Search

Your search keyword '"Symmans, W Fraser"' showing total 75 results
Start Over Author "Symmans, W Fraser" Publication Type Electronic Resources
75 results on '"Symmans, W Fraser"'

1. Clinical significance and biology of circulating tumor DNA in high-risk early-stage HER2-negative breast cancer receiving neoadjuvant chemotherapy

Author

Magbanua, Mark Jesus M, Magbanua, Mark Jesus M, Brown Swigart, Lamorna, Ahmed, Ziad, Sayaman, Rosalyn W, Renner, Derrick, Kalashnikova, Ekaterina, Hirst, Gillian L, Yau, Christina, Wolf, Denise M, Li, Wen, Delson, Amy L, Asare, Smita, Liu, Minetta C, Albain, Kathy, Chien, A Jo, Forero-Torres, Andres, Isaacs, Claudine, Nanda, Rita, Tripathy, Debu, Rodriguez, Angel, Sethi, Himanshu, Aleshin, Alexey, Rabinowitz, Matthew, Perlmutter, Jane, Symmans, W Fraser, Yee, Douglas, Hylton, Nola M, Esserman, Laura J, DeMichele, Angela M, Rugo, Hope S, van 't Veer, Laura J, Magbanua, Mark Jesus M, Magbanua, Mark Jesus M, Brown Swigart, Lamorna, Ahmed, Ziad, Sayaman, Rosalyn W, Renner, Derrick, Kalashnikova, Ekaterina, Hirst, Gillian L, Yau, Christina, Wolf, Denise M, Li, Wen, Delson, Amy L, Asare, Smita, Liu, Minetta C, Albain, Kathy, Chien, A Jo, Forero-Torres, Andres, Isaacs, Claudine, Nanda, Rita, Tripathy, Debu, Rodriguez, Angel, Sethi, Himanshu, Aleshin, Alexey, Rabinowitz, Matthew, Perlmutter, Jane, Symmans, W Fraser, Yee, Douglas, Hylton, Nola M, Esserman, Laura J, DeMichele, Angela M, Rugo, Hope S, and van 't Veer, Laura J

Abstract

Circulating tumor DNA (ctDNA) analysis may improve early-stage breast cancer treatment via non-invasive tumor burden assessment. To investigate subtype-specific differences in the clinical significance and biology of ctDNA shedding, we perform serial personalized ctDNA analysis in hormone receptor (HR)-positive/HER2-negative breast cancer and triple-negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. ctDNA positivity rates before, during, and after NAC are higher in TNBC than in HR-positive/HER2-negative breast cancer patients. Early clearance of ctDNA 3 weeks after treatment initiation predicts a favorable response to NAC in TNBC only. Whereas ctDNA positivity associates with reduced distant recurrence-free survival in both subtypes. Conversely, ctDNA negativity after NAC correlates with improved outcomes, even in patients with extensive residual cancer. Pretreatment tumor mRNA profiling reveals associations between ctDNA shedding and cell cycle and immune-associated signaling. On the basis of these findings, the I-SPY2 trial will prospectively test ctDNA for utility in redirecting therapy to improve response and prognosis.

Published
2023

2. HER-2 low status in early-stage invasive lobular carcinoma of the breast: associated factors and outcomes in an institutional series.

Author

Rothschild, Harriet T, Rothschild, Harriet T, Clelland, Elle, Patterson, Anne, Molina-Vega, Julissa, Kaur, Mandeep, Symmans, W Fraser, Schwartz, Christopher J, Chien, A Jo, Mukhtar, Rita A, Rothschild, Harriet T, Rothschild, Harriet T, Clelland, Elle, Patterson, Anne, Molina-Vega, Julissa, Kaur, Mandeep, Symmans, W Fraser, Schwartz, Christopher J, Chien, A Jo, and Mukhtar, Rita A

Abstract

PurposeHER2 overexpression has a central role in breast cancer carcinogenesis and is associated with poor prognosis if untreated. Lately, identification of HER2-low breast cancer has been proposed to select patients for novel HER2-directed chemotherapy and includes cancers with immunohistochemistry 1 + or 2 + with negative FISH, encompassing approximately 55-60% of all breast carcinomas. In early-stage breast cancer, the prognostic significance of HER2 low-disease is less well understood, with a particular paucity of data evaluating the prevalence and implications of HER2-low status in invasive lobular carcinoma (ILC).MethodsWe evaluated 666 stage I-III ILC tumors from a prospectively maintained institutional database, comparing clinicopathologic features and disease-free survival (DFS) using a multivariable Cox proportional hazards model.ResultsHER2-low status was common in this cohort of patients with ILC, but most clinicopathologic features did not differ between HER2-low and HER2-negative cases. However, when adjusting for tumor size, number of positive nodes, ER/PR status, and local therapy received, patients with HER2-low status had worse disease-free survival (DFS) than those with HER2-negative tumors (hazard ratio 2.0, 95% confidence interval 1.0-4.1, p = 0.05).ConclusionThis difference in DFS supports the notion that HER2-low and HER2-negative early stage ILC may differ clinically, despite similar clinicopathologic features. Further investigation into the potential benefit of HER2 targeted therapy in HER2-low early-stage breast cancer, and specifically lobular cancer, is warranted to ensure optimal outcomes in this distinct tumor subtype.

Published
2023

3. 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

4. Safety and efficacy of HSP90 inhibitor ganetespib for neoadjuvant treatment of stage II/III breast cancer.

Author

Lang, Julie E, Lang, Julie E, Forero-Torres, Andres, Yee, Douglas, Yau, Christina, Wolf, Denise, Park, John, Parker, Barbara A, Chien, A Jo, Wallace, Anne M, Murthy, Rashmi, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Yung, Rachel L, Isaacs, Claudine, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Stringer-Reasor, Erica, Price, Elissa, Joe, Bonnie, Liu, Minetta C, Brown-Swigart, Lamorna, Petricoin, Emanuel F, Wulfkuhle, Julia D, Buxton, Meredith, Clennell, Julia L, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Symmans, W Fraser, van 't Veer, Laura J, Hylton, Nola M, DeMichele, Angela M, Berry, Donald A, Esserman, Laura J, Lang, Julie E, Lang, Julie E, Forero-Torres, Andres, Yee, Douglas, Yau, Christina, Wolf, Denise, Park, John, Parker, Barbara A, Chien, A Jo, Wallace, Anne M, Murthy, Rashmi, Albain, Kathy S, Ellis, Erin D, Beckwith, Heather, Haley, Barbara B, Elias, Anthony D, Boughey, Judy C, Yung, Rachel L, Isaacs, Claudine, Clark, Amy S, Han, Hyo S, Nanda, Rita, Khan, Qamar J, Edmiston, Kristen K, Stringer-Reasor, Erica, Price, Elissa, Joe, Bonnie, Liu, Minetta C, Brown-Swigart, Lamorna, Petricoin, Emanuel F, Wulfkuhle, Julia D, Buxton, Meredith, Clennell, Julia L, Sanil, Ashish, Berry, Scott, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Asare, Adam L, Matthews, Jeffrey B, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Symmans, W Fraser, van 't Veer, Laura J, Hylton, Nola M, DeMichele, Angela M, Berry, Donald A, and Esserman, Laura J

Abstract

HSP90 inhibitors destabilize oncoproteins associated with cell cycle, angiogenesis, RAS-MAPK activity, histone modification, kinases and growth factors. We evaluated the HSP90-inhibitor ganetespib in combination with standard chemotherapy in patients with high-risk early-stage breast cancer. I-SPY2 is a multicenter, phase II adaptively randomized neoadjuvant (NAC) clinical trial enrolling patients with stage II-III breast cancer with tumors 2.5 cm or larger on the basis of hormone receptors (HR), HER2 and Mammaprint status. Multiple novel investigational agents plus standard chemotherapy are evaluated in parallel for the primary endpoint of pathologic complete response (pCR). Patients with HER2-negative breast cancer were eligible for randomization to ganetespib from October 2014 to October 2015. Of 233 women included in the final analysis, 140 were randomized to the standard NAC control; 93 were randomized to receive 150 mg/m2 ganetespib every 3 weeks with weekly paclitaxel over 12 weeks, followed by AC. Arms were balanced for hormone receptor status (51-52% HR-positive). Ganetespib did not graduate in any of the biomarker signatures studied before reaching maximum enrollment. Final estimated pCR rates were 26% vs. 18% HER2-negative, 38% vs. 22% HR-negative/HER2-negative, and 15% vs. 14% HR-positive/HER2-negative for ganetespib vs control, respectively. The predicted probability of success in phase 3 testing was 47% HER2-negative, 72% HR-negative/HER2-negative, and 19% HR-positive/HER2-negative. Ganetespib added to standard therapy is unlikely to yield substantially higher pCR rates in HER2-negative breast cancer compared to standard NAC, and neither HSP90 pathway nor replicative stress expression markers predicted response. HSP90 inhibitors remain of limited clinical interest in breast cancer, potentially in other clinical settings such as HER2-positive disease or in combination with anti-PD1 neoadjuvant chemotherapy in triple negative breast cancer.Trial registra

Published
2022

5. 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

6. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial.

