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1. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen

Author

Daidone Maria G, Reid James F, Ellis Paul, Ryder Kenneth, Gillet Cheryl, Tutt Andrew M, Lallemand Françoise, Wirapati Pratyaksha, Desmedt Christine, Haibe-Kains Benjamin, Loi Sherene, Pierotti Marco A, Berns Els MJJ, Jansen Maurice PHM, Foekens John A, Delorenzi Mauro, Bontempi Gianluca, Piccart Martine J, and Sotiriou Christos

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30–40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. Results We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29–3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. Conclusion We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.

Published
2008
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2. Adjuvant olaparib for patients with BRCA1- Or BRCA2-mutated breast cancer

Author

Tutt, Andrew M, Garber, Judy Ellen, Kaufman, Bella, Viale, Giuseppe, Fumagalli, Debora, Rastogi, Priya, Gelber, Richard, de Azambuja, Evandro, Fielding, Anitra, Balmaña, Judith, Domchek, Susan S.M., Gelmon, Karen K.A., Hollingsworth, Simon S.J., Korde, Larissa, Linderholm, Barbro B.K., Bandos, Hanna, Senkus, Elżbieta, Suga, Jennifer Marie, Shao, Zhimin, Pippas, Andrew A.W., Nowecki, Zbigniew, Huzarski, Tomasz, Ganz, Patricia A, Lucas, Peter P.C., Baker, Nigel, Loibl, Sibylle, McConnell, Robin, Piccart-Gebhart, Martine, Schmutzler, Rita, Steger, Günther G.G., Costantino, Joseph P, Arahmani, Amal, Wolmark, Norman, McFadden, Eleanor, Karantza, Vassiliki, Lakhani, Sunil S.R., Yothers, Greg, Campbell, Christine, Geyer Jr. Charles C.E., Tutt, Andrew M, Garber, Judy Ellen, Kaufman, Bella, Viale, Giuseppe, Fumagalli, Debora, Rastogi, Priya, Gelber, Richard, de Azambuja, Evandro, Fielding, Anitra, Balmaña, Judith, Domchek, Susan S.M., Gelmon, Karen K.A., Hollingsworth, Simon S.J., Korde, Larissa, Linderholm, Barbro B.K., Bandos, Hanna, Senkus, Elżbieta, Suga, Jennifer Marie, Shao, Zhimin, Pippas, Andrew A.W., Nowecki, Zbigniew, Huzarski, Tomasz, Ganz, Patricia A, Lucas, Peter P.C., Baker, Nigel, Loibl, Sibylle, McConnell, Robin, Piccart-Gebhart, Martine, Schmutzler, Rita, Steger, Günther G.G., Costantino, Joseph P, Arahmani, Amal, Wolmark, Norman, McFadden, Eleanor, Karantza, Vassiliki, Lakhani, Sunil S.R., Yothers, Greg, Campbell, Christine, and Geyer Jr. Charles C.E.

Abstract

BACKGROUND Poly(adenosine diphosphate–ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation–associated early breast cancer. METHODS We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease–free survival. RESULTS A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease–free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease–free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P=0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib af, SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Published
2021

3. Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: The EORTC 1307-BCG/ BIG5–13/TESARO PR-30–50–10-C BRAVO Study

Author

Turner, Nicholas C, Balmaña, Judith, Poncet, Coralie, Goulioti, Theodora, Tryfonidis, Konstantinos, Honkoop, Aafke A.H., Zoppoli, Gabriele, Razis, Evangelia, Johannsson, Oskar Th, Colleoni, Marco Angelo, Tutt, Andrew M, Audeh, William, Ignatiadis, Michail, Mailliez, Audrey, Tredan, Olivier, Musolino, Antonino, Vuylsteke, Peter, Juan-Fita, Maria Jose, Macpherson, Iain R J, Kaufman, Bella, Manso, Luis, Goldstein, Lori L.J., Ellard, Susan S.L., Láng, István, Jen, Kai Yu, Adam, Virginie, Litière, Saskia, Erban, John, Cameron, David A, Turner, Nicholas C, Balmaña, Judith, Poncet, Coralie, Goulioti, Theodora, Tryfonidis, Konstantinos, Honkoop, Aafke A.H., Zoppoli, Gabriele, Razis, Evangelia, Johannsson, Oskar Th, Colleoni, Marco Angelo, Tutt, Andrew M, Audeh, William, Ignatiadis, Michail, Mailliez, Audrey, Tredan, Olivier, Musolino, Antonino, Vuylsteke, Peter, Juan-Fita, Maria Jose, Macpherson, Iain R J, Kaufman, Bella, Manso, Luis, Goldstein, Lori L.J., Ellard, Susan S.L., Láng, István, Jen, Kai Yu, Adam, Virginie, Litière, Saskia, Erban, John, and Cameron, David A

