughey, Judy C, Goetz, Matthew P, Hoskin, Tanya, Gould, Rebekah, Valero, Vicente, Edge, Stephen B, Abraham, Jean E, Bartlett, John MS, Caldas, Carlos, Dunn, Janet, Earl, Helena, Hayward, Larry, Hiller, Louise, Provenzano, Elena, Sammut, Stephen-John, Thomas, Jeremy S, Cameron, David, Graham, Ashley, Hall, Peter, Mackintosh, Lorna, Fan, Fang, Godwin, Andrew K, Schwensen, Kelsey, Sharma, Priyanka, DeMichele, Angela M, Cole, Kimberly, Pusztai, Lajos, Kim, Mi-Ok, van 't Veer, Laura J, Esserman, Laura J, and Symmans, W Fraser
Abstract: BackgroundPrevious studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings.MethodsIn this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype.FindingsWe analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survi
Published: 2022

13. Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies.

Author: Wolf, Denise M, Wolf, Denise M, Yau, Christina, Wulfkuhle, Julia, Brown-Swigart, Lamorna, Gallagher, Rosa I, Lee, Pei Rong Evelyn, Zhu, Zelos, Magbanua, Mark J, Sayaman, Rosalyn, O'Grady, Nicholas, Basu, Amrita, Delson, Amy, Coppé, Jean Philippe, Lu, Ruixiao, Braun, Jerome, I-SPY2 Investigators, Asare, Smita M, Sit, Laura, Matthews, Jeffrey B, Perlmutter, Jane, Hylton, Nola, Liu, Minetta C, Pohlmann, Paula, Symmans, W Fraser, Rugo, Hope S, Isaacs, Claudine, DeMichele, Angela M, Yee, Douglas, Berry, Donald A, Pusztai, Lajos, Petricoin, Emanuel F, Hirst, Gillian L, Esserman, Laura J, van 't Veer, Laura J, Wolf, Denise M, Wolf, Denise M, Yau, Christina, Wulfkuhle, Julia, Brown-Swigart, Lamorna, Gallagher, Rosa I, Lee, Pei Rong Evelyn, Zhu, Zelos, Magbanua, Mark J, Sayaman, Rosalyn, O'Grady, Nicholas, Basu, Amrita, Delson, Amy, Coppé, Jean Philippe, Lu, Ruixiao, Braun, Jerome, I-SPY2 Investigators, Asare, Smita M, Sit, Laura, Matthews, Jeffrey B, Perlmutter, Jane, Hylton, Nola, Liu, Minetta C, Pohlmann, Paula, Symmans, W Fraser, Rugo, Hope S, Isaacs, Claudine, DeMichele, Angela M, Yee, Douglas, Berry, Donald A, Pusztai, Lajos, Petricoin, Emanuel F, Hirst, Gillian L, Esserman, Laura J, and van 't Veer, Laura J
Abstract: Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR+ subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization.
Published: 2022

14. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

Author: Yee, Douglas, Yee, Douglas, Isaacs, Claudine, Wolf, Denise M, Yau, Christina, Haluska, Paul, Giridhar, Karthik V, Forero-Torres, Andres, Jo Chien, A, Wallace, Anne M, Pusztai, Lajos, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Kemmer, Kathleen, Yung, Rachel L, Pohlmann, Paula R, Tripathy, Debu, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Petricoin, Emanuel F, Stringer-Reasor, Erica, Falkson, Carla I, Majure, Melanie, Mukhtar, Rita A, Helsten, Teresa L, Moulder, Stacy L, Robinson, Patricia A, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Hylton, Nola M, DeMichele, Angela, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Fraser Symmans, W, Van't Veer, Laura J, Berry, Donald A, Esserman, Laura J, Yee, Douglas, Yee, Douglas, Isaacs, Claudine, Wolf, Denise M, Yau, Christina, Haluska, Paul, Giridhar, Karthik V, Forero-Torres, Andres, Jo Chien, A, Wallace, Anne M, Pusztai, Lajos, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Kemmer, Kathleen, Yung, Rachel L, Pohlmann, Paula R, Tripathy, Debu, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Petricoin, Emanuel F, Stringer-Reasor, Erica, Falkson, Carla I, Majure, Melanie, Mukhtar, Rita A, Helsten, Teresa L, Moulder, Stacy L, Robinson, Patricia A, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Hylton, Nola M, DeMichele, Angela, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Fraser Symmans, W, Van't Veer, Laura J, Berry, Donald A, and Esserman, Laura J
Abstract: I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.
Published: 2021

15. Ganitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer.

Author: Yee, Douglas, Yee, Douglas, Isaacs, Claudine, Wolf, Denise M, Yau, Christina, Haluska, Paul, Giridhar, Karthik V, Forero-Torres, Andres, Jo Chien, A, Wallace, Anne M, Pusztai, Lajos, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Kemmer, Kathleen, Yung, Rachel L, Pohlmann, Paula R, Tripathy, Debu, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Petricoin, Emanuel F, Stringer-Reasor, Erica, Falkson, Carla I, Majure, Melanie, Mukhtar, Rita A, Helsten, Teresa L, Moulder, Stacy L, Robinson, Patricia A, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Hylton, Nola M, DeMichele, Angela, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Fraser Symmans, W, Van't Veer, Laura J, Berry, Donald A, Esserman, Laura J, Yee, Douglas, Yee, Douglas, Isaacs, Claudine, Wolf, Denise M, Yau, Christina, Haluska, Paul, Giridhar, Karthik V, Forero-Torres, Andres, Jo Chien, A, Wallace, Anne M, Pusztai, Lajos, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Kemmer, Kathleen, Yung, Rachel L, Pohlmann, Paula R, Tripathy, Debu, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Petricoin, Emanuel F, Stringer-Reasor, Erica, Falkson, Carla I, Majure, Melanie, Mukhtar, Rita A, Helsten, Teresa L, Moulder, Stacy L, Robinson, Patricia A, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Hylton, Nola M, DeMichele, Angela, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Fraser Symmans, W, Van't Veer, Laura J, Berry, Donald A, and Esserman, Laura J
Abstract: I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY's prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.
Published: 2021

16. Evaluating Serum Thymidine Kinase 1 in Patients with Hormone Receptor-Positive Metastatic Breast Cancer Receiving First-line Endocrine Therapy in the SWOG S0226 Trial.

