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

Author

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

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

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

Published
2022

6. Predictive Markers of Response to Neoadjuvant Durvalumab with Nab-Paclitaxel and Dose-Dense Doxorubicin/Cyclophosphamide in Basal-Like Triple-Negative Breast Cancer.

Author

Blenman, Kim RM, Marczyk, Michal, Karn, Thomas, Qing, Tao, Li, Xiaotong, Gunasekharan, Vignesh, Yaghoobi, Vesal, Bai, Yalai, Ibrahim, Eiman Y, Park, Tristen, Silber, Andrea, Wolf, Denise M, Reisenbichler, Emily, Denkert, Carsten, Sinn, Bruno V, Rozenblit, Mariya, Foldi, Julia, Rimm, David L, Loibl, Sibylle, and Pusztai, Lajos

Subjects
Genetics, Clinical Research, Cancer, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Albumins, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Breast Neoplasms, Cyclophosphamide, Doxorubicin, Female, Humans, Neoadjuvant Therapy, Paclitaxel, Transforming Growth Factor beta, Triple Negative Breast Neoplasms, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeWe examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC).Experimental designGermline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial.ResultsGene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK-STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial-mesenchymal transition, extracellular matrix, and TGFβ pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/β-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR.ConclusionsThe TGFβ pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.

Published
2022

8. The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group

Author

El Bairi, Khalid, Haynes, Harry R, Blackley, Elizabeth, Fineberg, Susan, Shear, Jeffrey, Turner, Sophia, de Freitas, Juliana Ribeiro, Sur, Daniel, Amendola, Luis Claudio, Gharib, Masoumeh, Kallala, Amine, Arun, Indu, Azmoudeh-Ardalan, Farid, Fujimoto, Luciana, Sua, Luz F, Liu, Shi-Wei, Lien, Huang-Chun, Kirtani, Pawan, Balancin, Marcelo, El Attar, Hicham, Guleria, Prerna, Yang, Wenxian, Shash, Emad, Chen, I-Chun, Bautista, Veronica, Do Prado Moura, Jose Fernando, Rapoport, Bernardo L, Castaneda, Carlos, Spengler, Eunice, Acosta-Haab, Gabriela, Frahm, Isabel, Sanchez, Joselyn, Castillo, Miluska, Bouchmaa, Najat, Md Zin, Reena R, Shui, Ruohong, Onyuma, Timothy, Yang, Wentao, Husain, Zaheed, Willard-Gallo, Karen, Coosemans, An, Perez, Edith A, Provenzano, Elena, Ericsson, Paula Gonzalez, Richardet, Eduardo, Mehrotra, Ravi, Sarancone, Sandra, Ehinger, Anna, Rimm, David L, Bartlett, John MS, Viale, Giuseppe, Denkert, Carsten, Hida, Akira I, Sotiriou, Christos, Loibl, Sibylle, Hewitt, Stephen M, Badve, Sunil, Symmans, William Fraser, Kim, Rim S, Pruneri, Giancarlo, Goel, Shom, Francis, Prudence A, Inurrigarro, Gloria, Yamaguchi, Rin, Garcia-Rivello, Hernan, Horlings, Hugo, Afqir, Said, Salgado, Roberto, Adams, Sylvia, Kok, Marleen, Dieci, Maria Vittoria, Michiels, Stefan, Demaria, Sandra, and Loi, Sherene

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Breast Cancer, Cancer, Clinical Research, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, International Immuno-Oncology Biomarker Working Group, Clinical sciences, Oncology and carcinogenesis, Epidemiology
Abstract

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Published
2021

12. Image analysis-based tumor infiltrating lymphocytes measurement predicts breast cancer pathologic complete response in SWOG S0800 neoadjuvant chemotherapy trial

Author

Fanucci, Kristina A., Bai, Yalai, Pelekanou, Vasiliki, Nahleh, Zeina A., Shafi, Saba, Burela, Sneha, Barlow, William E., Sharma, Priyanka, Thompson, Alastair M., Godwin, Andrew K., Rimm, David L., Hortobagyi, Gabriel N., Liu, Yihan, Wang, Leona, Wei, Wei, Pusztai, Lajos, and Blenman, Kim R. M.

Published
2023
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13. Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

Author

de Miguel, Fernando J., Gentile, Claudia, Feng, William W., Silva, Shannon J., Sankar, Akshay, Exposito, Francisco, Cai, Wesley L., Melnick, Mary Ann, Robles-Oteiza, Camila, Hinkley, Madeline M., Tsai, Jeanelle A., Hartley, Antja-Voy, Wei, Jin, Wurtz, Anna, Li, Fangyong, Toki, Maria I., Rimm, David L., Homer, Robert, Wilen, Craig B., Xiao, Andrew Z., Qi, Jun, Yan, Qin, Nguyen, Don X., Jänne, Pasi A., Kadoch, Cigall, and Politi, Katerina A.

Published
2023
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14. Deep learning-based scoring of tumour-infiltrating lymphocytes is prognostic in primary melanoma and predictive to PD-1 checkpoint inhibition in melanoma metastases

Author

Chatziioannou, Eftychia, Roßner, Jana, Aung, Thazin New, Rimm, David L., Niessner, Heike, Keim, Ulrike, Serna-Higuita, Lina Maria, Bonzheim, Irina, Kuhn Cuellar, Luis, Westphal, Dana, Steininger, Julian, Meier, Friedegund, Pop, Oltin Tiberiu, Forchhammer, Stephan, Flatz, Lukas, Eigentler, Thomas, Garbe, Claus, Röcken, Martin, Amaral, Teresa, and Sinnberg, Tobias

Published
2023
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17. Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer

Author

Fernandez, Aileen I., Robbins, Charles J., Gaule, Patricia, Agostini-Vulaj, Diana, Anders, Robert A., Bellizzi, Andrew M., Chen, Wei, Chen, Zongming Eric, Gopal, Purva, Zhao, Lei, Lisovsky, Mikhail, Liu, Xiuli, Shia, Jinru, Wang, Huamin, Yang, Zhaohai, McCann, Leena, Chan, Yvonne G., Weidler, Jodi, Bates, Michael, Zhang, Xuchen, and Rimm, David L.

Published
2023
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18. Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry

Author

Robbins, Charles J., Fernandez, Aileen I., Han, Gang, Wong, Serena, Harigopal, Malini, Podoll, Mirna, Singh, Kamaljeet, Ly, Amy, Kuba, M. Gabriela, Wen, Hannah, Sanders, Mary Ann, Brock, Jane, Wei, Shi, Fadare, Oluwole, Hanley, Krisztina, Jorns, Julie, Snir, Olivia L., Yoon, Esther, Rabe, Kim, Soong, T. Rinda, Reisenbichler, Emily S., and Rimm, David L.

Published
2023
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21. Development of an immunohistochemical assay for Siglec-15

Author

Shafi, Saba, Aung, Thazin Nwe, Robbins, Charles, Zugazagoitia, Jon, Vathiotis, Ioannis, Gavrielatou, Niki, Yaghoobi, Vesal, Fernandez, Aileen, Niu, Shuqiong, Liu, Linda N., Cusumano, Zachary T., Leelatian, Nalin, Cole, Kimberley, Wang, He, Homer, Robert, Herbst, Roy S., Langermann, Sol, and Rimm, David L.

Published
2022
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22. Programmed Death-Ligand 1 and Programmed Death-Ligand 2 mRNAs Measured Using Closed-System Quantitative Real-Time Polymerase Chain Reaction Are Associated With Outcome and High Negative Predictive Value in Immunotherapy-Treated NSCLC

Author

Fernandez, Aileen I., Gavrielatou, Niki, McCann, Leena, Shafi, Saba, Moutafi, Myrto K., Martinez-Morilla, Sandra, Vathiotis, Ioannis A., Aung, Thazin Nwe, Yaghoobi, Vesal, Bai, Yalai, Chan, Yvonne G., Weidler, Jodi, Herbst, Roy, Bates, Michael, and Rimm, David L.

Published
2022
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23. Objective assessment of tumor infiltrating lymphocytes as a prognostic marker in melanoma using machine learning algorithms

Author

Aung, Thazin Nwe, Shafi, Saba, Wilmott, James S., Nourmohammadi, Saeed, Vathiotis, Ioannis, Gavrielatou, Niki, Fernandez, Aileen, Yaghoobi, Vesal, Sinnberg, Tobias, Amaral, Teresa, Ikenberg, Kristian, Khosrotehrani, Kiarash, Osman, Iman, Acs, Balazs, Bai, Yalai, Martinez-Morilla, Sandra, Moutafi, Myrto, Thompson, John F., Scolyer, Richard A., and Rimm, David L.

Published
2022
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25. Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.

Author

Johnson, Douglas B, Bordeaux, Jennifer, Kim, Ju Young, Vaupel, Christine, Rimm, David L, Ho, Thai H, Joseph, Richard W, Daud, Adil I, Conry, Robert M, Gaughan, Elizabeth M, Hernandez-Aya, Leonel F, Dimou, Anastasios, Funchain, Pauline, Smithy, James, Witte, John S, McKee, Svetlana B, Ko, Jennifer, Wrangle, John M, Dabbas, Bashar, Tangri, Shabnam, Lameh, Jelveh, Hall, Jeffrey, Markowitz, Joseph, Balko, Justin M, and Dakappagari, Naveen

Subjects
Cell Line, Tumor, Humans, Melanoma, Neoplasm Metastasis, HLA-DR Antigens, Biopsy, Neoplasm Staging, Prognosis, Treatment Outcome, Retreatment, Immunohistochemistry, Protein Binding, Models, Biological, Adult, Aged, Middle Aged, Female, Male, Indoleamine-Pyrrole 2, 3, -Dioxygenase, Programmed Cell Death 1 Receptor, Biomarkers, Tumor, Antineoplastic Agents, Immunological, B7-H1 Antigen, Cancer, Prevention, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.

Published
2018

28. Author Correction: Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer

Author

Foldi, Julia, Silber, Andrea, Reisenbichler, Emily, Singh, Kamaljeet, Fischbach, Neal, Persico, Justin, Adelson, Kerin, Katoch, Anamika, Horowitz, Nina, Lannin, Donald, Chagpar, Anees, Park, Tristen, Marczyk, Michal, Frederick, Courtney, Burrello, Trisha, Ibrahim, Eiman, Qing, Tao, Bai, Yalai, Blenman, Kim, Rimm, David L., and Pusztai, Lajos

Published
2022
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36. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer

Author

Reisenbichler, Emily S., Han, Gang, Bellizzi, Andrew, Bossuyt, Veerle, Brock, Jane, Cole, Kimberly, Fadare, Oluwole, Hameed, Omar, Hanley, Krisztina, Harrison, Beth T., Kuba, M. Gabriela, Ly, Amy, Miller, Dylan, Podoll, Mirna, Roden, Anja C., Singh, Kamaljeet, Sanders, Mary Ann, Wei, Shi, Wen, Hannah, Pelekanou, Vasiliki, Yaghoobi, Vesal, Ahmed, Fahad, Pusztai, Lajos, and Rimm, David L.

Published
2020
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37. SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer.

Author

Garrido-Castro, Ana Christina, primary, Kim, Se Eun, additional, Desrosiers, Jennifer, additional, Nanda, Rita, additional, Carey, Lisa A., additional, Clark, Amy Sanders, additional, Sacks, Ruth Lauren, additional, O'Connor, Thomas Patrick, additional, Sinclair, Natalie Faye, additional, Lo, K.M. Steve, additional, Thomas, Amy, additional, Wrabel, Eileen, additional, O'Meara, Tess, additional, Lin, Nancy U., additional, Burstein, Harold J., additional, He, Mengni, additional, Rimm, David L., additional, Mittendorf, Elizabeth A., additional, Tayob, Nabihah, additional, and Tolaney, Sara M., additional

Published
2024
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39. High-throughput transcriptome profiling indicates ribosomal RNAs to be associated with resistance to immunotherapy in non-small cell lung cancer (NSCLC)

Author

Moutafi, Myrto K, primary, Bates, Katherine M, additional, Aung, Thazin Nwe, additional, Milian, Rolando Garcia, additional, Xirou, Vasiliki, additional, Vathiotis, Ioannis A, additional, Gavrielatou, Niki, additional, Angelakis, Athanasios, additional, Schalper, Kurt A, additional, Salichos, Leonidas, additional, and Rimm, David L, additional

Published
2024
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41. “Interchangeability” of PD-L1 immunohistochemistry assays: a meta-analysis of diagnostic accuracy

Author

Torlakovic, Emina, Lim, Hyun J., Adam, Julien, Barnes, Penny, Bigras, Gilbert, Chan, Anthony W.H., Cheung, Carol C., Chung, Jin-Haeng, Couture, Christian, Fiset, Pierre O., Fujimoto, Daichi, Han, Gang, Hirsch, Fred R., Ilie, Marius, Ionescu, Diana, Li, Chao, Munari, Enrico, Okuda, Katsuhiro, Ratcliffe, Marianne J., Rimm, David L., Ross, Catherine, Røge, Rasmus, Scheel, Andreas H., Soo, Ross A., Swanson, Paul E., Tretiakova, Maria, To, Ka F., Vainer, Gilad W., Wang, Hangjun, Xu, Zhaolin, Zielinski, Dirk, and Tsao, Ming-Sound

Published
2020
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42. Quantitative assessment of PD-L1 as an analyte in immunohistochemistry diagnostic assays using a standardized cell line tissue microarray

Author

Martinez-Morilla, Sandra, McGuire, John, Gaule, Patricia, Moore, Lauren, Acs, Balazs, Cougot, Delphine, Gown, Allen M., Yaziji, Hadi, Wang, Wei-Lien, Cartun, Richard W., Hornick, Jason L., Sholl, Lynette M., Qiu, Jingxin, Mino-Kenudson, Mari, Yi, Eunhee S., Beasley, Mary Beth, Merrick, Daniel T., Ambaye, Abiy B., Zhang, Zhong J., Walker, Jill, and Rimm, David L.

Published
2020
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43. Estrogen and Progesterone Receptor Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Guideline Update

Author

Allison, Kimberly H., Hammond, M. Elizabeth H., Dowsett, Mitchell, McKernin, Shannon E., Carey, Lisa A., Fitzgibbons, Patrick L., Hayes, Daniel F., Lakhani, Sunil R., Chavez-MacGregor, Mariana, Perlmutter, Jane, Perou, Charles M., Regan, Meredith M., Rimm, David L., Symmans, W. Fraser, Torlakovic, Emina E., Varella, Leticia, Viale, Giuseppe, Weisberg, Tracey F., McShane, Lisa M., and Wolff, Antonio C.

Subjects
Merck & Company Inc., Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca PLC, College of American Pathologists, Diseases, Care and treatment, Ductal carcinoma in situ -- Care and treatment, Cancer prevention, Medical societies, Immunohistochemistry, Medical research, Estrogens, Progesterone, Pharmaceutical industry, Phenols (Class of compounds), Breast cancer, Carcinoma, Tumors, Sex hormones, Setting (Literature), Professional associations
Abstract

INTRODUCTION First released in 2010, the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) estrogen receptor (ER) and progesterone receptor (PgR) testing guideline is aimed at improving the [...], * Purpose.--To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen receptor (ER) and progesterone receptor (PgR) testing in breast cancer guideline. Methods.--A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. Recommendations.--The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco.org/breast-cancer-guidelines. (Arch Pathol Lab Med. 2020;144:545-563; doi: 10.5858/arpa.2019-0904-SA)

Published
2020
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45. Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology

Author

Bernards, Rene, Bogaerts, Jan, Canetta, Renzo, Sullivan, Richard, Tejpar, Sabine, Lukinova, Nina, Lyerly, Herbert K., Moore, Helen, Smith, Malcolm A., Yee, Laura, DuBois, Ray, Hahn, William C., Janne, Pasi, Solit, David B., Willman, Cheryl L., Rimm, David, Bateman-House, Alison, Makady, Amr, Bergmann, Lothar, Nagai, Sumimasa, Thomas, Marlene, Cree, Ian A., Hegde, Priti, Hopper, Shirley, Smith, Chris, Robson, Marc, Savage, Mary, Voest, Emile, Sweeney, Christopher, Ingelman-Sundberg, Magnus, Nichols, Gwen, Maignen, Francois, Besse, Benjamin, Swierzewski, Rafal, Lambin, Philippe, Kiermaier, Astrid, Lacombe, Denis, Lively, Tracy, Massard, Christophe, Caliguri, Michael, Velculescu, Victor, Foggi, Paolo, Hahn, Willem C., Salgado, Roberto, Golfinopoulos, Vassilis, Rimm, David L., Lyerly, Kim, Span, Paul N., Bergmann, L., Robson, Mark, Harris, Lyndsay, and Massard, Chistophe

Published
2019
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46. Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies

Author

Jeon, Young Joo, Khelifa, Sihem, Ratnikov, Boris, Scott, David A, Feng, Yongmei, Parisi, Fabio, Ruller, Chelsea, Lau, Eric, Kim, Hyungsoo, Brill, Laurence M, Jiang, Tingting, Rimm, David L, Cardiff, Robert D, Mills, Gordon B, Smith, Jeffrey W, Osterman, Andrei L, Kluger, Yuval, and Ronai, Ze’ev A

Subjects
Cancer, Breast Cancer, Amino Acid Transport System A, Amino Acid Transport System ASC, Animals, Antineoplastic Agents, Apoptosis, Autophagy, Breast Neoplasms, Citric Acid Cycle, DNA-Binding Proteins, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Humans, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Minor Histocompatibility Antigens, Paclitaxel, Proteolysis, Signal Transduction, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases, Ubiquitination, Neurosciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

Published
2015

47. Proceedings From the ASCO/College of American Pathologists Immune Checkpoint Inhibitor Predictive Biomarker Summit

Author

Hayes, Daniel F., Herbst, Roy S., Myles, Jonathan L., Topalian, Suzanne L., Yohe, Sophia L., Aronson, Naomi, Bellizzi, Andrew M., Basu Roy, Upal, Bradshaw, Georganne, Edwards, Robin H., El-Gabry, Ehab A., Elvin, Julia, Gajewski, Thomas F., McShane, Lisa M., Oberley, Matthew, Philip, Reena, Rimm, David L., Rosenbaum, Jason N., Rubin, Eric H., Schlager, Lisa, Sherwood, Shimere W., Stewart, Mark, Taube, Janis M., Thurin, Magdalena, Vasalos, Patricia, and Laser, Jordan

Published
2022
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48. Interplay between copy number alterations and immune profiles in the early breast cancer Scandinavian Breast Group 2004-1 randomized phase II trial: results from a feasibility study

Author

Zerdes, Ioannis, Simonetti, Michele, Matikas, Alexios, Harbers, Luuk, Acs, Balazs, Boyaci, Ceren, Zhang, Ning, Salgkamis, Dimitrios, Agartz, Susanne, Moreno-Ruiz, Pablo, Bai, Yalai, Rimm, David L., Hartman, Johan, Mezheyeuski, Artur, Bergh, Jonas, Crosetto, Nicola, and Foukakis, Theodoros

Published
2021
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