Abstract

Purpose: To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. Patients and Methods: BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician’s choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor–positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results: After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n ¼ 141) versus 3.1 months in the PC arm [n ¼ 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65–1.44; P ¼ 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63–1.42) and 0.65 (95% CI, 0.46–0.93), respectively. ORR was 35% (95% CI, 26–45) with niraparib and 31% (95% CI, 19–46) in the PC arm. Conclusions: Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib’s activity in this patient population., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021

4. Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials.

Author

Hudeček, Jan, Voorwerk, Leonie, van Seijen, Maartje, Nederlof, Iris, de Maaker, Michiel, van den Berg, Jose, van de Vijver, Koen K, Sikorska, Karolina, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil, Michiels, Stefan, Symmans, William Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen M, Denkert, Carsten, Loibl, Sibylle, Loi, Sherene, Bartlett, John M S, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie C U, Tutt, Andrew M, Hall, Jacqueline Anne, Kos, Zuzana, Salgado, Roberto, Kok, Marleen, Horlings, Hugo Mark, International Immuno-Oncology Biomarker Working Group, Hudeček, Jan, Voorwerk, Leonie, van Seijen, Maartje, Nederlof, Iris, de Maaker, Michiel, van den Berg, Jose, van de Vijver, Koen K, Sikorska, Karolina, Adams, Sylvia, Demaria, Sandra, Viale, Giuseppe, Nielsen, Torsten O, Badve, Sunil, Michiels, Stefan, Symmans, William Fraser, Sotiriou, Christos, Rimm, David L, Hewitt, Stephen M, Denkert, Carsten, Loibl, Sibylle, Loi, Sherene, Bartlett, John M S, Pruneri, Giancarlo, Dillon, Deborah A, Cheang, Maggie C U, Tutt, Andrew M, Hall, Jacqueline Anne, Kos, Zuzana, Salgado, Roberto, Kok, Marleen, Horlings, Hugo Mark, and International Immuno-Oncology Biomarker Working Group

Abstract

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2020

5. 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

6. Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Author

Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B, Martin, Sancha, Wedge, David C, Van Loo, Peter, Ju, Young Seok, Smid, Marcel, Brinkman, Arie B, Morganella, Sandro, Aure, Miriam R, Lingjærde, Ole Christian, Langerød, Anita, Ringnér, Markus, Ahn, Sung-Min, Boyault, Sandrine, Brock, Jane E, Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc Y, Dronov, Serge, Fatima, Aquila, Foekens, John A, Gerstung, Moritz, Hooijer, Gerrit K J, Jang, Se Jin, Jones, David R, Kim, Hyung Yong, King, Tari A, Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong-Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O'Meara, Sarah, Pauporté, Iris, Pivot, Xavier, Purdie, Colin A, Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-González, Germán FG, Romieu, Gilles, Sieuwerts, Anieta M, Simpson, Peter T, Shepherd, Rebecca, Stebbings, Lucy A, Stefansson, Olafur A, Teague, Jon W, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert, Vermeulen, Peter B., Vincent-Salomon, Anne, Yates, Lucy R., Caldas, Carlos, Van't Veer, Laura, Tutt, Andrew M, Knappskog, Stian, Tan, Benita Kiat Tee BK, Jonkers, Jos, Borg, Åke A., Ueno, Naoto T, Sotiriou, Christos, Viari, Alain, Futreal, P Andrew, Campbell, Peter J, Span, Paul N, Van Laere, Steven, Lakhani, Sunil R, Eyfjord, Jorunn E, Thompson, Alastair M, Birney, Ewan, Stunnenberg, Hendrik G, van de Vijver, Marc J, Martens, John W M, Børresen-Dale, Anne Lise, Richardson, Andrea L, Kong, Gu, Thomas, Gilles, Stratton, Michael R, Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B, Martin, Sancha, Wedge, David C, Van Loo, Peter, Ju, Young Seok, Smid, Marcel, Brinkman, Arie B, Morganella, Sandro, Aure, Miriam R, Lingjærde, Ole Christian, Langerød, Anita, Ringnér, Markus, Ahn, Sung-Min, Boyault, Sandrine, Brock, Jane E, Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc Y, Dronov, Serge, Fatima, Aquila, Foekens, John A, Gerstung, Moritz, Hooijer, Gerrit K J, Jang, Se Jin, Jones, David R, Kim, Hyung Yong, King, Tari A, Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong-Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O'Meara, Sarah, Pauporté, Iris, Pivot, Xavier, Purdie, Colin A, Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-González, Germán FG, Romieu, Gilles, Sieuwerts, Anieta M, Simpson, Peter T, Shepherd, Rebecca, Stebbings, Lucy A, Stefansson, Olafur A, Teague, Jon W, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert, Vermeulen, Peter B., Vincent-Salomon, Anne, Yates, Lucy R., Caldas, Carlos, Van't Veer, Laura, Tutt, Andrew M, Knappskog, Stian, Tan, Benita Kiat Tee BK, Jonkers, Jos, Borg, Åke A., Ueno, Naoto T, Sotiriou, Christos, Viari, Alain, Futreal, P Andrew, Campbell, Peter J, Span, Paul N, Van Laere, Steven, Lakhani, Sunil R, Eyfjord, Jorunn E, Thompson, Alastair M, Birney, Ewan, Stunnenberg, Hendrik G, van de Vijver, Marc J, Martens, John W M, Børresen-Dale, Anne Lise, Richardson, Andrea L, Kong, Gu, Thomas, Gilles, and Stratton, Michael R