Author: Paoletti, Costanza, Paoletti, Costanza, Barlow, William E, Cobain, Erin F, Bergqvist, Mattias, Mehta, Rita S, Gralow, Julie R, Hortobagyi, Gabriel N, Albain, Kathy S, Pusztai, Lajos, Sharma, Priyanka, Godwin, Andrew K, Thompson, Alastair M, Hayes, Daniel F, Rae, James M, Paoletti, Costanza, Paoletti, Costanza, Barlow, William E, Cobain, Erin F, Bergqvist, Mattias, Mehta, Rita S, Gralow, Julie R, Hortobagyi, Gabriel N, Albain, Kathy S, Pusztai, Lajos, Sharma, Priyanka, Godwin, Andrew K, Thompson, Alastair M, Hayes, Daniel F, and Rae, James M
Abstract: PurposeSerum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor-positive MBC treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F).Patients and methodssTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier, log-rank tests, and Cox regression.ResultsBL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43-2.16); P < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; 95% CI (1.91-2.98); P < 0.0001]. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; 95% CI (0.38-0.87); P = 0.0087]. Patients with low sTK1 had no difference in outcomes by therapy (P = 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, 95% CI (1.34-2.17); P < 0.0001, OS HR = 2.51, 95% CI (1.93-3.26); P < 0.0001].ConclusionsHigh sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.
Published: 2021

17. Copy number aberration analysis to predict response to neoadjuvant antiHER2 therapy: results from the NeoALTTO phase III clinical trial

Author: Venet, David, Rediti, Mattia, Maetens, Marion M., Fumagalli, Debora, Brown, David Norman, Majjaj, Samira, Salgado, Roberto, Pusztai, Lajos, Harbeck, Nadia, El-Abed, Sarra, Wang, Yingbo, Saura, Cristina, Gomez, H.L., Semiglazov, Vladimir Fedorovich, de Azambuja, Evandro, Huober, J., Nuciforo, Paolo Giovanni, Di Cosimo, Serena, Piccart-Gebhart, Martine, Loi, Sherene, Rothé, Françoise, Sotiriou, Christos, Venet, David, Rediti, Mattia, Maetens, Marion M., Fumagalli, Debora, Brown, David Norman, Majjaj, Samira, Salgado, Roberto, Pusztai, Lajos, Harbeck, Nadia, El-Abed, Sarra, Wang, Yingbo, Saura, Cristina, Gomez, H.L., Semiglazov, Vladimir Fedorovich, de Azambuja, Evandro, Huober, J., Nuciforo, Paolo Giovanni, Di Cosimo, Serena, Piccart-Gebhart, Martine, Loi, Sherene, Rothé, Françoise, and Sotiriou, Christos
Abstract: Purpose: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNAs) in predicting pathological complete response (pCR) and survival outcomes in the NeoALTTO trial. Experimental design: The neoadjuvant phase III NeoALTTO trial enrolled 455 HER2-positive early-stage breast cancer patients. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0. Results: Copy number aberrations estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the ER-positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared to TP53 mutated tumors, with copy number levels resulting significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number. Conclusions: Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti-HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2021

18. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer.

Author: UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim R M, Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P, Hanna, Matthew G, Soler-Monsó, M Teresa, Bethmann, Daniel, Castaneda, Carlos A, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group, Van Bockstal, Mieke, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria-Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine, Blenman, Kim R M, Penault-Llorca, Frédérique, Schnitt, Stuart, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy P, Hanna, Matthew G, Soler-Monsó, M Teresa, Bethmann, Daniel, Castaneda, Carlos A, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group, and Van Bockstal, Mieke
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.
Published: 2020

19. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author: Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Singh, Rajendra, Balslev, Eva, Stovgaard, Elisabeth Ida Specht, Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Singh, Rajendra, Balslev, Eva, and Stovgaard, Elisabeth Ida Specht
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.
Published: 2020

20. Early modulation of circulating microRNAs levels in HER2-positive breast cancer patients treated with trastuzumab-based neoadjuvant therapy

Author: Di Cosimo, Serena, Appierto, Valentina, Pizzamiglio, Sara, Silvestri, Marco, Baselga, José, Piccart-Gebhart, Martine, Huober, J., Izquierdo, Miguel, de la Peña, Lorena, Hilbers, Florentine FS, de Azambuja, Evandro, Untch, Michael, Pusztai, Lajos, Pritchard, Kathleen, Nuciforo, Paolo Giovanni, Vincent-Salomon, A., Symmans, Fraser, Apolone, Giovanni, De Braud, Filippo De, Iorio, Marilena Valeria, Verderio, Paolo, Daidone, Maria Grazia, Di Cosimo, Serena, Appierto, Valentina, Pizzamiglio, Sara, Silvestri, Marco, Baselga, José, Piccart-Gebhart, Martine, Huober, J., Izquierdo, Miguel, de la Peña, Lorena, Hilbers, Florentine FS, de Azambuja, Evandro, Untch, Michael, Pusztai, Lajos, Pritchard, Kathleen, Nuciforo, Paolo Giovanni, Vincent-Salomon, A., Symmans, Fraser, Apolone, Giovanni, De Braud, Filippo De, Iorio, Marilena Valeria, Verderio, Paolo, and Daidone, Maria Grazia
Abstract: Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2‐targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%–68%), and 44% (95%CI 22%–69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23–9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%–81%) and 0% (95%CI 0%–31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab‐based neoadjuvant therapy., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

21. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer.

Author: Kos, Zuzana, Roblin, Elvire, Kim, Seong-Rim, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen M, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew M, Hall, Jacqueline Anne, Kok, Marleen, Horlings, Hugo Mark, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge Sergio, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine L, Blenman, Kim KRM, Penault-Llorca, Frédérique, Schnitt, Stuart J, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy JP, Hanna, Matthew G, Soler-Monsó, Teresa MT, Bethmann, Daniel, Castaneda, Carlos Altamirano, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, International Immuno-Oncology Biomarker Working Group, Kos, Zuzana, Roblin, Elvire, Kim, Seong-Rim, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen M, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew M, Hall, Jacqueline Anne, Kok, Marleen, Horlings, Hugo Mark, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Yang, Wentao, AbdulJabbar, Khalid, Yuan, Yinyin, Singh, Rajendra, Hiley, Crispin, Bakir, Maise Al, Lazar, Alexander J, Naber, Stephen, Wienert, Stephan, Castillo, Miluska, Curigliano, Giuseppe, Dieci, Maria Vittoria, André, Fabrice, Swanton, Charles, Reis-Filho, Jorge Sergio, Sparano, Joseph, Balslev, Eva, Chen, I-Chun, Stovgaard, Elisabeth Ida Specht, Pogue-Geile, Katherine L, Blenman, Kim KRM, Penault-Llorca, Frédérique, Schnitt, Stuart J, Lakhani, Sunil R, Vincent-Salomon, Anne, Rojo, Federico, Braybrooke, Jeremy JP, Hanna, Matthew G, Soler-Monsó, Teresa MT, Bethmann, Daniel, Castaneda, Carlos Altamirano, Willard-Gallo, Karen, Sharma, Ashish, Lien, Huang-Chun, Fineberg, Susan, Thagaard, Jeppe, Comerma, Laura, Gonzalez-Ericsson, Paula, Brogi, Edi, Loi, Sherene, Saltz, Joel, Klaushen, Frederick, Cooper, Lee, Amgad, Mohamed, Moore, David A, Salgado, Roberto, and International Immuno-Oncology Biomarker Working Group
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

22. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author: Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Singh, Rajendra, Balslev, Eva, Stovgaard, Elisabeth Ida Specht, Kos, Zuzana, Roblin, Elvire, Kim, Rim S, Michiels, Stefan, Gallas, Brandon D, Chen, Weijie, van de Vijver, Koen K, Goel, Shom, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil S, Symmans, W Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen, Denkert, Carsten, Loibl, Sibylle, Luen, Stephen J, Bartlett, John M S, Savas, Peter, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie Chon U, Tutt, Andrew, Hall, Jacqueline A, Kok, Marleen, Horlings, Hugo M, Madabhushi, Anant, van der Laak, Jeroen, Ciompi, Francesco, Laenkholm, Anne-Vibeke, Bellolio, Enrique, Gruosso, Tina, Fox, Stephen B, Araya, Juan Carlos, Floris, Giuseppe, Hudeček, Jan, Voorwerk, Leonie, Beck, Andrew H, Kerner, Jen, Larsimont, Denis, Declercq, Sabine, Van den Eynden, Gert, Pusztai, Lajos, Ehinger, Anna, Singh, Rajendra, Balslev, Eva, and Stovgaard, Elisabeth Ida Specht
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls.
Published: 2020

23. CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies

Author: Feng, William W.W., Wilkins, Owen, Bang, Scott, Ung, Matthew, Li, Jiaqi, An, Jennifer, del Genio, Carmen, Canfield, Kaleigh, DiRenzo, James, Wells, Wendy, Gaur, Arti, Robey, Brooks R.B., Guo, Jessie Yanxiang, Powles, Ryan Lee, Sotiriou, Christos, Pusztai, Lajos, Febbraio, Maria, Cheng, Chao, Kinlaw, William W.B., Kurokawa, Manabu, Feng, William W.W., Wilkins, Owen, Bang, Scott, Ung, Matthew, Li, Jiaqi, An, Jennifer, del Genio, Carmen, Canfield, Kaleigh, DiRenzo, James, Wells, Wendy, Gaur, Arti, Robey, Brooks R.B., Guo, Jessie Yanxiang, Powles, Ryan Lee, Sotiriou, Christos, Pusztai, Lajos, Febbraio, Maria, Cheng, Chao, Kinlaw, William W.B., and Kurokawa, Manabu
Abstract: The functional significance of lipid metabolism in cancer cells is not fully understood. Feng et al. show that the fatty acid transporter CD36 is essential for survival of breast cancer cells during anti-HER2 therapy, highlighting the role of lipid metabolism in acquired resistance to targeted therapy., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019

24. Association of T-Cell Receptor Repertoire Use With Response to Combined Trastuzumab-Lapatinib Treatment of HER2-Positive Breast Cancer: Secondary Analysis of the NeoALTTO Randomized Clinical Trial.

Author: Powles, Ryan L, Redmond, David, Sotiriou, Christos, Loi, Sherene, Fumagalli, Debora, Nuciforo, Paolo, Harbeck, Nadia, de Azambuja, Evandro, Sarp, Severine, Di Cosimo, Serena, Huober, Jens, Baselga, José, Piccart-Gebhart, Martine, Elemento, Olivier, Pusztai, Lajos, Hatzis, Christos, Powles, Ryan L, Redmond, David, Sotiriou, Christos, Loi, Sherene, Fumagalli, Debora, Nuciforo, Paolo, Harbeck, Nadia, de Azambuja, Evandro, Sarp, Severine, Di Cosimo, Serena, Huober, Jens, Baselga, José, Piccart-Gebhart, Martine, Elemento, Olivier, Pusztai, Lajos, and Hatzis, Christos
Abstract: Dual anti-HER2 blockade increased the rate of pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, and high immune gene expression was associated with pCR in all treatment arms. So far, no marker has been identified that is specifically associated with the benefit from dual HER2 blockade., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2018

25. Functional germline variants as potential co-oncogenes

Author: Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, Hatzis, Christos, Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, and Hatzis, Christos
Abstract: Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.
Published: 2017
Full Text: View/download PDF

26. Functional germline variants as potential co-oncogenes

Author: Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, Hatzis, Christos, Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, and Hatzis, Christos
Abstract: Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.
Published: 2017
Full Text: View/download PDF

27. Functional germline variants as potential co-oncogenes

Author: Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, Hatzis, Christos, Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, and Hatzis, Christos
Abstract: Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.
Published: 2017
Full Text: View/download PDF

28. Functional germline variants as potential co-oncogenes

Author: Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, Hatzis, Christos, Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, and Hatzis, Christos
Abstract: Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.
Published: 2017
Full Text: View/download PDF

29. Control of dataset bias in combined affymetrix cohorts of triple negative breast cancer

Author: Karn, Thomas, Rody, Achim, Müller, Volkmar, Schmidt, Marcus, Becker, Sven, Holtrich, Uwe, Pusztai, Lajos, Karn, Thomas, Rody, Achim, Müller, Volkmar, Schmidt, Marcus, Becker, Sven, Holtrich, Uwe, and Pusztai, Lajos
Abstract: Heterogenous subtypes of breast cancer need to be analyzed separately. Pooling of datasets can provide reasonable sample sizes but dataset bias is an important concern. We assembled a combined dataset of 579 Affymetrix microarrays from triple negative breast cancer (TNBC) in Gene Expression Omnibus (GEO) series GSE31519. We developed a method for selecting comparable datasets and to control for the amount of dataset bias of individual probesets.
Published: 2017

30. Functional germline variants as potential co-oncogenes

Author: Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, Hatzis, Christos, Agarwal, Divyansh, Nowak, Christoph, Zhang, Nancy R., Pusztai, Lajos, and Hatzis, Christos
Abstract: Germline variants that affect the expression or function of proteins contribute to phenotypic variation in humans and likely determine individual characteristics and susceptibility to diseases including cancer. A number of high penetrance germline variants that increase cancer risk have been identified and studied, but germline functional polymorphisms are not typically considered in the context of cancer biology, where the focus is primarily on somatic mutations. Yet, there is evidence from familial cancers indicating that specific cancer subtypes tend to arise in carriers of high-risk germline variants (e.g., triple negative breast cancers in mutated BRCA carriers), which suggests that pre-existing germline variants may determine which complementary somatic driver mutations are needed to drive tumorigenesis. Recent genome sequencing studies of large breast cancer cohorts reported only a handful of highly recurrent driver mutations, suggesting that different oncogenic events drive individual cancers. Here, we propose that germline polymorphisms can function as oncogenic modifiers, or co-oncogenes, and these determine what complementary subsequent somatic events are required for full malignant transformation. Therefore, we propose that germline aberrations should be considered together with somatic mutations to determine what genes drive cancer and how they may be targeted.
Published: 2017
Full Text: View/download PDF

31. Cardiac biomarkers for early detection and prediction of trastuzumab and/or lapatinib-induced cardiotoxicity in patients with HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06).