Author

Clark, Amy S, Clark, Amy S, Yau, Christina, Wolf, Denise M, Petricoin, Emanuel F, van 't Veer, Laura J, Yee, Douglas, Moulder, Stacy L, Wallace, Anne M, Chien, A Jo, Isaacs, Claudine, Boughey, Judy C, Albain, Kathy S, Kemmer, Kathleen, Haley, Barbara B, Han, Hyo S, Forero-Torres, Andres, Elias, Anthony, Lang, Julie E, Ellis, Erin D, Yung, Rachel, Tripathy, Debu, Nanda, Rita, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Gallagher, Rosa I, Helsten, Teresa, Roesch, Erin, Ewing, Cheryl A, Alvarado, Michael, Crane, Erin P, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Steeg, Katherine, Asare, Adam, Matthews, Jeffrey B, Berry, Scott, Sanil, Ashish, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Schwab, Richard B, Symmans, W Fraser, Hylton, Nola M, Berry, Donald A, Esserman, Laura J, DeMichele, Angela M, Clark, Amy S, Clark, Amy S, Yau, Christina, Wolf, Denise M, Petricoin, Emanuel F, van 't Veer, Laura J, Yee, Douglas, Moulder, Stacy L, Wallace, Anne M, Chien, A Jo, Isaacs, Claudine, Boughey, Judy C, Albain, Kathy S, Kemmer, Kathleen, Haley, Barbara B, Han, Hyo S, Forero-Torres, Andres, Elias, Anthony, Lang, Julie E, Ellis, Erin D, Yung, Rachel, Tripathy, Debu, Nanda, Rita, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Gallagher, Rosa I, Helsten, Teresa, Roesch, Erin, Ewing, Cheryl A, Alvarado, Michael, Crane, Erin P, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Steeg, Katherine, Asare, Adam, Matthews, Jeffrey B, Berry, Scott, Sanil, Ashish, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Schwab, Richard B, Symmans, W Fraser, Hylton, Nola M, Berry, Donald A, Esserman, Laura J, and DeMichele, Angela M

Abstract

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Published
2021

7. Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial.

Author

Clark, Amy S, Clark, Amy S, Yau, Christina, Wolf, Denise M, Petricoin, Emanuel F, van 't Veer, Laura J, Yee, Douglas, Moulder, Stacy L, Wallace, Anne M, Chien, A Jo, Isaacs, Claudine, Boughey, Judy C, Albain, Kathy S, Kemmer, Kathleen, Haley, Barbara B, Han, Hyo S, Forero-Torres, Andres, Elias, Anthony, Lang, Julie E, Ellis, Erin D, Yung, Rachel, Tripathy, Debu, Nanda, Rita, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Gallagher, Rosa I, Helsten, Teresa, Roesch, Erin, Ewing, Cheryl A, Alvarado, Michael, Crane, Erin P, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Steeg, Katherine, Asare, Adam, Matthews, Jeffrey B, Berry, Scott, Sanil, Ashish, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Schwab, Richard B, Symmans, W Fraser, Hylton, Nola M, Berry, Donald A, Esserman, Laura J, DeMichele, Angela M, Clark, Amy S, Clark, Amy S, Yau, Christina, Wolf, Denise M, Petricoin, Emanuel F, van 't Veer, Laura J, Yee, Douglas, Moulder, Stacy L, Wallace, Anne M, Chien, A Jo, Isaacs, Claudine, Boughey, Judy C, Albain, Kathy S, Kemmer, Kathleen, Haley, Barbara B, Han, Hyo S, Forero-Torres, Andres, Elias, Anthony, Lang, Julie E, Ellis, Erin D, Yung, Rachel, Tripathy, Debu, Nanda, Rita, Wulfkuhle, Julia D, Brown-Swigart, Lamorna, Gallagher, Rosa I, Helsten, Teresa, Roesch, Erin, Ewing, Cheryl A, Alvarado, Michael, Crane, Erin P, Buxton, Meredith, Clennell, Julia L, Paoloni, Melissa, Asare, Smita M, Wilson, Amy, Hirst, Gillian L, Singhrao, Ruby, Steeg, Katherine, Asare, Adam, Matthews, Jeffrey B, Berry, Scott, Sanil, Ashish, Melisko, Michelle, Perlmutter, Jane, Rugo, Hope S, Schwab, Richard B, Symmans, W Fraser, Hylton, Nola M, Berry, Donald A, Esserman, Laura J, and DeMichele, Angela M

Abstract

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms 'graduate' in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome.

Published
2021

8. 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

9. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo M, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil S, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Rim S, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes F S, van der Laak, Jeroen A W M, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A D, International Immuno-Oncology Biomarker Working Group, Van Bockstal, Mieke, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service d'anatomie pathologique, Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo M, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil S, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Rim S, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes F S, van der Laak, Jeroen A W M, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A D, International Immuno-Oncology Biomarker Working Group, and Van Bockstal, Mieke

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

Published
2020

10. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A. D., Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, and Cooper, Lee A. D.

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Funding Agencies|National Institutes of Health National Cancer Institute (NCI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA220401, U24CA19436201]; Breast Cancer Research Foundation (BCRF) [17-194]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1UG3CA225021, 1U24CA215109, 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA21657901A1, R01 CA220581-01A1, 1U01 CA239055-01, Leidos 14 x 138]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [1 C06 RR12463-01]; VA Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service [IBX004121A]; DOD Prostate Cancer Idea Development Award [W81XWH-15-1-0558]; DOD Lung Cancer InvestigatorInitiated Translational Research Award [W81XWH-18-1-0440]; DOD Peer Reviewed Cancer Research Program [W81XWH-16-1-0329]; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University; Susan G Komen FoundationSusan G. Komen Breast Cancer Foundation [CCR CCR18547966]; Breast Cancer Alliance; Canadian Cancer Society; DHHS/NCI Cancer Center Support Grant (CCSG)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA16672]