Abstract

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected., SCOPUS: er.j, info:eu-repo/semantics/published

Published
2019

7. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.

Author

Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B, Rahbari, Raheleh, Wedge, David C, Davies, Helen R, Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O'Meara, Sarah, Giri, Dilip DD, Sauer, Torril, Pinder, Sarah SE, Purdie, Colin A, Borg, Åke A., Stunnenberg, Henk, Van de Vijver, Marc J, Tan, Benita Kiat Tee BK, Caldas, Carlos, Tutt, Andrew M, Ueno, Naoto T, Van't Veer, Laura, Martens, John W M, Sotiriou, Christos, Knappskog, Stian, Span, Paul N, Lakhani, Sunil R, Eyfjörd, Jórunn Erla, Børresen-Dale, Anne Lise, Richardson, Andrea L, Thompson, Alastair M, Viari, Alain, Hurles, Matthew ME, Nik-Zainal, Serena, Campbell, Peter J, Stratton, Michael R, Ju, Young Seok, Martincorena, Inigo, Gerstung, Moritz, Petljak, Mia, Alexandrov, Ludmil B, Rahbari, Raheleh, Wedge, David C, Davies, Helen R, Ramakrishna, Manasa, Fullam, Anthony, Martin, Sancha, Alder, Christopher, Patel, Nikita, Gamble, Steve, O'Meara, Sarah, Giri, Dilip DD, Sauer, Torril, Pinder, Sarah SE, Purdie, Colin A, Borg, Åke A., Stunnenberg, Henk, Van de Vijver, Marc J, Tan, Benita Kiat Tee BK, Caldas, Carlos, Tutt, Andrew M, Ueno, Naoto T, Van't Veer, Laura, Martens, John W M, Sotiriou, Christos, Knappskog, Stian, Span, Paul N, Lakhani, Sunil R, Eyfjörd, Jórunn Erla, Børresen-Dale, Anne Lise, Richardson, Andrea L, Thompson, Alastair M, Viari, Alain, Hurles, Matthew ME, Nik-Zainal, Serena, Campbell, Peter J, and Stratton, Michael R

Abstract

Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

8. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures.

Author

Davies, Helen, Glodzik, Dominik, Morganella, Sandro, Yates, Lucy R., Staaf, Johan, Zou, Xueqing, Ramakrishna, Manasa, Martin, Sancha, Boyault, Sandrine, Sieuwerts, Anieta M, Simpson, Peter T, King, Tari A, Raine, Keiran, Eyfjörd, Jórunn Erla, Kong, Gu, Borg, Åke A., Birney, Ewan, Stunnenberg, Hendrik G, Van de Vijver, Marc J, Børresen-Dale, Anne Lise, Martens, John W M, Span, Paul N, Lakhani, Sunil R, Vincent-Salomon, Anne, Sotiriou, Christos, Tutt, Andrew M, Thompson, Alastair M, Van Laere, Steven, Richardson, Andrea L, Viari, Alain, Campbell, Peter J, Stratton, Michael R, Nik-Zainal, Serena, Davies, Helen, Glodzik, Dominik, Morganella, Sandro, Yates, Lucy R., Staaf, Johan, Zou, Xueqing, Ramakrishna, Manasa, Martin, Sancha, Boyault, Sandrine, Sieuwerts, Anieta M, Simpson, Peter T, King, Tari A, Raine, Keiran, Eyfjörd, Jórunn Erla, Kong, Gu, Borg, Åke A., Birney, Ewan, Stunnenberg, Hendrik G, Van de Vijver, Marc J, Børresen-Dale, Anne Lise, Martens, John W M, Span, Paul N, Lakhani, Sunil R, Vincent-Salomon, Anne, Sotiriou, Christos, Tutt, Andrew M, Thompson, Alastair M, Van Laere, Steven, Richardson, Andrea L, Viari, Alain, Campbell, Peter J, Stratton, Michael R, and Nik-Zainal, Serena

Abstract

Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

9. Genomic Evolution of Breast Cancer Metastasis and Relapse

Author

Yates, Lucy R., Lilleng, Peer Kaare, Gundem, Gunes, Gerstung, Moritz, Pappaemmanuil, Elli, Gazinska, Patrycja, Bhosle, Shriram S.G., Jones, David, Raine, Keiran, Mudie, Laura, Latimer, Calli, Knappskog, Stian, Sawyer, Elinor, Desmedt, Christine, Sotiriou, Christos, Stratton, Michael M.R., Sieuwerts, Anieta M, Lynch, Andy G, Martens, John W M, Richardson, Andrea Lynn, Tutt, Andrew M, Lønning, Per Eystein, Wedge, David, Campbell, Peter J, Farmery, James J.H.R., Gonzalez, Santiago, Martincorena, Inigo, Alexandrov, Ludmil B, Van Loo, Peter, Haugland, Hans Kristian, Yates, Lucy R., Lilleng, Peer Kaare, Gundem, Gunes, Gerstung, Moritz, Pappaemmanuil, Elli, Gazinska, Patrycja, Bhosle, Shriram S.G., Jones, David, Raine, Keiran, Mudie, Laura, Latimer, Calli, Knappskog, Stian, Sawyer, Elinor, Desmedt, Christine, Sotiriou, Christos, Stratton, Michael M.R., Sieuwerts, Anieta M, Lynch, Andy G, Martens, John W M, Richardson, Andrea Lynn, Tutt, Andrew M, Lønning, Per Eystein, Wedge, David, Campbell, Peter J, Farmery, James J.H.R., Gonzalez, Santiago, Martincorena, Inigo, Alexandrov, Ludmil B, Van Loo, Peter, and Haugland, Hans Kristian

Abstract

Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. These include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2-STAT3 pathways., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

10. Corrigendum: Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

Author

Ju, Young Seok, Tubio, Jose M C, Mifsud, William, Fu, Beiyuan, Davies, Helen R, Ramakrishna, Manasa, Li, Yilong, Yates, Lucy R., Gundem, Gunes, Tarpey, Patrick S, Behjati, Sam, Papaemmanuil, Elli, Martin, Sancha, Fullam, Anthony, Gerstung, Moritz, ICGC Prostate Cancer Working Group, ICGC Bone Cancer Working Group, ICGC Breast Cancer Working Group, Nangalia, Jyoti, Green, Anthony R, Caldas, Carlos, Borg, Åke A., Tutt, Andrew M, Lee, Ming Ta Michael MT, Van't Veer, Laura, Tan, Benita Kiat Tee BK, Aparicio, Samuel, Span, Paul N, Martens, John W M, Knappskog, Stian, Vincent-Salomon, Anne, Børresen-Dale, Anne Lise, Eyfjörd, Jórunn Erla, Myklebost, Ola, Flanagan, Adrienne M, Foster, Christopher, Neal, David E, Cooper, Colin, Eeles, Rosalind, Bova, Steven GS, Lakhani, Sunil R, Desmedt, Christine, Thomas, Gilles, Richardson, Andrea L, Purdie, Colin A, Thompson, Alastair M, McDermott, Ultan, Yang, Fengtang, Nik-Zainal, Serena, Campbell, Peter J, and Stratton, Michael R

Subjects
DNA Replication, 0301 basic medicine, Mitochondrial DNA, DNA End-Joining Repair, Nuclear gene, DNA Copy Number Variations, Somatic cell, Molecular Sequence Data, Computational biology, Biology, Bioinformatics, DNA, Mitochondrial, Chromosomes, 03 medical and health sciences, Genome research, Cell Line, Tumor, Neoplasms, Genetics, Humans, Amino Acid Sequence, In Situ Hybridization, Fluorescence, Genetics (clinical), Cell Nucleus, Genome, Human, Published Erratum, Reproducibility of Results, Médecine pathologie humaine, Sequence Analysis, DNA, Sciences bio-médicales et agricoles, Corrigenda, Mitochondria, Cancérologie, 030104 developmental biology, Genome, Mitochondrial, Human cancer, HeLa Cells
Abstract

Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

Published
2016

11. Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Author

Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B, Martin, Sancha, Wedge, David C, Van Loo, Peter, Ju, Young Seok, Smid, Michiel M., Brinkman, Arie B, Morganella, Sandro, Aure, Miriam R, Lingjærde, Ole Christian, Langerød, Anita, Ringnér, Markus, Ahn, Sung-Min, Boyault, Sandrine, Brock, Jane E, Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc Y, Dronov, Serge, Fatima, Aquila, Foekens, John A, Gerstung, Moritz, Hooijer, Gerrit GK, Jang, Se Jin, Jones, David R, Kim, Hyung Yong, King, Tari TA, Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong-Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O'Meara, Sarah, Pauporté, Iris, Pivot, Xavier, Purdie, Colin CA, Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-González, Germán FG, Romieu, Gilles, Sieuwerts, Anieta M, Simpson, Peter PT, Shepherd, Rebecca, Stebbings, Lucy A, Stefansson, Olafur OA, Teague, Jon W, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert, Vermeulen, Peter B., Vincent-Salomon, Anne, Yates, Lucy R., Caldas, Carlos, Van't Veer, Laura, Tutt, Andrew M, Knappskog, Stian, Tan, Benita Kiat Tee BK, Jonkers, Jos, Borg, Åke A., Ueno, Naoto T, Sotiriou, Christos, Viari, Alain, Futreal, P Andrew, Campbell, Peter J, Span, Paul N, Van Laere, Steven, Lakhani, Sunil R, Eyfjörd, Jórunn Erla, Thompson, Alastair M, Birney, Ewan, Stunnenberg, Hendrik G, Van de Vijver, Marc J, Martens, John W M, Børresen-Dale, Anne Lise, Richardson, Andrea L, Kong, Gu, Thomas, Gilles, Stratton, Michael R, Nik-Zainal, Serena, Davies, Helen, Staaf, Johan, Ramakrishna, Manasa, Glodzik, Dominik, Zou, Xueqing, Martincorena, Inigo, Alexandrov, Ludmil B, Martin, Sancha, Wedge, David C, Van Loo, Peter, Ju, Young Seok, Smid, Michiel M., Brinkman, Arie B, Morganella, Sandro, Aure, Miriam R, Lingjærde, Ole Christian, Langerød, Anita, Ringnér, Markus, Ahn, Sung-Min, Boyault, Sandrine, Brock, Jane E, Broeks, Annegien, Butler, Adam, Desmedt, Christine, Dirix, Luc Y, Dronov, Serge, Fatima, Aquila, Foekens, John A, Gerstung, Moritz, Hooijer, Gerrit GK, Jang, Se Jin, Jones, David R, Kim, Hyung Yong, King, Tari TA, Krishnamurthy, Savitri, Lee, Hee Jin, Lee, Jeong-Yeon, Li, Yilong, McLaren, Stuart, Menzies, Andrew, Mustonen, Ville, O'Meara, Sarah, Pauporté, Iris, Pivot, Xavier, Purdie, Colin CA, Raine, Keiran, Ramakrishnan, Kamna, Rodríguez-González, Germán FG, Romieu, Gilles, Sieuwerts, Anieta M, Simpson, Peter PT, Shepherd, Rebecca, Stebbings, Lucy A, Stefansson, Olafur OA, Teague, Jon W, Tommasi, Stefania, Treilleux, Isabelle, Van den Eynden, Gert, Vermeulen, Peter B., Vincent-Salomon, Anne, Yates, Lucy R., Caldas, Carlos, Van't Veer, Laura, Tutt, Andrew M, Knappskog, Stian, Tan, Benita Kiat Tee BK, Jonkers, Jos, Borg, Åke A., Ueno, Naoto T, Sotiriou, Christos, Viari, Alain, Futreal, P Andrew, Campbell, Peter J, Span, Paul N, Van Laere, Steven, Lakhani, Sunil R, Eyfjörd, Jórunn Erla, Thompson, Alastair M, Birney, Ewan, Stunnenberg, Hendrik G, Van de Vijver, Marc J, Martens, John W M, Børresen-Dale, Anne Lise, Richardson, Andrea L, Kong, Gu, Thomas, Gilles, and Stratton, Michael R