Author: Ponde, Noam, Bradbury, Ian, Lambertini, Matteo, Ewer, Michael S, Campbell, Christine, Ameels, Helene, Zardavas, Dimitrios, Di Cosimo, Serena, Baselga, José, Huober, Jens, Izquierdo, Miguel, Fumagalli, Debora, Bozovic-Spasojevic, Ivana, Maetens, Marion M., Harbeck, Nadia, Pusztai, Lajos, Berghorn, Michael, Im, Young Hyuck, Borrego, Manuel Ruiz, Chen, Dar-Ren, Rodeheffer, Richard, Piccart-Gebhart, Martine, Suter, Thomas, de Azambuja, Evandro, Ponde, Noam, Bradbury, Ian, Lambertini, Matteo, Ewer, Michael S, Campbell, Christine, Ameels, Helene, Zardavas, Dimitrios, Di Cosimo, Serena, Baselga, José, Huober, Jens, Izquierdo, Miguel, Fumagalli, Debora, Bozovic-Spasojevic, Ivana, Maetens, Marion M., Harbeck, Nadia, Pusztai, Lajos, Berghorn, Michael, Im, Young Hyuck, Borrego, Manuel Ruiz, Chen, Dar-Ren, Rodeheffer, Richard, Piccart-Gebhart, Martine, Suter, Thomas, and de Azambuja, Evandro
Abstract: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017

32. Deregulation of A-to-I RNA editing is associated with poor prognosis in HER2+ breast cancers in the neoALTTO trial

Author: 40th San Antonio Breast Cancer Symposium (40: 05-09/12/2017: San Antonio, TX, USA), Venet, David, Rothé, Françoise, Dupont, Floriane, Maetens, Marion M., Fumagalli, Debora, Salgado, Roberto, Bradbury, Ian, Pusztai, Lajos, Harbeck, Nadia, Izquierdo, M, de la Peña, Lorena, Ignatiadis, Michail, de Azambuja, Evandro, Huober, Jens, Nuciforo, P, Baselga, José, Piccart-Gebhart, Martine, Loi, Sherene, Sotiriou, Christos, 40th San Antonio Breast Cancer Symposium (40: 05-09/12/2017: San Antonio, TX, USA), Venet, David, Rothé, Françoise, Dupont, Floriane, Maetens, Marion M., Fumagalli, Debora, Salgado, Roberto, Bradbury, Ian, Pusztai, Lajos, Harbeck, Nadia, Izquierdo, M, de la Peña, Lorena, Ignatiadis, Michail, de Azambuja, Evandro, Huober, Jens, Nuciforo, P, Baselga, José, Piccart-Gebhart, Martine, Loi, Sherene, and Sotiriou, Christos
Abstract: info:eu-repo/semantics/nonPublished
Published: 2017

33. [P2-09-01] T-cell receptor beta chain variable region (TRBV) expression patterns predict response to combined trastuzumab/lapatinib treatment in the NeoALTTO/BIG-1-06 trial

Author: 40th San Antonio Breast Cancer Symposium (40: 05-09/12/2017: San Antonio), Powles, R., Redmond, David, Sotiriou, Christos, Loi, Sherene, Fumagalli, Debora, Nuciforo, Paolo, Harbeck, Nadia, de Azambuja, Evandro, Sarp, Severine, Di Cosimo, Serena, Huober, Jens, Baselga, J, Piccart-Gebhart, Martine, Elemonto, Olivier, Hatzis, Christos, Pusztai, Lajos, 40th San Antonio Breast Cancer Symposium (40: 05-09/12/2017: San Antonio), Powles, R., Redmond, David, Sotiriou, Christos, Loi, Sherene, Fumagalli, Debora, Nuciforo, Paolo, Harbeck, Nadia, de Azambuja, Evandro, Sarp, Severine, Di Cosimo, Serena, Huober, Jens, Baselga, J, Piccart-Gebhart, Martine, Elemonto, Olivier, Hatzis, Christos, and Pusztai, Lajos
Abstract: info:eu-repo/semantics/nonPublished
Published: 2017

34. Deregulation of A-to-I RNA editing is associated with poor prognosis in HER2+ breast cancers in the neoALTTO trial

Author: 40th San Antonio Breast Cancer Symposium (40: 05-09/12/2017: San Antonio), Venet, David, Rothé, Françoise, Dupont, Floriane, Maetens, Marion M., Fumagalli, Debora, Salgado, Roberto, Bradbury, Ian, Pusztai, Lajos, Harbeck, Nadia, Izquierdo, M, de la Peña, Lorena, Ignatiadis, Michail, de Azambuja, Evandro, Huober, Jens, Nuciforo, P, Baselga, J, Piccart-Gebhart, Martine, Loi, Sherene, Sotiriou, Christos, 40th San Antonio Breast Cancer Symposium (40: 05-09/12/2017: San Antonio), Venet, David, Rothé, Françoise, Dupont, Floriane, Maetens, Marion M., Fumagalli, Debora, Salgado, Roberto, Bradbury, Ian, Pusztai, Lajos, Harbeck, Nadia, Izquierdo, M, de la Peña, Lorena, Ignatiadis, Michail, de Azambuja, Evandro, Huober, Jens, Nuciforo, P, Baselga, J, Piccart-Gebhart, Martine, Loi, Sherene, and Sotiriou, Christos
Abstract: info:eu-repo/semantics/nonPublished
Published: 2017

35. Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

Author: Brown, David Norman, Smeets, D, Szekely, B, Larsimont, Denis, Szász, András, Adnet, Pierre-Yves, Rothé, Françoise, Rouas, Ghizlane, Nagy, Z., Faragó, Zsófia, Tokes, AM, Dank, Magdolna, Szentmártoni, Gyöngyvér, Udvarhelyi, Nóra, Zoppoli, Gabriele, Pusztai, Lajos, Piccart-Gebhart, Martine, Kulka, Janina, Lambrechts, Diether, Sotiriou, Christos, Desmedt, Christine, Brown, David Norman, Smeets, D, Szekely, B, Larsimont, Denis, Szász, András, Adnet, Pierre-Yves, Rothé, Françoise, Rouas, Ghizlane, Nagy, Z., Faragó, Zsófia, Tokes, AM, Dank, Magdolna, Szentmártoni, Gyöngyvér, Udvarhelyi, Nóra, Zoppoli, Gabriele, Pusztai, Lajos, Piccart-Gebhart, Martine, Kulka, Janina, Lambrechts, Diether, Sotiriou, Christos, and Desmedt, Christine
Abstract: Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017

36. RNA Sequencing to Predict Response to Neoadjuvant Anti-HER2 Therapy: A Secondary Analysis of the NeoALTTO Randomized Clinical Trial.