Published
2020
Full Text
View/download PDF

11. MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

Author

Chien, A Jo, Chien, A Jo, Tripathy, Debasish, Albain, Kathy S, Symmans, W Fraser, Rugo, Hope S, Melisko, Michelle E, Wallace, Anne M, Schwab, Richard, Helsten, Teresa, Forero-Torres, Andres, Stringer-Reasor, Erica, Ellis, Erin D, Kaplan, Henry G, Nanda, Rita, Jaskowiak, Nora, Murthy, Rashmi, Godellas, Constantine, Boughey, Judy C, Elias, Anthony D, Haley, Barbara B, Kemmer, Kathleen, Isaacs, Claudine, Clark, Amy S, Lang, Julie E, Lu, Janice, Korde, Larissa, Edmiston, Kirsten K, Northfelt, Donald W, Viscusi, Rebecca K, Yee, Douglas, Perlmutter, Jane, Hylton, Nola M, Van't Veer, Laura J, DeMichele, Angela, Wilson, Amy, Peterson, Garry, Buxton, Meredith B, Paoloni, Melissa, Clennell, Julia, Berry, Scott, Matthews, Jeffrey B, Steeg, Katherine, Singhrao, Ruby, Hirst, Gillian L, Sanil, Ashish, Yau, Christina, Asare, Smita M, Berry, Donald A, Esserman, Laura J, I-SPY 2 Consortium, Chien, A Jo, Chien, A Jo, Tripathy, Debasish, Albain, Kathy S, Symmans, W Fraser, Rugo, Hope S, Melisko, Michelle E, Wallace, Anne M, Schwab, Richard, Helsten, Teresa, Forero-Torres, Andres, Stringer-Reasor, Erica, Ellis, Erin D, Kaplan, Henry G, Nanda, Rita, Jaskowiak, Nora, Murthy, Rashmi, Godellas, Constantine, Boughey, Judy C, Elias, Anthony D, Haley, Barbara B, Kemmer, Kathleen, Isaacs, Claudine, Clark, Amy S, Lang, Julie E, Lu, Janice, Korde, Larissa, Edmiston, Kirsten K, Northfelt, Donald W, Viscusi, Rebecca K, Yee, Douglas, Perlmutter, Jane, Hylton, Nola M, Van't Veer, Laura J, DeMichele, Angela, Wilson, Amy, Peterson, Garry, Buxton, Meredith B, Paoloni, Melissa, Clennell, Julia, Berry, Scott, Matthews, Jeffrey B, Steeg, Katherine, Singhrao, Ruby, Hirst, Gillian L, Sanil, Ashish, Yau, Christina, Asare, Smita M, Berry, Donald A, Esserman, Laura J, and I-SPY 2 Consortium

Abstract

PurposeThe phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer.Patients and methodsI-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week.ResultsMK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform).ConclusionThe Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in H

Published
2020

12. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A. D., Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, and Cooper, Lee A. D.

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Funding Agencies|National Institutes of Health National Cancer Institute (NCI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA220401, U24CA19436201]; Breast Cancer Research Foundation (BCRF) [17-194]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1UG3CA225021, 1U24CA215109, 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA21657901A1, R01 CA220581-01A1, 1U01 CA239055-01, Leidos 14 x 138]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [1 C06 RR12463-01]; VA Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service [IBX004121A]; DOD Prostate Cancer Idea Development Award [W81XWH-15-1-0558]; DOD Lung Cancer InvestigatorInitiated Translational Research Award [W81XWH-18-1-0440]; DOD Peer Reviewed Cancer Research Program [W81XWH-16-1-0329]; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University; Susan G Komen FoundationSusan G. Komen Breast Cancer Foundation [CCR CCR18547966]; Breast Cancer Alliance; Canadian Cancer Society; DHHS/NCI Cancer Center Support Grant (CCSG)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA16672]

Published
2020
Full Text
View/download PDF

13. 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

14. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A. D., Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, and Cooper, Lee A. D.

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Funding Agencies|National Institutes of Health National Cancer Institute (NCI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA220401, U24CA19436201]; Breast Cancer Research Foundation (BCRF) [17-194]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1UG3CA225021, 1U24CA215109, 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA21657901A1, R01 CA220581-01A1, 1U01 CA239055-01, Leidos 14 x 138]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [1 C06 RR12463-01]; VA Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service [IBX004121A]; DOD Prostate Cancer Idea Development Award [W81XWH-15-1-0558]; DOD Lung Cancer InvestigatorInitiated Translational Research Award [W81XWH-18-1-0440]; DOD Peer Reviewed Cancer Research Program [W81XWH-16-1-0329]; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University; Susan G Komen FoundationSusan G. Komen Breast Cancer Foundation [CCR CCR18547966]; Breast Cancer Alliance; Canadian Cancer Society; DHHS/NCI Cancer Center Support Grant (CCSG)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA16672]

Published
2020
Full Text
View/download PDF

15. 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

16. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Author

Amgad, Mohamed, Stovgaard, Elisabeth Ida Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo Mark, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen JK, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Seong-Rim, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes LFS, van der Laak, Jeroen A W M JAWM, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael R., Salgado, Roberto, Cooper, Lee A D, International Immuno-Oncology Biomarker Working Group, Amgad, Mohamed, Stovgaard, Elisabeth Ida Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K, Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H, Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M, Horlings, Hugo Mark, Hudeček, Jan, Ciompi, Francesco, Moore, David A, Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen JK, Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P, Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J, Lakhani, Sunil R, Rojo, Federico, Comerma, Laura, Badve, Sunil, Khojasteh, Mehrnoush, Symmans, W Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L, Kim, Seong-Rim, Rimm, David L, Viale, Giuseppe, Hewitt, Stephen M, Bartlett, John M S, Penault-Llorca, Frédérique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G, Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O, Lazar, Alexander J, Bago-Horvath, Zsuzsanna, Kooreman, Loes LFS, van der Laak, Jeroen A W M JAWM, Saltz, Joel, Gallas, Brandon D, Kurkure, Uday, Barnes, Michael R., Salgado, Roberto, Cooper, Lee A D, and International Immuno-Oncology Biomarker Working Group

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2020

17. 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

18. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A. D., Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, and Cooper, Lee A. D.

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Funding Agencies|National Institutes of Health National Cancer Institute (NCI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA220401, U24CA19436201]; Breast Cancer Research Foundation (BCRF) [17-194]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1UG3CA225021, 1U24CA215109, 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA21657901A1, R01 CA220581-01A1, 1U01 CA239055-01, Leidos 14 x 138]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [1 C06 RR12463-01]; VA Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service [IBX004121A]; DOD Prostate Cancer Idea Development Award [W81XWH-15-1-0558]; DOD Lung Cancer InvestigatorInitiated Translational Research Award [W81XWH-18-1-0440]; DOD Peer Reviewed Cancer Research Program [W81XWH-16-1-0329]; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University; Susan G Komen FoundationSusan G. Komen Breast Cancer Foundation [CCR CCR18547966]; Breast Cancer Alliance; Canadian Cancer Society; DHHS/NCI Cancer Center Support Grant (CCSG)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA16672]

Published
2020
Full Text
View/download PDF

19. Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Author

Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, Cooper, Lee A. D., Amgad, Mohamed, Stovgaard, Elisabeth Specht, Balslev, Eva, Thagaard, Jeppe, Chen, Weijie, Dudgeon, Sarah, Sharma, Ashish, Kerner, Jennifer K., Denkert, Carsten, Yuan, Yinyin, AbdulJabbar, Khalid, Wienert, Stephan, Savas, Peter, Voorwerk, Leonie, Beck, Andrew H., Madabhushi, Anant, Hartman, Johan, Sebastian, Manu M., Horlings, Hugo M., Hudecek, Jan, Ciompi, Francesco, Moore, David A., Singh, Rajendra, Roblin, Elvire, Balancin, Marcelo Luiz, Mathieu, Marie-Christine, Lennerz, Jochen K., Kirtani, Pawan, Chen, I-Chun, Braybrooke, Jeremy P., Pruneri, Giancarlo, Demaria, Sandra, Adams, Sylvia, Schnitt, Stuart J., Lakhani, Sunil R., Rojo, Federico, Comerma, Laura, Badve, Sunil S., Khojasteh, Mehrnoush, Symmans, W. Fraser, Sotiriou, Christos, Gonzalez-Ericsson, Paula, Pogue-Geile, Katherine L., Kim, Rim S., Rimm, David L., Viale, Giuseppe, Hewitt, Stephen M., Bartlett, John M. S., Penault-Llorca, Frederique, Goel, Shom, Lien, Huang-Chun, Loibl, Sibylle, Kos, Zuzana, Loi, Sherene, Hanna, Matthew G., Michiels, Stefan, Kok, Marleen, Nielsen, Torsten O., Lazar, Alexander J., Bago-Horvath, Zsuzsanna, Kooreman, Loes F. S., van der Laak, Jeroen, Saltz, Joel, Gallas, Brandon D., Kurkure, Uday, Barnes, Michael, Salgado, Roberto, and Cooper, Lee A. D.