Abstract

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2016

12. New approaches for improving outcomes in breast cancer in Europe

Author

Di Leo, Angelo, Curigliano, Giuseppe, Diéras, Véronique, Malorni, Luca, Sotiriou, Christos, Swanton, Charles, Thompson, Alastair, Tutt, Andrew M, Piccart-Gebhart, Martine, Di Leo, Angelo, Curigliano, Giuseppe, Diéras, Véronique, Malorni, Luca, Sotiriou, Christos, Swanton, Charles, Thompson, Alastair, Tutt, Andrew M, and Piccart-Gebhart, Martine

Abstract

Considerable progress has been made in breast cancer treatment in Europe over the past three decades, yet survival rates for metastatic disease remain poor, underlining the need for further advances. While the use of predictive biomarkers for response to systemic therapy could improve drug development efficiency, progress in identifying such markers has been slow. The currently inadequate classification of breast cancer subtypes is a further challenge. Improved understanding of the molecular pathology of the disease has led to the identification of new targets for drug treatment, and evolving classifications should reflect these developments. Further ongoing challenges include difficulties in finding optimal combinations and sequences of systemic therapies, circumventing multidrug resistance and intra-tumor heterogeneity, problems associated with fragmentation in clinical trials and translational research efforts. Adoption of some of the strategies identified in this article may lead to further improvements in outcomes for patients with the disease., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2015

13. Evolution from primary breast cancer to relapse and metastasis.

Author

European Cancer Congress 2015 (ECCO 18 - ESMO 40: 09/2015: Vienna, Austria), Yates, Lucy R., Wedge, David C., Alexandrov, Ludmil B, Desmedt, Christine, Knappskog, Stian, Richardson, Andrea L, Sotiriou, Christos, Sieuwerts, Anieta M, Tutt, Andrew M, Stratton, Michael, Campbell, Peter J, European Cancer Congress 2015 (ECCO 18 - ESMO 40: 09/2015: Vienna, Austria), Yates, Lucy R., Wedge, David C., Alexandrov, Ludmil B, Desmedt, Christine, Knappskog, Stian, Richardson, Andrea L, Sotiriou, Christos, Sieuwerts, Anieta M, Tutt, Andrew M, Stratton, Michael, and Campbell, Peter J

Abstract

Poster session: Breast Cancer - Advanced Disease - abstract 1818, info:eu-repo/semantics/nonPublished

Published
2015

14. Dissecting the heterogeneity of triple-negative breast cancer.

Author

Metzger-Filho, Otto, Tutt, Andrew M, Azambuja, Evandro, Saini, Kamal, Viale, Giuseppe, Loi, Sherene, Bradbury, Ian, Bliss, Judith M, Abdel Azim, Hatem Hamdy, Ellis, Paul, Di Leo, Angelo, Baselga, José, Sotiriou, Christos, Piccart-Gebhart, Martine, Metzger-Filho, Otto, Tutt, Andrew M, Azambuja, Evandro, Saini, Kamal, Viale, Giuseppe, Loi, Sherene, Bradbury, Ian, Bliss, Judith M, Abdel Azim, Hatem Hamdy, Ellis, Paul, Di Leo, Angelo, Baselga, José, Sotiriou, Christos, and Piccart-Gebhart, Martine

Abstract

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancers. It is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. TNBC is associated with a significantly higher probability of relapse and poorer overall survival in the first few years after diagnosis when compared with other breast cancer subtypes. This is observed despite its usual high sensitivity to chemotherapy. In the advanced setting, responses observed with chemotherapy lack durability. Early-stage clinical studies suggested impressive potential when a poly (ADP-ribose) polymerase (PARP) inhibitor is given for the treatment of advanced TNBC with BRCA gene dysfunction. The molecular complexity of TNBC has led to proposed subclassifications, which will be of great value for the development of targeted therapies. In this review, we discuss the biology of TNBC at the pathologic and the molecular levels. We also elaborate on the role of systemic therapies and the results of the first phase III clinical trial evaluating the addition of iniparib, a novel investigational anticancer agent that does not possess characteristics typical of the PARP inhibitor class, in combination with chemotherapy in advanced TNBC., Journal Article, Research Support, Non-U.S. Gov't, Review, SCOPUS: re.j, info:eu-repo/semantics/published

Published
2012

15. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen.

Author

Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Wirapati, Pratyaksha, Lallemand, Françoise, Tutt, Andrew M, Gillet, Cheryl, Ellis, P., Ryder, Kenneth, Reid, James F, Daidone, Maria G, Pierotti, Marco A, Berns, Els Mjj, Jansen, Maurice Phm, Foekens, John A, Delorenzi, Mauro, Bontempi, Gianluca, Piccart-Gebhart, Martine, Sotiriou, Christos, Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Wirapati, Pratyaksha, Lallemand, Françoise, Tutt, Andrew M, Gillet, Cheryl, Ellis, P., Ryder, Kenneth, Reid, James F, Daidone, Maria G, Pierotti, Marco A, Berns, Els Mjj, Jansen, Maurice Phm, Foekens, John A, Delorenzi, Mauro, Bontempi, Gianluca, Piccart-Gebhart, Martine, and Sotiriou, Christos

Abstract

BACKGROUND: Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30-40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. RESULTS: We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29-3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. CONCLUSION: We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen., Journal Article, Research Support, Non-U.S. Gov't, Validation Studies, info:eu-repo/semantics/published

Published
2008

16. Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.

Author

Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Lallemand, Françoise, Tutt, Andrew M, Gillet, Cheryl, Ellis, P., Harris, Adrian, Bergh, Jonas, Foekens, John A, Klijn, J G, Larsimont, Denis, Buyse, Marc, Bontempi, Gianluca, Delorenzi, Mauro, Piccart-Gebhart, Martine, Sotiriou, Christos, Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Lallemand, Françoise, Tutt, Andrew M, Gillet, Cheryl, Ellis, P., Harris, Adrian, Bergh, Jonas, Foekens, John A, Klijn, J G, Larsimont, Denis, Buyse, Marc, Bontempi, Gianluca, Delorenzi, Mauro, Piccart-Gebhart, Martine, and Sotiriou, Christos

Abstract

PURPOSE: A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. MATERIALS AND METHODS: We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. RESULTS: Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. CONCLUSION: The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC., Journal Article, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2007

17. Comprehensive analysis integrating both clinicopathological and gene expression data in more than 1,500 samples: Proliferation captured by gene expression grade index appears to be the strongest prognostic factor in breast cancer (BC)

Author

Sotiriou, Christos, Wirapati, Pratyaksha, Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Tutt, Andrew M, Ellis, P., Buyse, Marc, Delorenzi, Mauro, Piccart-Gebhart, Martine, Sotiriou, Christos, Wirapati, Pratyaksha, Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Tutt, Andrew M, Ellis, P., Buyse, Marc, Delorenzi, Mauro, and Piccart-Gebhart, Martine

Abstract

info:eu-repo/semantics/published

Published
2006

18. Gene Expression Analaysis of Tamoxifen Resistance in Breast Cancer

Author

Computational Learning and Intelligence, research Contact Day (25 September 2006: Vrussels, Belgium), Haibe-Kains, Benjamin, Loi, Sherene, Desmedt, Christine, Lallemand, Françoise, Tutt, Andrew M, Gillet, Céline, Ellis, P., Ryder, Kenneth, Harris, Adrian, Bergh, Jonas, Larsimont, Denis, Buyse, Marc, Bontempi, Gianluca, Piccart-Gebhart, Martine, Sotiriou, Christos, Computational Learning and Intelligence, research Contact Day (25 September 2006: Vrussels, Belgium), Haibe-Kains, Benjamin, Loi, Sherene, Desmedt, Christine, Lallemand, Françoise, Tutt, Andrew M, Gillet, Céline, Ellis, P., Ryder, Kenneth, Harris, Adrian, Bergh, Jonas, Larsimont, Denis, Buyse, Marc, Bontempi, Gianluca, Piccart-Gebhart, Martine, and Sotiriou, Christos

Abstract

info:eu-repo/semantics/nonPublished

Published
2006

19. Comprehensive analysis integrating both clinicopathological and gene expression data in more than 1500 samples: Proliferation captured by gene expression grade index appears to be the strongest prognostic factor in breast cancer (BC).

Author

Annual Meeting - American Association of Clinical Oncology (ASCO) (2006-06), Sotiriou, Christos, Wirapati, Pratyaksha, Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Tutt, Andrew M, Ellis, Matthew J C, Buyse, Marc, Delorenzi, Mauro, Piccart-Gebhart, Martine, Annual Meeting - American Association of Clinical Oncology (ASCO) (2006-06), Sotiriou, Christos, Wirapati, Pratyaksha, Loi, Sherene, Haibe-Kains, Benjamin, Desmedt, Christine, Tutt, Andrew M, Ellis, Matthew J C, Buyse, Marc, Delorenzi, Mauro, and Piccart-Gebhart, Martine