Author: Fumagalli, Debora, Venet, David, Ignatiadis, Michail, Abdel Azim, Hatem Hamdy, Maetens, Marion M., Rothé, Françoise, Salgado, Roberto, Bradbury, Ian, Pusztai, Lajos, Harbeck, Nadia, Gomez, Henry, Chang, Tsai-Wang, Coccia-Portugal, Maria, Di Cosimo, Serena, de Azambuja, Evandro, de la Peña, Lorena, Nuciforo, Paolo, Brase, Jan JC, Huober, Jens, Baselga, José, Piccart-Gebhart, Martine, Loi, Sherene, Sotiriou, Christos, Fumagalli, Debora, Venet, David, Ignatiadis, Michail, Abdel Azim, Hatem Hamdy, Maetens, Marion M., Rothé, Françoise, Salgado, Roberto, Bradbury, Ian, Pusztai, Lajos, Harbeck, Nadia, Gomez, Henry, Chang, Tsai-Wang, Coccia-Portugal, Maria, Di Cosimo, Serena, de Azambuja, Evandro, de la Peña, Lorena, Nuciforo, Paolo, Brase, Jan JC, Huober, Jens, Baselga, José, Piccart-Gebhart, Martine, Loi, Sherene, and Sotiriou, Christos
Abstract: In neoadjuvant trials, treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancers with dual HER2 blockade resulted in increased pathologic complete response (pCR) rates compared with each targeted agent alone. Amplification and/or overexpression of HER2 currently remains the only biomarker for therapeutic decisions, but it is insufficient to explain the heterogeneous response to anti-HER2 agents., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017

37. Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial.

Author: Shi, W, Jiang, T, Nuciforo, Paolo, Hatzis, Christos, Holmes, E, Harbeck, Nadia, Sotiriou, Christos, Peña, L, Loi, Sherene, Rosa, D D, Chia, S, Wardley, Andrew, Ueno, T, Rossari, José, Eidtmann, H, Armour, A, Piccart-Gebhart, Martine, Rimm, David D.L., Baselga, José, Pusztai, Lajos, Shi, W, Jiang, T, Nuciforo, Paolo, Hatzis, Christos, Holmes, E, Harbeck, Nadia, Sotiriou, Christos, Peña, L, Loi, Sherene, Rosa, D D, Chia, S, Wardley, Andrew, Ueno, T, Rossari, José, Eidtmann, H, Armour, A, Piccart-Gebhart, Martine, Rimm, David D.L., Baselga, José, and Pusztai, Lajos
Abstract: We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2017

38. Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

Author: Rugo, Hope S, Rugo, Hope S, Olopade, Olufunmilayo I, DeMichele, Angela, Yau, Christina, van 't Veer, Laura J, Buxton, Meredith B, Hogarth, Michael, Hylton, Nola M, Paoloni, Melissa, Perlmutter, Jane, Symmans, W Fraser, Yee, Douglas, Chien, A Jo, Wallace, Anne M, Kaplan, Henry G, Boughey, Judy C, Haddad, Tufia C, Albain, Kathy S, Liu, Minetta C, Isaacs, Claudine, Khan, Qamar J, Lang, Julie E, Viscusi, Rebecca K, Pusztai, Lajos, Moulder, Stacy L, Chui, Stephen Y, Kemmer, Kathleen A, Elias, Anthony D, Edmiston, Kirsten K, Euhus, David M, Haley, Barbara B, Nanda, Rita, Northfelt, Donald W, Tripathy, Debasish, Wood, William C, Ewing, Cheryl, Schwab, Richard, Lyandres, Julia, Davis, Sarah E, Hirst, Gillian L, Sanil, Ashish, Berry, Donald A, Esserman, Laura J, I-SPY 2 Investigators, Rugo, Hope S, Rugo, Hope S, Olopade, Olufunmilayo I, DeMichele, Angela, Yau, Christina, van 't Veer, Laura J, Buxton, Meredith B, Hogarth, Michael, Hylton, Nola M, Paoloni, Melissa, Perlmutter, Jane, Symmans, W Fraser, Yee, Douglas, Chien, A Jo, Wallace, Anne M, Kaplan, Henry G, Boughey, Judy C, Haddad, Tufia C, Albain, Kathy S, Liu, Minetta C, Isaacs, Claudine, Khan, Qamar J, Lang, Julie E, Viscusi, Rebecca K, Pusztai, Lajos, Moulder, Stacy L, Chui, Stephen Y, Kemmer, Kathleen A, Elias, Anthony D, Edmiston, Kirsten K, Euhus, David M, Haley, Barbara B, Nanda, Rita, Northfelt, Donald W, Tripathy, Debasish, Wood, William C, Ewing, Cheryl, Schwab, Richard, Lyandres, Julia, Davis, Sarah E, Hirst, Gillian L, Sanil, Ashish, Berry, Donald A, Esserman, Laura J, and I-SPY 2 Investigators
Abstract: BackgroundThe genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin.MethodsIn this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well.ResultsWith regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathol
Published: 2016

39. Adaptive Randomization of Neratinib in Early Breast Cancer.

Author: Park, John W, Park, John W, Liu, Minetta C, Yee, Douglas, Yau, Christina, van 't Veer, Laura J, Symmans, W Fraser, Paoloni, Melissa, Perlmutter, Jane, Hylton, Nola M, Hogarth, Michael, DeMichele, Angela, Buxton, Meredith B, Chien, A Jo, Wallace, Anne M, Boughey, Judy C, Haddad, Tufia C, Chui, Stephen Y, Kemmer, Kathleen A, Kaplan, Henry G, Isaacs, Claudine, Nanda, Rita, Tripathy, Debasish, Albain, Kathy S, Edmiston, Kirsten K, Elias, Anthony D, Northfelt, Donald W, Pusztai, Lajos, Moulder, Stacy L, Lang, Julie E, Viscusi, Rebecca K, Euhus, David M, Haley, Barbara B, Khan, Qamar J, Wood, William C, Melisko, Michelle, Schwab, Richard, Helsten, Teresa, Lyandres, Julia, Davis, Sarah E, Hirst, Gillian L, Sanil, Ashish, Esserman, Laura J, Berry, Donald A, I-SPY 2 Investigators, Park, John W, Park, John W, Liu, Minetta C, Yee, Douglas, Yau, Christina, van 't Veer, Laura J, Symmans, W Fraser, Paoloni, Melissa, Perlmutter, Jane, Hylton, Nola M, Hogarth, Michael, DeMichele, Angela, Buxton, Meredith B, Chien, A Jo, Wallace, Anne M, Boughey, Judy C, Haddad, Tufia C, Chui, Stephen Y, Kemmer, Kathleen A, Kaplan, Henry G, Isaacs, Claudine, Nanda, Rita, Tripathy, Debasish, Albain, Kathy S, Edmiston, Kirsten K, Elias, Anthony D, Northfelt, Donald W, Pusztai, Lajos, Moulder, Stacy L, Lang, Julie E, Viscusi, Rebecca K, Euhus, David M, Haley, Barbara B, Khan, Qamar J, Wood, William C, Melisko, Michelle, Schwab, Richard, Helsten, Teresa, Lyandres, Julia, Davis, Sarah E, Hirst, Gillian L, Sanil, Ashish, Esserman, Laura J, Berry, Donald A, and I-SPY 2 Investigators
Abstract: BackgroundThe heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery).MethodsWe used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature.ResultsNeratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls
Published: 2016

40. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study.

Author: Nanda, Rita, Chow, Laura Q M LQ, Claire Dees, E., Berger, Raanan, Gupta, Shilpa, Geva, Ravit, Pusztai, Lajos, Pathiraja, Kumudu, Aktan, Gursel, Cheng, Jonathan D, Karantza, Vassiliki, Buisseret, Laurence, Nanda, Rita, Chow, Laura Q M LQ, Claire Dees, E., Berger, Raanan, Gupta, Shilpa, Geva, Ravit, Pusztai, Lajos, Pathiraja, Kumudu, Aktan, Gursel, Cheng, Jonathan D, Karantza, Vassiliki, and Buisseret, Laurence
Abstract: Immune checkpoint inhibition has been demonstrated to be an effective anticancer strategy. Several lines of evidence support the study of immunotherapy in triple-negative breast cancer (TNBC). We assessed the safety and antitumor activity of the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab in patients with advanced TNBC., info:eu-repo/semantics/published
Published: 2016

41. Whole exome sequencing of pre-treatment biopsies from the neoALTTO trial to identify DNA aberrations associated with response to HER2-targeted therapies.

Author: San Antonio Breast Cancer Symposium (December 11, 2015: San Antonio, Tx, USA), Pusztai, Lajos, Shi, W, Jiang, T, Nuciforo, P, Holmes, E, Harbeck, Nadia, Sotiriou, Christos, Rimm, David D.L., Hatzis, Christos, de la Peña, Lorena, Armour, A, Piccart-Gebhart, Martine, Baselga, J, San Antonio Breast Cancer Symposium (December 11, 2015: San Antonio, Tx, USA), Pusztai, Lajos, Shi, W, Jiang, T, Nuciforo, P, Holmes, E, Harbeck, Nadia, Sotiriou, Christos, Rimm, David D.L., Hatzis, Christos, de la Peña, Lorena, Armour, A, Piccart-Gebhart, Martine, and Baselga, J
Abstract: info:eu-repo/semantics/nonPublished
Published: 2015

42. High HER2 expression correlates with response to the combination of lapatinib and trastuzumab

Author: Scaltriti. Maurizio, Parra, Josep Lluis, Prudkin, Ludmila, Molina Jimenez, José, Aura, Claudia Monica, Harbeck, Nadia, Pusztai, Lajos, Ellis, Catherine, Eidtmann, Holger, Arribas, Joaquin, Cortes, Javier, Nuciforo, Paolo Giovanni, de Azambuja, Evandro, Piccart-Gebhart, Martine, Baselga, José, Bradbury, Ian, Sperinde, Jeff, Agbor-Tarh, Dominique, Campbell, Christine, Chenna, Ahmed, Winslow, John, Serra, Violeta, Scaltriti. Maurizio, Parra, Josep Lluis, Prudkin, Ludmila, Molina Jimenez, José, Aura, Claudia Monica, Harbeck, Nadia, Pusztai, Lajos, Ellis, Catherine, Eidtmann, Holger, Arribas, Joaquin, Cortes, Javier, Nuciforo, Paolo Giovanni, de Azambuja, Evandro, Piccart-Gebhart, Martine, Baselga, José, Bradbury, Ian, Sperinde, Jeff, Agbor-Tarh, Dominique, Campbell, Christine, Chenna, Ahmed, Winslow, John, and Serra, Violeta
Abstract: Purpose: Expression of p95HER2 has been associated with resistance to trastuzumab-based therapy in patients with metastatic breast cancer. Conversely, high levels of HER2 have been linked with increased clinical benefit from anti-HER2 therapy. In this work, we aimed to investigate whether the levels of p95HER2 and HER2 can predict response to anti-HER2 therapy in patients with breast cancer. Experimental Design: We measured p95HER2 and HER2 by VeraTag and HERmark, respectively, in primary tumors of patients enrolled in the neoadjuvant phase III study NeoALTTO and correlated these variables with pathologic complete response (pCR) and progression-free survival (PFS) following lapatinib (L), trastuzumab (T), or the combination of both agents (L+T). Results: A positive correlation between p95HER2 and HER2 levels was found in the 274 cases (60%) in which quantification of both markers was possible. High levels of these markers were predictive for pCR, especially in the hormone receptor (HR)-positive subset of patients. High HER2 expression was associated with increased pCR rate upon L+T irrespective of the HR status. To examine whether the levels of either p95HER2 or HER2 could predict for PFS in patients treated with lapatinib, trastuzumab or L+T, we fit to the PFS data in Cox models containing log2 (p95HER2) or log2(HER2). Both variables correlated with longer PFS. Conclusions: Increasing HER2 protein expression correlated with increased benefit of adding lapatinib to trastuzumab. HER2 expression is a stronger predictor of pCR and PFS than p95HER2 for response to lapatinib, trastuzumab and, more significantly, L+T., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2015

43. Whole exome sequencing of pre-treatment biopsies from the neoALTTO trial to identify DNA aberrations associated with response to HER2-targeted therapies

Author: Pusztai, Lajos, Shi, W, Jiang, T, Nuciforo, P, Holmes, E, Harbeck, Nadia, Sotiriou, Christos, Rimm, David D.L., Hatzis, Christos, de la Peña, Lorena, Armour, A, Piccart-Gebhart, Martine, Baselga, José, Pusztai, Lajos, Shi, W, Jiang, T, Nuciforo, P, Holmes, E, Harbeck, Nadia, Sotiriou, Christos, Rimm, David D.L., Hatzis, Christos, de la Peña, Lorena, Armour, A, Piccart-Gebhart, Martine, and Baselga, José
Abstract: n°S5-01, info:eu-repo/semantics/published
Published: 2015

44. TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers.

Author: Győrffy, Balázs, Bottai, Giulia, Lehmann-Che, Jacqueline, Kéri, György, Orfi, László, Iwamoto, Takayuki, Desmedt, Christine, Bianchini, Giampaolo, Turner, Nicholas C, de Thé, Hugues, Andre, Fabrice, Sotiriou, Christos, Hortobagyi, Gabriel N., Di Leo, Angelo, Pusztai, Lajos, Santarpia, Libero, Győrffy, Balázs, Bottai, Giulia, Lehmann-Che, Jacqueline, Kéri, György, Orfi, László, Iwamoto, Takayuki, Desmedt, Christine, Bianchini, Giampaolo, Turner, Nicholas C, de Thé, Hugues, Andre, Fabrice, Sotiriou, Christos, Hortobagyi, Gabriel N., Di Leo, Angelo, Pusztai, Lajos, and Santarpia, Libero
Abstract: Breast cancers (BC) carry a complex set of gene mutations that can influence their gene expression and clinical behavior. We aimed to identify genes driven by the TP53 mutation status and assess their clinical relevance in estrogen receptor (ER)-positive and ER-negative BC, and their potential as targets for patients with TP53 mutated tumors. Separate ROC analyses of each gene expression according to TP53 mutation status were performed. The prognostic value of genes with the highest AUC were assessed in a large dataset of untreated, and neoadjuvant chemotherapy treated patients. The mitotic checkpoint gene MPS1 was the most significant gene correlated with TP53 status, and the most significant prognostic marker in all ER-positive BC datasets. MPS1 retained its prognostic value independently from the type of treatment administered. The biological functions of MPS1 were investigated in different BC cell lines. We also assessed the effects of a potent small molecule inhibitor of MPS1, SP600125, alone and in combination with chemotherapy. Consistent with the gene expression profiling and siRNA assays, the inhibition of MPS1 by SP600125 led to a reduction in cell viability and a significant increase in cell death, selectively in TP53-mutated BC cells. Furthermore, the chemical inhibition of MPS1 sensitized BC cells to conventional chemotherapy, particularly taxanes. Our results collectively demonstrate that TP53-correlated kinase MPS1, is a potential therapeutic target in BC patients with TP53 mutated tumors, and that SP600125 warrant further development in future clinical trials., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2014

45. TP53 mutation-correlated genes predict the risk of tumor relapse and identify MPS1 as a potential therapeutic kinase in TP53-mutated breast cancers.

Author: Győrffy, Balázs, Bottai, Giulia, Lehmann-Che, Jacqueline, Kéri, György, Orfi, László, Iwamoto, Takayuki, Desmedt, Christine, Bianchini, Giampaolo, Turner, Nicholas C, de Thé, Hugues, Andre, Fabrice, Sotiriou, Christos, Hortobagyi, Gabriel N., Di Leo, Angelo, Pusztai, Lajos, Santarpia, Libero, Győrffy, Balázs, Bottai, Giulia, Lehmann-Che, Jacqueline, Kéri, György, Orfi, László, Iwamoto, Takayuki, Desmedt, Christine, Bianchini, Giampaolo, Turner, Nicholas C, de Thé, Hugues, Andre, Fabrice, Sotiriou, Christos, Hortobagyi, Gabriel N., Di Leo, Angelo, Pusztai, Lajos, and Santarpia, Libero
Abstract: Breast cancers (BC) carry a complex set of gene mutations that can influence their gene expression and clinical behavior. We aimed to identify genes driven by the TP53 mutation status and assess their clinical relevance in estrogen receptor (ER)-positive and ER-negative BC, and their potential as targets for patients with TP53 mutated tumors. Separate ROC analyses of each gene expression according to TP53 mutation status were performed. The prognostic value of genes with the highest AUC were assessed in a large dataset of untreated, and neoadjuvant chemotherapy treated patients. The mitotic checkpoint gene MPS1 was the most significant gene correlated with TP53 status, and the most significant prognostic marker in all ER-positive BC datasets. MPS1 retained its prognostic value independently from the type of treatment administered. The biological functions of MPS1 were investigated in different BC cell lines. We also assessed the effects of a potent small molecule inhibitor of MPS1, SP600125, alone and in combination with chemotherapy. Consistent with the gene expression profiling and siRNA assays, the inhibition of MPS1 by SP600125 led to a reduction in cell viability and a significant increase in cell death, selectively in TP53-mutated BC cells. Furthermore, the chemical inhibition of MPS1 sensitized BC cells to conventional chemotherapy, particularly taxanes. Our results collectively demonstrate that TP53-correlated kinase MPS1, is a potential therapeutic target in BC patients with TP53 mutated tumors, and that SP600125 warrant further development in future clinical trials., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2014

46. Unraveling breast cancer progression through geographical and temporal sequencing.

Author: Annual meeting of AACR 2014 (April 6, 2014: San Diego, USA), Desmedt, Christine, Brown, David Norman, Szekely, B, Smeets, D, Szasz, MA, Adnet, Pierre-Yves, Rothé, Françoise, Nagy, Z., Farago, Z, Tokes, AM, Zardavas, Dimitrios, Zoppoli, Gabriele, Ignatiadis, Michail, Pusztai, Lajos, Piccart-Gebhart, Martine, Larsimont, Denis, Lambrechts, Diether, Kulka, Janina, Sotiriou, Christos, Annual meeting of AACR 2014 (April 6, 2014: San Diego, USA), Desmedt, Christine, Brown, David Norman, Szekely, B, Smeets, D, Szasz, MA, Adnet, Pierre-Yves, Rothé, Françoise, Nagy, Z., Farago, Z, Tokes, AM, Zardavas, Dimitrios, Zoppoli, Gabriele, Ignatiadis, Michail, Pusztai, Lajos, Piccart-Gebhart, Martine, Larsimont, Denis, Lambrechts, Diether, Kulka, Janina, and Sotiriou, Christos
Abstract: Oral presentation- Molecular and Cellular Biology 15 session (abstract 986)., info:eu-repo/semantics/nonPublished
Published: 2014

47. Genome-wide gene expression profiling to predict resistance to anthracyclines in breast cancer patients

Author: Haibe-Kains, Benjamin, Desmedt, Christine, Di Leo, Angelo, Azambuja, Evandro, Larsimont, Denis, Selleslags, Jean, Delaloge, Suzette, Duhem, Caroline, Kains, Jean-Pierre, Carly, Birgit, Maerevoet, Marie, Vindevoghel, Anita, Rouas, Ghizlane, Lallemand, Françoise, Durbecq, Virginie, Cardoso, Fatima, Salgado, Roberto, Kraft Rovere, Rodrigo, Bontempi, Gianluca, Michiels, Stefan, Buyse, Marc, Nogaret, Jean-Marie, Qi, Yuan, Symmans, William Fraser, Pusztai, Lajos, D'Hondt, Veronique, Piccart-Gebhart, Martine, Sotiriou, Christos, Haibe-Kains, Benjamin, Desmedt, Christine, Di Leo, Angelo, Azambuja, Evandro, Larsimont, Denis, Selleslags, Jean, Delaloge, Suzette, Duhem, Caroline, Kains, Jean-Pierre, Carly, Birgit, Maerevoet, Marie, Vindevoghel, Anita, Rouas, Ghizlane, Lallemand, Françoise, Durbecq, Virginie, Cardoso, Fatima, Salgado, Roberto, Kraft Rovere, Rodrigo, Bontempi, Gianluca, Michiels, Stefan, Buyse, Marc, Nogaret, Jean-Marie, Qi, Yuan, Symmans, William Fraser, Pusztai, Lajos, D'Hondt, Veronique, Piccart-Gebhart, Martine, and Sotiriou, Christos
Abstract: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al. 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. © 2013 The Authors., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2013

48. Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers.