Abstract

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring., Funding Agencies|National Institutes of Health National Cancer Institute (NCI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [U01CA220401, U24CA19436201]; Breast Cancer Research Foundation (BCRF) [17-194]; NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [1UG3CA225021, 1U24CA215109, 1U24CA199374-01, R01CA202752-01A1, R01CA208236-01A1, R01 CA21657901A1, R01 CA220581-01A1, 1U01 CA239055-01, Leidos 14 x 138]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [1 C06 RR12463-01]; VA Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service [IBX004121A]; DOD Prostate Cancer Idea Development Award [W81XWH-15-1-0558]; DOD Lung Cancer InvestigatorInitiated Translational Research Award [W81XWH-18-1-0440]; DOD Peer Reviewed Cancer Research Program [W81XWH-16-1-0329]; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University; Susan G Komen FoundationSusan G. Komen Breast Cancer Foundation [CCR CCR18547966]; Breast Cancer Alliance; Canadian Cancer Society; DHHS/NCI Cancer Center Support Grant (CCSG)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30 CA16672]

Published
2020
Full Text
View/download PDF

20. Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Author

Boughey, Judy C, Boughey, Judy C, Alvarado, Michael D, Lancaster, Rachael B, Symmans, W Fraser, Mukhtar, Rita, Wong, Jasmine M, Ewing, Cheryl A, Potter, David A, Tuttle, Todd M, Hieken, Tina J, Carter, Jodi M, Jakub, James W, Kaplan, Henry G, Buchanan, Claire L, Jaskowiak, Nora T, Sattar, Husain A, Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J, Pohlmann, Paula R, Lynce, Filipa, Tousimis, Eleni A, Zeck, Jay C, Lee, M Catherine, Lang, Julie E, Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Goodellas, Constantine, Chen, Margaret, Kalinsky, Kevin M, Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L, Asare, Smita, Matthews, Jeffrey B, Perlmutter, Jane, Esserman, Laura J, I-SPY2 Investigators, Boughey, Judy C, Boughey, Judy C, Alvarado, Michael D, Lancaster, Rachael B, Symmans, W Fraser, Mukhtar, Rita, Wong, Jasmine M, Ewing, Cheryl A, Potter, David A, Tuttle, Todd M, Hieken, Tina J, Carter, Jodi M, Jakub, James W, Kaplan, Henry G, Buchanan, Claire L, Jaskowiak, Nora T, Sattar, Husain A, Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J, Pohlmann, Paula R, Lynce, Filipa, Tousimis, Eleni A, Zeck, Jay C, Lee, M Catherine, Lang, Julie E, Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Goodellas, Constantine, Chen, Margaret, Kalinsky, Kevin M, Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L, Asare, Smita, Matthews, Jeffrey B, Perlmutter, Jane, Esserman, Laura J, and I-SPY2 Investigators

Abstract

[This corrects the article DOI: 10.1038/s41523-018-0074-6.].

Published
2019

21. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study.

Author

Hurvitz, Sara A, Hurvitz, Sara A, Martin, Miguel, Jung, Kyung Hae, Huang, Chiun-Sheng, Harbeck, Nadia, Valero, Vicente, Stroyakovskiy, Daniil, Wildiers, Hans, Campone, Mario, Boileau, Jean-François, Fasching, Peter A, Afenjar, Karen, Spera, Gonzalo, Lopez-Valverde, Vanesa, Song, Chunyan, Trask, Peter, Boulet, Thomas, Sparano, Joseph A, Symmans, W Fraser, Thompson, Alastair M, Slamon, Dennis, Hurvitz, Sara A, Hurvitz, Sara A, Martin, Miguel, Jung, Kyung Hae, Huang, Chiun-Sheng, Harbeck, Nadia, Valero, Vicente, Stroyakovskiy, Daniil, Wildiers, Hans, Campone, Mario, Boileau, Jean-François, Fasching, Peter A, Afenjar, Karen, Spera, Gonzalo, Lopez-Valverde, Vanesa, Song, Chunyan, Trask, Peter, Boulet, Thomas, Sparano, Joseph A, Symmans, W Fraser, Thompson, Alastair M, and Slamon, Dennis

Abstract

PurposeThe KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.MethodsPatients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).ResultsOf patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.ConclusionCompared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadju

Published
2019

22. Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Author

Boughey, Judy C, Boughey, Judy C, Alvarado, Michael D, Lancaster, Rachael B, Symmans, W Fraser, Mukhtar, Rita, Wong, Jasmine M, Ewing, Cheryl A, Potter, David A, Tuttle, Todd M, Hieken, Tina J, Carter, Jodi M, Jakub, James W, Kaplan, Henry G, Buchanan, Claire L, Jaskowiak, Nora T, Sattar, Husain A, Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J, Pohlmann, Paula R, Lynce, Filipa, Tousimis, Eleni A, Zeck, Jay C, Lee, M Catherine, Lang, Julie E, Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Goodellas, Constantine, Chen, Margaret, Kalinsky, Kevin M, Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L, Asare, Smita, Matthews, Jeffrey B, Perlmutter, Jane, Esserman, Laura J, I-SPY2 Investigators, Boughey, Judy C, Boughey, Judy C, Alvarado, Michael D, Lancaster, Rachael B, Symmans, W Fraser, Mukhtar, Rita, Wong, Jasmine M, Ewing, Cheryl A, Potter, David A, Tuttle, Todd M, Hieken, Tina J, Carter, Jodi M, Jakub, James W, Kaplan, Henry G, Buchanan, Claire L, Jaskowiak, Nora T, Sattar, Husain A, Mueller, Jeffrey, Nanda, Rita, Isaacs, Claudine J, Pohlmann, Paula R, Lynce, Filipa, Tousimis, Eleni A, Zeck, Jay C, Lee, M Catherine, Lang, Julie E, Mhawech-Fauceglia, Paulette, Rao, Roshni, Taback, Bret, Goodellas, Constantine, Chen, Margaret, Kalinsky, Kevin M, Hibshoosh, Hanina, Killelea, Brigid, Sanft, Tara, Hirst, Gillian L, Asare, Smita, Matthews, Jeffrey B, Perlmutter, Jane, Esserman, Laura J, and I-SPY2 Investigators

Abstract

[This corrects the article DOI: 10.1038/s41523-018-0074-6.].

Published
2019

23. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes From the Phase III KRISTINE Study.

Author

Hurvitz, Sara A, Hurvitz, Sara A, Martin, Miguel, Jung, Kyung Hae, Huang, Chiun-Sheng, Harbeck, Nadia, Valero, Vicente, Stroyakovskiy, Daniil, Wildiers, Hans, Campone, Mario, Boileau, Jean-François, Fasching, Peter A, Afenjar, Karen, Spera, Gonzalo, Lopez-Valverde, Vanesa, Song, Chunyan, Trask, Peter, Boulet, Thomas, Sparano, Joseph A, Symmans, W Fraser, Thompson, Alastair M, Slamon, Dennis, Hurvitz, Sara A, Hurvitz, Sara A, Martin, Miguel, Jung, Kyung Hae, Huang, Chiun-Sheng, Harbeck, Nadia, Valero, Vicente, Stroyakovskiy, Daniil, Wildiers, Hans, Campone, Mario, Boileau, Jean-François, Fasching, Peter A, Afenjar, Karen, Spera, Gonzalo, Lopez-Valverde, Vanesa, Song, Chunyan, Trask, Peter, Boulet, Thomas, Sparano, Joseph A, Symmans, W Fraser, Thompson, Alastair M, and Slamon, Dennis

Abstract

PurposeThe KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.MethodsPatients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).ResultsOf patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.ConclusionCompared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadju

Published
2019

24. A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with neoadjuvant chemotherapy.

Author

ASCO Annual meeting 2017 (June 2017: Chicago, IL, USA), Bayar, M.A., Criscitiello, Carmen, Curigliano, G, Symmans, W Fraser, Desmedt, Christine, Bonnefoi, H, Sinn, Bruno BV, Pruneri, Giancarlo, Vicier, C, Pierga, Jean-Yves, Denkert, Carsten, Loibl, Sibylle, Sotiriou, Christos, Michiels, Stefan, Andre, Fabrice, ASCO Annual meeting 2017 (June 2017: Chicago, IL, USA), Bayar, M.A., Criscitiello, Carmen, Curigliano, G, Symmans, W Fraser, Desmedt, Christine, Bonnefoi, H, Sinn, Bruno BV, Pruneri, Giancarlo, Vicier, C, Pierga, Jean-Yves, Denkert, Carsten, Loibl, Sibylle, Sotiriou, Christos, Michiels, Stefan, and Andre, Fabrice

Abstract

Publié dans J Clin Oncol 35, 2017 (suppl; abstr 575)., info:eu-repo/semantics/nonPublished

Published
2017

25. 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

26. 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

27. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.

Author

Salgado, Roberto, Denkert, Carsten, Demaria, S, Sirtaine, N., Klauschen, F, Pruneri, Giancarlo, Wienert, S, Van den Eynden, Gert, Baehner, Frederick L, Pénault-Llorca, Frederique, Perez, E A, Thompson, E A, Symmans, W Fraser, Richardson, A L, Brock, John, Criscitiello, Carmen, Bailey, H, Ignatiadis, Michail, Floris, Giuseppe, Sparano, Joseph A, Kos, Z, Nielsen, T, Rimm, David D.L., Allison, K H, Reis-Filho, Jorge Sergio, Loibl, Sibylle, Sotiriou, Christos, Viale, G, Badve, S, Adams, S., Willard-Gallo, Karen, Loi, Sherene, Salgado, Roberto, Denkert, Carsten, Demaria, S, Sirtaine, N., Klauschen, F, Pruneri, Giancarlo, Wienert, S, Van den Eynden, Gert, Baehner, Frederick L, Pénault-Llorca, Frederique, Perez, E A, Thompson, E A, Symmans, W Fraser, Richardson, A L, Brock, John, Criscitiello, Carmen, Bailey, H, Ignatiadis, Michail, Floris, Giuseppe, Sparano, Joseph A, Kos, Z, Nielsen, T, Rimm, David D.L., Allison, K H, Reis-Filho, Jorge Sergio, Loibl, Sibylle, Sotiriou, Christos, Viale, G, Badve, S, Adams, S., Willard-Gallo, Karen, and Loi, Sherene

Abstract

The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2014

28. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.

Author

Salgado, Roberto, Denkert, Carsten, Demaria, S, Sirtaine, N., Klauschen, F, Pruneri, Giancarlo, Wienert, S, Van den Eynden, Gert, Baehner, Frederick L, Pénault-Llorca, Frederique, Perez, E A, Thompson, E A, Symmans, W Fraser, Richardson, A L, Brock, John, Criscitiello, Carmen, Bailey, H, Ignatiadis, Michail, Floris, Giuseppe, Sparano, Joseph A, Kos, Z, Nielsen, T, Rimm, David D.L., Allison, K H, Reis-Filho, Jorge Sergio, Loibl, Sibylle, Sotiriou, Christos, Viale, G, Badve, S, Adams, S., Willard-Gallo, Karen, Loi, Sherene, Salgado, Roberto, Denkert, Carsten, Demaria, S, Sirtaine, N., Klauschen, F, Pruneri, Giancarlo, Wienert, S, Van den Eynden, Gert, Baehner, Frederick L, Pénault-Llorca, Frederique, Perez, E A, Thompson, E A, Symmans, W Fraser, Richardson, A L, Brock, John, Criscitiello, Carmen, Bailey, H, Ignatiadis, Michail, Floris, Giuseppe, Sparano, Joseph A, Kos, Z, Nielsen, T, Rimm, David D.L., Allison, K H, Reis-Filho, Jorge Sergio, Loibl, Sibylle, Sotiriou, Christos, Viale, G, Badve, S, Adams, S., Willard-Gallo, Karen, and Loi, Sherene

Abstract

The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC., SCOPUS: re.j, info:eu-repo/semantics/published

Published
2014

29. 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

30. 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

31. 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

Introduction: 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. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest

Published
2013

32. Progression of genomic signatures in local and metastatic estrogen receptor-positive (ER+) breast cancer: Relevance to palliative treatment.

Author

Symmans, W Fraser, Andreopoulou, Eleni, Booser, Daniel J, Hatzis, Christos, Wallace, Matthew, Zhang, Y., Gong, Yun, Ignatiadis, Michail, Sotiriou, Christos, Andre, Fabrice, Peintinger, Florentia, Regitnig, Peter, Marth, C, Desmedt, Christine, Loi, Sherene, Moulder, SL, Hortobagyi, Gabriel N., Pusztai, Lajos, Valero, Vicente, Symmans, W Fraser, Andreopoulou, Eleni, Booser, Daniel J, Hatzis, Christos, Wallace, Matthew, Zhang, Y., Gong, Yun, Ignatiadis, Michail, Sotiriou, Christos, Andre, Fabrice, Peintinger, Florentia, Regitnig, Peter, Marth, C, Desmedt, Christine, Loi, Sherene, Moulder, SL, Hortobagyi, Gabriel N., Pusztai, Lajos, and Valero, Vicente

Abstract

515, info:eu-repo/semantics/published

Published
2012

33. Progression of genomic signatures in local and metastatic estrogen receptor-positive (ER+) breast cancer: Relevance to palliative treatment.

Author

Symmans, W Fraser, Andreopoulou, Eleni, Booser, Daniel J, Hatzis, Christos, Wallace, Matthew, Zhang, Y., Gong, Yun, Ignatiadis, Michail, Sotiriou, Christos, Andre, Fabrice, Peintinger, Florentia, Regitnig, Peter, Marth, C, Desmedt, Christine, Loi, Sherene, Moulder, SL, Hortobagyi, Gabriel N., Pusztai, Lajos, Valero, Vicente, Symmans, W Fraser, Andreopoulou, Eleni, Booser, Daniel J, Hatzis, Christos, Wallace, Matthew, Zhang, Y., Gong, Yun, Ignatiadis, Michail, Sotiriou, Christos, Andre, Fabrice, Peintinger, Florentia, Regitnig, Peter, Marth, C, Desmedt, Christine, Loi, Sherene, Moulder, SL, Hortobagyi, Gabriel N., Pusztai, Lajos, and Valero, Vicente

Abstract

515, info:eu-repo/semantics/published

Published
2012

34. Effect of sample preservation method and transportation duration on tumor gene expression profiling in breast cancer.

Author

San Antonio Breast Cancer Conference - SABCS (December 15, 2012: San Antonio, Tx, USA), Fumagalli, Debora, Jose, Vinu, Salgado, Roberto, Majjaj, Samira, Singhal, Sandeep, Vincent, Delphine, Maetens, Marion M., Larsimont, Denis, Piccart-Gebhart, Martine, Symmans, W Fraser, Dinh, Phuong, Michiels, Stefan, Sotiriou, Christos, Loi, Sherene, San Antonio Breast Cancer Conference - SABCS (December 15, 2012: San Antonio, Tx, USA), Fumagalli, Debora, Jose, Vinu, Salgado, Roberto, Majjaj, Samira, Singhal, Sandeep, Vincent, Delphine, Maetens, Marion M., Larsimont, Denis, Piccart-Gebhart, Martine, Symmans, W Fraser, Dinh, Phuong, Michiels, Stefan, Sotiriou, Christos, and Loi, Sherene

Abstract

info:eu-repo/semantics/nonPublished

Published
2012

35. Effect of sample preservation method and transportation duration on tumor gene expression profiling in breast cancer

Author

Fumagalli, Debora, Jose, Vinu, Salgado, Roberto, Majjaj, Samira, Singhal, Sandeep, Vincent, Delphine, Maetens, Marion M., Larsimont, Denis, Piccart-Gebhart, Martine, Symmans, W Fraser, Dinh, Phuong, Michiels, Stefan, Sotiriou, Christos, Loi, Sherene, Fumagalli, Debora, Jose, Vinu, Salgado, Roberto, Majjaj, Samira, Singhal, Sandeep, Vincent, Delphine, Maetens, Marion M., Larsimont, Denis, Piccart-Gebhart, Martine, Symmans, W Fraser, Dinh, Phuong, Michiels, Stefan, Sotiriou, Christos, and Loi, Sherene

Abstract

nr. P1-07-08, info:eu-repo/semantics/published

Published
2012

36. Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer.

Author

Gonzalez-Angulo, Ana M, Gonzalez-Angulo, Ana M, Hennessy, Bryan T, Meric-Bernstam, Funda, Sahin, Aysegul, Liu, Wenbin, Ju, Zhenlin, Carey, Mark S, Myhre, Simen, Speers, Corey, Deng, Lei, Broaddus, Russell, Lluch, Ana, Aparicio, Sam, Brown, Powel, Pusztai, Lajos, Symmans, W Fraser, Alsner, Jan, Overgaard, Jens, Borresen-Dale, Anne-Lise, Hortobagyi, Gabriel N, Coombes, Kevin R, Mills, Gordon B, Gonzalez-Angulo, Ana M, Gonzalez-Angulo, Ana M, Hennessy, Bryan T, Meric-Bernstam, Funda, Sahin, Aysegul, Liu, Wenbin, Ju, Zhenlin, Carey, Mark S, Myhre, Simen, Speers, Corey, Deng, Lei, Broaddus, Russell, Lluch, Ana, Aparicio, Sam, Brown, Powel, Pusztai, Lajos, Symmans, W Fraser, Alsner, Jan, Overgaard, Jens, Borresen-Dale, Anne-Lise, Hortobagyi, Gabriel N, Coombes, Kevin R, and Mills, Gordon B

Abstract

PurposeTo determine whether functional proteomics improves breast cancer classification and prognostication and can predict pathological complete response (pCR) in patients receiving neoadjuvant taxane and anthracycline-taxane-based systemic therapy (NST).MethodsReverse phase protein array (RPPA) using 146 antibodies to proteins relevant to breast cancer was applied to three independent tumor sets. Supervised clustering to identify subgroups and prognosis in surgical excision specimens from a training set (n = 712) was validated on a test set (n = 168) in two cohorts of patients with primary breast cancer. A score was constructed using ordinal logistic regression to quantify the probability of recurrence in the training set and tested in the test set. The score was then evaluated on 132 FNA biopsies of patients treated with NST to determine ability to predict pCR.ResultsSix breast cancer subgroups were identified by a 10-protein biomarker panel in the 712 tumor training set. They were associated with different recurrence-free survival (RFS) (log-rank p = 8.8 E-10). The structure and ability of the six subgroups to predict RFS was confirmed in the test set (log-rank p = 0.0013). A prognosis score constructed using the 10 proteins in the training set was associated with RFS in both training and test sets (p = 3.2E-13, for test set). There was a significant association between the prognostic score and likelihood of pCR to NST in the FNA set (p = 0.0021).ConclusionWe developed a 10-protein biomarker panel that classifies breast cancer into prognostic groups that may have potential utility in the management of patients who receive anthracycline-taxane-based NST.

Published
2011

37. Maximum predictive power of the microarray-based models for clinical outcomes is limited by correlation between endpoint and gene expression profile

Author

Zhao, Chen, Shi, Leming, Tong, Weida, Shaughnessy, John D., Jr., Oberthuer, Andre, Pusztai, Lajos, Deng, Youping, Symmans, W. Fraser, Shi, Tieliu, Zhao, Chen, Shi, Leming, Tong, Weida, Shaughnessy, John D., Jr., Oberthuer, Andre, Pusztai, Lajos, Deng, Youping, Symmans, W. Fraser, and Shi, Tieliu

Abstract

Background: Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance. Results: We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile. Conclusion: For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications.

Published
2011

38. Proposals for uniform collection of biospecimens from neoadjuvant breast cancer clinical trials: timing and specimen types.

Author

Loi, Sherene, Symmans, W Fraser, Bartlett, John M S, Fumagalli, Debora, Van't Veer, Laura, Forbes, John F, Bedard, Philippe L, Denkert, Carsten, Zujewski, Jo Anne, Viale, Giuseppe, Pusztai, Lajos, Esserman, Laura J, Leyland-Jones, Brian, Loi, Sherene, Symmans, W Fraser, Bartlett, John M S, Fumagalli, Debora, Van't Veer, Laura, Forbes, John F, Bedard, Philippe L, Denkert, Carsten, Zujewski, Jo Anne, Viale, Giuseppe, Pusztai, Lajos, Esserman, Laura J, and Leyland-Jones, Brian

Abstract

In this Personal View, we outline proposals for uniform collection of biospecimens obtained in neoadjuvant breast cancer trials undertaken by the Breast International Group (BIG) and the National Cancer Institute-sponsored North American Breast Cancer Group (NABCG). These proposals aim to standardise collection of high-quality specimens, with respect to both type and timing, to enhance and allow integration of results obtained from neoadjuvant trials done by several groups. They should be considered in parallel with recommendations for tissue-specimen collection and handling previously developed by BIG and NABCG. We propose that tumour tissue (formalin-fixed, paraffin-embedded and samples dedicated for molecular studies) should be taken at baseline, 1-3 weeks after the start of treatment, and at definitive surgery, with clear prioritisation in the study protocol of number, order, and preservation of samples to be gathered. This step should be accompanied by blood collection (plasma, serum, and whole blood) whenever possible. We advocate strongly a move towards one diagnostic and research biopsy procedure in all women with breast cancers potentially suitable for neoadjuvant treatment. If possible, patients should be referred at the outset to specialised centres to give them the opportunity to participate in neoadjuvant clinical trials, thereby avoiding several biopsy procedures., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: no.j, info:eu-repo/semantics/published

Published
2011

39. Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response.

Author

Li, Qiyuan, Eklund, Aron C, Birkbak, Nicolai J, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Symmans, W Fraser, Pusztai, Lajos, Brunak, Søren, Richardson, Andrea L, Szallasi, Zoltan, Li, Qiyuan, Eklund, Aron C, Birkbak, Nicolai J, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Symmans, W Fraser, Pusztai, Lajos, Brunak, Søren, Richardson, Andrea L, and Szallasi, Zoltan

Abstract

Genome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

40. Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer.

Author

Gonzalez-Angulo, Ana M, Gonzalez-Angulo, Ana M, Hennessy, Bryan T, Meric-Bernstam, Funda, Sahin, Aysegul, Liu, Wenbin, Ju, Zhenlin, Carey, Mark S, Myhre, Simen, Speers, Corey, Deng, Lei, Broaddus, Russell, Lluch, Ana, Aparicio, Sam, Brown, Powel, Pusztai, Lajos, Symmans, W Fraser, Alsner, Jan, Overgaard, Jens, Borresen-Dale, Anne-Lise, Hortobagyi, Gabriel N, Coombes, Kevin R, Mills, Gordon B, Gonzalez-Angulo, Ana M, Gonzalez-Angulo, Ana M, Hennessy, Bryan T, Meric-Bernstam, Funda, Sahin, Aysegul, Liu, Wenbin, Ju, Zhenlin, Carey, Mark S, Myhre, Simen, Speers, Corey, Deng, Lei, Broaddus, Russell, Lluch, Ana, Aparicio, Sam, Brown, Powel, Pusztai, Lajos, Symmans, W Fraser, Alsner, Jan, Overgaard, Jens, Borresen-Dale, Anne-Lise, Hortobagyi, Gabriel N, Coombes, Kevin R, and Mills, Gordon B

Abstract

PurposeTo determine whether functional proteomics improves breast cancer classification and prognostication and can predict pathological complete response (pCR) in patients receiving neoadjuvant taxane and anthracycline-taxane-based systemic therapy (NST).MethodsReverse phase protein array (RPPA) using 146 antibodies to proteins relevant to breast cancer was applied to three independent tumor sets. Supervised clustering to identify subgroups and prognosis in surgical excision specimens from a training set (n = 712) was validated on a test set (n = 168) in two cohorts of patients with primary breast cancer. A score was constructed using ordinal logistic regression to quantify the probability of recurrence in the training set and tested in the test set. The score was then evaluated on 132 FNA biopsies of patients treated with NST to determine ability to predict pCR.ResultsSix breast cancer subgroups were identified by a 10-protein biomarker panel in the 712 tumor training set. They were associated with different recurrence-free survival (RFS) (log-rank p = 8.8 E-10). The structure and ability of the six subgroups to predict RFS was confirmed in the test set (log-rank p = 0.0013). A prognosis score constructed using the 10 proteins in the training set was associated with RFS in both training and test sets (p = 3.2E-13, for test set). There was a significant association between the prognostic score and likelihood of pCR to NST in the FNA set (p = 0.0021).ConclusionWe developed a 10-protein biomarker panel that classifies breast cancer into prognostic groups that may have potential utility in the management of patients who receive anthracycline-taxane-based NST.

Published
2011

41. Maximum predictive power of the microarray-based models for clinical outcomes is limited by correlation between endpoint and gene expression profile

Author

Zhao, Chen, Shi, Leming, Tong, Weida, Shaughnessy, John D., Jr., Oberthuer, Andre, Pusztai, Lajos, Deng, Youping, Symmans, W. Fraser, Shi, Tieliu, Zhao, Chen, Shi, Leming, Tong, Weida, Shaughnessy, John D., Jr., Oberthuer, Andre, Pusztai, Lajos, Deng, Youping, Symmans, W. Fraser, and Shi, Tieliu

Abstract

Background: Microarray data have been used for gene signature selection to predict clinical outcomes. Many studies have attempted to identify factors that affect models' performance with only little success. Fine-tuning of model parameters and optimizing each step of the modeling process often results in over-fitting problems without improving performance. Results: We propose a quantitative measurement, termed consistency degree, to detect the correlation between disease endpoint and gene expression profile. Different endpoints were shown to have different consistency degrees to gene expression profiles. The validity of this measurement to estimate the consistency was tested with significance at a p-value less than 2.2e-16 for all of the studied endpoints. According to the consistency degree score, overall survival milestone outcome of multiple myeloma was proposed to extend from 730 days to 1561 days, which is more consistent with gene expression profile. Conclusion: For various clinical endpoints, the maximum predictive powers of different microarray-based models are limited by the correlation between endpoint and gene expression profile of disease samples as indicated by the consistency degree score. In addition, previous defined clinical outcomes can also be reassessed and refined more coherent according to related disease gene expression profile. Our findings point to an entirely new direction for assessing the microarray-based predictive models and provide important information to gene signature based clinical applications.

Published
2011

42. Proposals for uniform collection of biospecimens from neoadjuvant breast cancer clinical trials: timing and specimen types.

Author

Loi, Sherene, Symmans, W Fraser, Bartlett, John M S, Fumagalli, Debora, Van't Veer, Laura, Forbes, John F, Bedard, Philippe L, Denkert, Carsten, Zujewski, Jo Anne, Viale, Giuseppe, Pusztai, Lajos, Esserman, Laura J, Leyland-Jones, Brian, Loi, Sherene, Symmans, W Fraser, Bartlett, John M S, Fumagalli, Debora, Van't Veer, Laura, Forbes, John F, Bedard, Philippe L, Denkert, Carsten, Zujewski, Jo Anne, Viale, Giuseppe, Pusztai, Lajos, Esserman, Laura J, and Leyland-Jones, Brian

Abstract

In this Personal View, we outline proposals for uniform collection of biospecimens obtained in neoadjuvant breast cancer trials undertaken by the Breast International Group (BIG) and the National Cancer Institute-sponsored North American Breast Cancer Group (NABCG). These proposals aim to standardise collection of high-quality specimens, with respect to both type and timing, to enhance and allow integration of results obtained from neoadjuvant trials done by several groups. They should be considered in parallel with recommendations for tissue-specimen collection and handling previously developed by BIG and NABCG. We propose that tumour tissue (formalin-fixed, paraffin-embedded and samples dedicated for molecular studies) should be taken at baseline, 1-3 weeks after the start of treatment, and at definitive surgery, with clear prioritisation in the study protocol of number, order, and preservation of samples to be gathered. This step should be accompanied by blood collection (plasma, serum, and whole blood) whenever possible. We advocate strongly a move towards one diagnostic and research biopsy procedure in all women with breast cancers potentially suitable for neoadjuvant treatment. If possible, patients should be referred at the outset to specialised centres to give them the opportunity to participate in neoadjuvant clinical trials, thereby avoiding several biopsy procedures., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: no.j, info:eu-repo/semantics/published

Published
2011

43. Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response.

Author

Li, Qiyuan, Eklund, Aron C, Birkbak, Nicolai J, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Symmans, W Fraser, Pusztai, Lajos, Brunak, Søren, Richardson, Andrea L, Szallasi, Zoltan, Li, Qiyuan, Eklund, Aron C, Birkbak, Nicolai J, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Symmans, W Fraser, Pusztai, Lajos, Brunak, Søren, Richardson, Andrea L, and Szallasi, Zoltan

Abstract

Genome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2011

44. Consistent metagenes from cancer expression profiles yield agent specific predictors of chemotherapy response

Author

Li, Qiyuan, Eklund, Aron Charles, Birkbak, Nicolai Juul, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Symmans, W. Fraser, Pusztai, Lajos, Brunak, Søren, Richardson, Andrea L, Szallasi, Zoltan Imre, Li, Qiyuan, Eklund, Aron Charles, Birkbak, Nicolai Juul, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Symmans, W. Fraser, Pusztai, Lajos, Brunak, Søren, Richardson, Andrea L, and Szallasi, Zoltan Imre

Abstract

BACKGROUND: Genome scale expression profiling of human tumor samples is likely to yield improved cancer treatment decisions. However, identification of clinically predictive or prognostic classifiers can be challenging when a large number of genes are measured in a small number of tumors. RESULTS: We describe an unsupervised method to extract robust, consistent metagenes from multiple analogous data sets. We applied this method to expression profiles from five "double negative breast cancer" (DNBC) (not expressing ESR1 or HER2) cohorts and derived four metagenes. We assessed these metagenes in four similar but independent cohorts and found strong associations between three of the metagenes and agent-specific response to neoadjuvant therapy. Furthermore, we applied the method to ovarian and early stage lung cancer, two tumor types that lack reliable predictors of outcome, and found that the metagenes yield predictors of survival for both. CONCLUSIONS: These results suggest that the use of multiple data sets to derive potential biomarkers can filter out data set-specific noise and can increase the efficiency in identifying clinically accurate biomarkers.

Published
2011

45. Genomic index of sensitivity to endocrine therapy for breast cancer.

Author

Symmans, W Fraser, Hatzis, Christos, Sotiriou, Christos, Andre, Fabrice, Peintinger, Florentia, Regitnig, Peter, Daxenbichler, Guenter, Desmedt, Christine, Domont, Julien, Marth, Christian, Delaloge, Suzette, Bauernhofer, Thomas, Valero, Vicente, Booser, Daniel J, Hortobagyi, Gabriel N., Pusztai, Lajos, Symmans, W Fraser, Hatzis, Christos, Sotiriou, Christos, Andre, Fabrice, Peintinger, Florentia, Regitnig, Peter, Daxenbichler, Guenter, Desmedt, Christine, Domont, Julien, Marth, Christian, Delaloge, Suzette, Bauernhofer, Thomas, Valero, Vicente, Booser, Daniel J, Hortobagyi, Gabriel N., and Pusztai, Lajos

Abstract

We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, info:eu-repo/semantics/published

Published
2010

46. The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models

Author

Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjö, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, Wolfinger, Russell D, Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjö, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, and Wolfinger, Russell D

Abstract

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Published
2010
Full Text
View/download PDF

47. The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Author

DNAVision SA, Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjo, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, Wolfinger, Russell D, MAQC Consortium, DNAVision SA, Shi, Leming, Campbell, Gregory, Jones, Wendell D, Campagne, Fabien, Wen, Zhining, Walker, Stephen J, Su, Zhenqiang, Chu, Tzu-Ming, Goodsaid, Federico M, Pusztai, Lajos, Shaughnessy, John D, Oberthuer, André, Thomas, Russell S, Paules, Richard S, Fielden, Mark, Barlogie, Bart, Chen, Weijie, Du, Pan, Fischer, Matthias, Furlanello, Cesare, Gallas, Brandon D, Ge, Xijin, Megherbi, Dalila B, Symmans, W Fraser, Wang, May D, Zhang, John, Bitter, Hans, Brors, Benedikt, Bushel, Pierre R, Bylesjo, Max, Chen, Minjun, Cheng, Jie, Cheng, Jing, Chou, Jeff, Davison, Timothy S, Delorenzi, Mauro, Deng, Youping, Devanarayan, Viswanath, Dix, David J, Dopazo, Joaquin, Dorff, Kevin C, Elloumi, Fathi, Fan, Jianqing, Fan, Shicai, Fan, Xiaohui, Fang, Hong, Gonzaludo, Nina, Hess, Kenneth R, Hong, Huixiao, Huan, Jun, Irizarry, Rafael A, Judson, Richard, Juraeva, Dilafruz, Lababidi, Samir, Lambert, Christophe G, Li, Li, Li, Yanen, Li, Zhen, Lin, Simon M, Liu, Guozhen, Lobenhofer, Edward K, Luo, Jun, Luo, Wen, McCall, Matthew N, Nikolsky, Yuri, Pennello, Gene A, Perkins, Roger G, Philip, Reena, Popovici, Vlad, Price, Nathan D, Qian, Feng, Scherer, Andreas, Shi, Tieliu, Shi, Weiwei, Sung, Jaeyun, Thierry-Mieg, Danielle, Thierry-Mieg, Jean, Thodima, Venkata, Trygg, Johan, Vishnuvajjala, Lakshmi, Wang, Sue Jane, Wu, Jianping, Wu, Yichao, Xie, Qian, Yousef, Waleed A, Zhang, Liang, Zhang, Xuegong, Zhong, Sheng, Zhou, Yiming, Zhu, Sheng, Arasappan, Dhivya, Bao, Wenjun, Lucas, Anne Bergstrom, Berthold, Frank, Brennan, Richard J, Buness, Andreas, Catalano, Jennifer G, Chang, Chang, Chen, Rong, Cheng, Yiyu, Cui, Jian, Czika, Wendy, Demichelis, Francesca, Deng, Xutao, Dosymbekov, Damir, Eils, Roland, Feng, Yang, Fostel, Jennifer, Fulmer-Smentek, Stephanie, Fuscoe, James C, Gatto, Laurent, Ge, Weigong, Goldstein, Darlene R, Guo, Li, Halbert, Donald N, Han, Jing, Harris, Stephen C, Hatzis, Christos, Herman, Damir, Huang, Jianping, Jensen, Roderick V, Jiang, Rui, Johnson, Charles D, Jurman, Giuseppe, Kahlert, Yvonne, Khuder, Sadik A, Kohl, Matthias, Li, Jianying, Li, Menglong, Li, Quan-Zhen, Li, Shao, Li, Zhiguang, Liu, Jie, Liu, Ying, Liu, Zhichao, Meng, Lu, Madera, Manuel, Martinez-Murillo, Francisco, Medina, Ignacio, Meehan, Joseph, Miclaus, Kelci, Moffitt, Richard A, Montaner, David, Mukherjee, Piali, Mulligan, George J, Neville, Padraic, Nikolskaya, Tatiana, Ning, Baitang, Page, Grier P, Parker, Joel, Parry, R Mitchell, Peng, Xuejun, Peterson, Ron L, Phan, John H, Quanz, Brian, Ren, Yi, Riccadonna, Samantha, Roter, Alan H, Samuelson, Frank W, Schumacher, Martin M, Shambaugh, Joseph D, Shi, Qiang, Shippy, Richard, Si, Shengzhu, Smalter, Aaron, Sotiriou, Christos, Soukup, Mat, Staedtler, Frank, Steiner, Guido, Stokes, Todd H, Sun, Qinglan, Tan, Pei-Yi, Tang, Rong, Tezak, Zivana, Thorn, Brett, Tsyganova, Marina, Turpaz, Yaron, Vega, Silvia C, Visintainer, Roberto, von Frese, Juergen, Wang, Charles, Wang, Eric, Wang, Junwei, Wang, Wei, Westermann, Frank, Willey, James C, Woods, Matthew, Wu, Shujian, Xiao, Nianqing, Xu, Joshua, Xu, Lei, Yang, Lun, Zeng, Xiao, Zhang, Jialu, Zhang, Li, Zhang, Min, Zhao, Chen, Puri, Raj K, Scherf, Uwe, Tong, Weida, Wolfinger, Russell D, and MAQC Consortium

Abstract

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Published
2010

48. PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.

Author

Loi, Sherene, Haibe-Kains, Benjamin, Majjaj, Samira, Lallemand, Françoise, Durbecq, Virginie, Larsimont, Denis, Gonzalez-Angulo, Ana Maria, Pusztai, Lajos, Symmans, W Fraser, Bardelli, A., Ellis, P., Tutt, A. NJ, Gillett, C. E., Hennessy, B T, Mills, Gordon B, Phillips, W.A., Piccart-Gebhart, Martine, Speed, Terence P, McArthur, Grant A, Sotiriou, Christos, Loi, Sherene, Haibe-Kains, Benjamin, Majjaj, Samira, Lallemand, Françoise, Durbecq, Virginie, Larsimont, Denis, Gonzalez-Angulo, Ana Maria, Pusztai, Lajos, Symmans, W Fraser, Bardelli, A., Ellis, P., Tutt, A. NJ, Gillett, C. E., Hennessy, B T, Mills, Gordon B, Phillips, W.A., Piccart-Gebhart, Martine, Speed, Terence P, McArthur, Grant A, and Sotiriou, Christos

Abstract

PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor-positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation-associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression-induced changes. However, in ER+/HER2- BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS was also assessed. Although the PIK3CA-GS was not associated with prognosis in ER- and HER2+ BC, it could identify better clinical outcomes in ER+/HER2- disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

49. Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

Author

Lehmann-Che, Jacqueline, Andre, Fabrice, Desmedt, Christine, Mazouni, Chafika, Giacchetti, S, Turpin, Elisabeth, Espié, Marc, Plassa, Louis-François, Marty, Michel, Bertheau, Philippe, Sotiriou, Christos, Piccart-Gebhart, Martine, Symmans, W Fraser, Pusztai, Lajos, de Thé, Hugues, Lehmann-Che, Jacqueline, Andre, Fabrice, Desmedt, Christine, Mazouni, Chafika, Giacchetti, S, Turpin, Elisabeth, Espié, Marc, Plassa, Louis-François, Marty, Michel, Bertheau, Philippe, Sotiriou, Christos, Piccart-Gebhart, Martine, Symmans, W Fraser, Pusztai, Lajos, and de Thé, Hugues

Abstract

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

50. Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials.

Author

Juul, Nicolai, Szallasi, Zoltan, Eklund, Aron C, Li, Qiyuan, Burrell, Rebecca A, Gerlinger, Marco, Valero, Vicente, Andreopoulou, Eleni, Esteva, Francisco J, Symmans, W Fraser, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Pusztai, Lajos, Swanton, Charles, Juul, Nicolai, Szallasi, Zoltan, Eklund, Aron C, Li, Qiyuan, Burrell, Rebecca A, Gerlinger, Marco, Valero, Vicente, Andreopoulou, Eleni, Esteva, Francisco J, Symmans, W Fraser, Desmedt, Christine, Haibe-Kains, Benjamin, Sotiriou, Christos, Pusztai, Lajos, and Swanton, Charles

Abstract

BACKGROUND: Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER)/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple-negative breast cancer. METHODS: We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple-negative breast cancer treated with neoadjuvant chemotherapy; two cohorts treated with paclitaxel (n=27, 30) and four treated without paclitaxel (n=88, 28, 48, 39). FINDINGS: The metagene was associated with pCR in paclitaxel-treated cohorts (AUC 0.79 [95% CI 0.53-0.93], 0.72 [0.48-0.90]) but not in non-paclitaxel treated cohorts (0.53 [0.31-0.77], 0.59 [0.22-0.82], 0.53 [0.36-0.71], 0.64 [0.43-0.81]). In multivariate logistic regression, the metagene was associated with pCR (OR 19.92, 2.62-151.57; p=0.0039) with paclitaxel-containing chemotherapy. INTERPRETATION: The paclitaxel response metagene shows promise as a paclitaxel-specific predictor of pCR in patients with triple-negative breast cancer. The metagene is suitable for development into, JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results