Abstract

info:eu-repo/semantics/nonPublished

Published
2006

20. Prediction of early distant relapses on tamoxifen in early-stage breast cancer (BC): A potential tool for adjuvant aromatase inhibitor (AI) tailoring

Author

Loi, Sherene, Piccart-Gebhart, Martine, Haibe-Kains, Benjamin, Desmedt, Christine, Harris, Adrian L, Bergh, Jonas, Tutt, Andrew M, Miller, LD, Liu, Edison Tak-Bun, Sotiriou, Christos, Loi, Sherene, Piccart-Gebhart, Martine, Haibe-Kains, Benjamin, Desmedt, Christine, Harris, Adrian L, Bergh, Jonas, Tutt, Andrew M, Miller, LD, Liu, Edison Tak-Bun, and Sotiriou, Christos

Abstract

info:eu-repo/semantics/published

Published
2005

21. Four genes by RT-PCR predicts distant relapse for women given adjuvant tamoxifen

Author

Desmedt, Christine, Loi, Sherene, Haibe-Kains, Benjamin, Soree, Anne, Lallemand, Françoise, Durbecq, Virginie, Larsimont, Denis, Tutt, Andrew M, Ellis, P., Gillett, C. E., Ryder, Kenneth, Harris, Adrian, Cardoso, Fatima, Martiat, Philippe, Piccart-Gebhart, Martine, Sotiriou, Christos, Desmedt, Christine, Loi, Sherene, Haibe-Kains, Benjamin, Soree, Anne, Lallemand, Françoise, Durbecq, Virginie, Larsimont, Denis, Tutt, Andrew M, Ellis, P., Gillett, C. E., Ryder, Kenneth, Harris, Adrian, Cardoso, Fatima, Martiat, Philippe, Piccart-Gebhart, Martine, and Sotiriou, Christos

Abstract

28th San Antonio Breast Cancer Symposium - Poster Session - abstr. 3025, San Antonio breast cancer symposium 2005 poster session number 3025, info:eu-repo/semantics/published

Published
2005

22. Predicting relapse in estrogen receptor (ER) positive breast cancer (luminal) subgroups treated with adjuvant tamoxifen

Author

Loi, Sherene, Desmedt, Christine, Haibe-Kains, Benjamin, Lallemand, Françoise, Gillett, C. E., Tutt, Andrew M, Ryder, Kenneth, Ellis, P., Harris, Adrian, Smeds, Johanna, Bergh, Jonas, Cardoso, Fatima, Piccart-Gebhart, Martine, Sotiriou, Christos, Loi, Sherene, Desmedt, Christine, Haibe-Kains, Benjamin, Lallemand, Françoise, Gillett, C. E., Tutt, Andrew M, Ryder, Kenneth, Ellis, P., Harris, Adrian, Smeds, Johanna, Bergh, Jonas, Cardoso, Fatima, Piccart-Gebhart, Martine, and Sotiriou, Christos

Abstract

28th San Antonio Breast Cancer Symposium (SABCS), San Antonio, USA - Dec. 2005 - Poster Session - Abstract 3016, San Antonio breast Cancer Symposium 2005 poster session number 3016, info:eu-repo/semantics/published

Published
2005

23. Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen

Author

Loi, Sherene, primary, Haibe-Kains, Benjamin, additional, Desmedt, Christine, additional, Wirapati, Pratyaksha, additional, Lallemand, Françoise, additional, Tutt, Andrew M, additional, Gillet, Cheryl, additional, Ellis, Paul, additional, Ryder, Kenneth, additional, Reid, James F, additional, Daidone, Maria G, additional, Pierotti, Marco A, additional, Berns, Els MJJ, additional, Jansen, Maurice PHM, additional, Foekens, John A, additional, Delorenzi, Mauro, additional, Bontempi, Gianluca, additional, Piccart, Martine J, additional, and Sotiriou, Christos, additional

Published
2008
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24. Definition of Clinically Distinct Molecular Subtypes in Estrogen Receptor–Positive Breast Carcinomas Through Genomic Grade

Author

Loi, Sherene, primary, Haibe-Kains, Benjamin, additional, Desmedt, Christine, additional, Lallemand, Françoise, additional, Tutt, Andrew M., additional, Gillet, Cheryl, additional, Ellis, Paul, additional, Harris, Adrian, additional, Bergh, Jonas, additional, Foekens, John A., additional, Klijn, Jan G.M., additional, Larsimont, Denis, additional, Buyse, Marc, additional, Bontempi, Gianluca, additional, Delorenzi, Mauro, additional, Piccart, Martine J., additional, and Sotiriou, Christos, additional

Published
2007
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