Author: Bianchini, Giampaolo, Pusztai, Lajos, Karn, Thomas, Iwamoto, Takayuki, Rody, Achim, Kelly, Catherine M, Müller, Volkmar, Schmidt, Marcus, Qi, Yuan, Holtrich, Uwe, Becker, Sven, Santarpia, Libero, Fasolo, Angelica, Del Conte, Gianluca, Zambetti, Milvia, Sotiriou, Christos, Haibe-Kains, Benjamin, Symmans, W Fraser, Gianni, Luca, Bianchini, Giampaolo, Pusztai, Lajos, Karn, Thomas, Iwamoto, Takayuki, Rody, Achim, Kelly, Catherine M, Müller, Volkmar, Schmidt, Marcus, Qi, Yuan, Holtrich, Uwe, Becker, Sven, Santarpia, Libero, Fasolo, Angelica, Del Conte, Gianluca, Zambetti, Milvia, Sotiriou, Christos, Haibe-Kains, Benjamin, Symmans, W Fraser, and Gianni, Luca
Abstract: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2013

49. Distinct tumor protein p53 mutants in breast cancer subgroups.

Author: Dumay, Anne, Feugeas, Jean-Paul, Wittmer, Evelyne, Lehmann-Che, Jacqueline, Bertheau, Philippe, Espié, Marc, Plassa, Louis-François, Cottu, Paul, Marty, Michel, Andre, Fabrice, Sotiriou, Christos, Pusztai, Lajos, de Thé, Hugues, Dumay, Anne, Feugeas, Jean-Paul, Wittmer, Evelyne, Lehmann-Che, Jacqueline, Bertheau, Philippe, Espié, Marc, Plassa, Louis-François, Cottu, Paul, Marty, Michel, Andre, Fabrice, Sotiriou, Christos, Pusztai, Lajos, and de Thé, Hugues
Abstract: Tumor protein p53 (TP53) is mutated in approximately 30% of breast cancers, but this frequency fluctuates widely between subclasses. We investigated the p53 mutation status in 572 breast tumors, classified into luminal, basal and molecular apocrine subgroups. As expected, the lowest mutation frequency was observed in luminal (26%), and the highest in basal (88%) tumors. Luminal tumors showed significantly higher frequency of substitutions (82 vs. 65%), notably A/T to G/C transitions (31 vs. 15%), whereas molecular apocrine and basal tumors presented much higher frequencies of complex mutations (deletions/insertions) (36 and 33%, respectively, vs. 18%). Accordingly, missense mutations were significantly more frequent in luminal tumors (75 vs. 54%), whereas basal tumors displayed significantly increased rates of TP53 truncations (43 vs. 25%), resulting in loss of function and/or expression. Interestingly, as basal tumors, molecular apocrine tumors presented with a high rate of complex mutations, but paradoxically, these were not associated with increased frequency of p53 truncation. As in luminal tumors, this could reflect a selective pressure for p53 gain of function, possibly through P63/P73 inactivation. Collectively, these observations point not only to different mechanisms of TP53 alterations, but also to different functional consequences in the different breast cancer subtypes., JOURNAL ARTICLE, FLWIN, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2013

50. Developing safety criteria for introducing new agents into neoadjuvant trials.

Author: DeMichele, Angela, DeMichele, Angela, Berry, Donald A, Zujewski, JoAnne, Hunsberger, Sally, Rubinstein, Larry, Tomaszewski, Joseph E, Kelloff, Gary, Perlmutter, Jane, Buxton, Meredith, Lyandres, Julia, Albain, Kathy S, Benz, Chris, Chien, A Jo, Haluska, Paul, Leyland-Jones, Brian, Liu, Minetta C, Munster, Pamela, Olopade, Olufunmilayo, Park, John W, Parker, Barbara A, Pusztai, Lajos, Tripathy, Debu, Rugo, Hope, Yee, Douglas, Esserman, Laura, DeMichele, Angela, DeMichele, Angela, Berry, Donald A, Zujewski, JoAnne, Hunsberger, Sally, Rubinstein, Larry, Tomaszewski, Joseph E, Kelloff, Gary, Perlmutter, Jane, Buxton, Meredith, Lyandres, Julia, Albain, Kathy S, Benz, Chris, Chien, A Jo, Haluska, Paul, Leyland-Jones, Brian, Liu, Minetta C, Munster, Pamela, Olopade, Olufunmilayo, Park, John W, Parker, Barbara A, Pusztai, Lajos, Tripathy, Debu, Rugo, Hope, Yee, Douglas, and Esserman, Laura
Abstract: New approaches to drug development are critically needed to lessen the time, cost, and resources necessary to identify and optimize active agents. Strategies to accelerate drug development include testing drugs earlier in the disease process, such as the neoadjuvant setting. The U.S. Food and Drug Administration (FDA) has issued guidance designed to accelerate drug approval through the use of neoadjuvant studies in which the surrogate short-term endpoint, pathologic response, can be used to identify active agents and shorten the time to approval of both efficacious drugs and biomarkers identifying patients most likely to respond. However, this approach has unique challenges. In particular, issues of patient safety are paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience. Key components to safe drug development in the neoadjuvant setting include defining a study population at sufficiently poor prognosis with standard therapy to justify exposure to investigational agents, defining the extent and adequacy of safety data from phase I, detecting potentially harmful interactions between investigational and standard therapies, improving study designs, such as adaptive strategies, that limit patient exposure to ineffective agents, and intensifying safety monitoring in the course of the trial. The I-SPY2 trial is an example of a phase II neoadjuvant trial of novel agents for breast cancer in which these issues have been addressed, both in the design and conduct of the trial. These adaptations of phase II design enable acceleration of drug development by reducing time and cost to screen novel therapies for activity without compromising safety.
Published: 2013

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Publication Year Range

Publication Type

Database

Publisher

125 results on '"Pusztai, Lajos"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources