Prevalence and mutational determinants of high tumor mutation burden in breast cancer

被引:240
作者
Barroso-Sousa, R. [1 ,2 ,6 ]
Jain, E. [2 ,3 ]
Cohen, O. [2 ,3 ]
Kim, D. [2 ,3 ]
Buendia-Buendia, J. [2 ,3 ]
Winer, E. [1 ,4 ,5 ]
Lin, N. [1 ,4 ,5 ]
Tolaney, S. M. [1 ,4 ,5 ]
Wagle, N. [1 ,2 ,3 ,4 ,5 ]
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave,Dana 820A, Boston, MA 02215 USA
[2] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA
[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA
[4] Harvard Med Sch, Boston, MA 02115 USA
[5] Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA
[6] Hosp Sirio Libanes Brasilia, Oncol Ctr, Brasilia, DF, Brazil
关键词
breast cancer; tumor mutational burden; APOBEC; mutational signatures; immunotherapy; mismatch repair deficiency; CTLA-4; BLOCKADE; PD-1; EXPRESSION; LANDSCAPE; EXOME;
D O I
10.1016/j.annonc.2019.11.010
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. Patients and methods: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had >= 10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. Results: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 x 10(-16)). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 x 10(-14)). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pembrolizumab-based therapies derived an objective and durable response to therapy. Conclusion: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.
引用
收藏
页码:387 / 394
页数:8
相关论文
共 30 条
  • [1] Current Landscape of Immunotherapy in Breast Cancer: A Review
    Adams, Sylvia
    Gatti-Mays, Margaret E.
    Kalinsky, Kevin
    Korde, Larissa A.
    Sharon, Elad
    Amiri-Kordestani, Laleh
    Bear, Harry
    McArthur, Heather L.
    Frank, Elizabeth
    Perlmutter, Jane
    Page, David B.
    Vincent, Benjamin
    Hayes, Jennifer F.
    Gulley, James L.
    Litton, Jennifer K.
    Hortobagyi, Gabriel N.
    Chia, Stephen
    Krop, Ian
    White, Julia
    Sparano, Joseph
    Disis, Mary L.
    Mittendorf, Elizabeth A.
    [J]. JAMA ONCOLOGY, 2019, 5 (08) : 1205 - 1214
  • [2] High expression of PD-1 ligands is associated with kataegis mutational signature and APOBEC3 alterations
    Boichard, Amelie
    Tsigelny, Igor F.
    Kurzrock, Razelle
    [J]. ONCOIMMUNOLOGY, 2017, 6 (03):
  • [3] Comprehensive Analysis of Hypermutation in Human Cancer
    Campbell, Brittany B.
    Light, Nicholas
    Fabrizio, David
    Zatzman, Matthew
    Fuligni, Fabio
    de Borja, Richard
    Davidson, Scott
    Edwards, Melissa
    Elvin, Julia A.
    Hodel, Karl P.
    Zahurancik, Walter J.
    Suo, Zucai
    Lipman, Tatiana
    Wimmer, Katharina
    Kratz, Christian P.
    Bowers, Daniel C.
    Laetsch, Theodore W.
    Dunn, Gavin P.
    Johanns, Tanner M.
    Grimmer, Matthew R.
    Smirnov, Ivan V.
    Larouche, Valerie
    Samuel, David
    Bronsema, Annika
    Osborn, Michael
    Stearns, Duncan
    Raman, Pichai
    Cole, Kristina A.
    Storm, Phillip B.
    Yalon, Michal
    Opocher, Enrico
    Mason, Gary
    Thomas, Gregory A.
    Sabel, Magnus
    George, Ben
    Ziegler, David S.
    Lindhorst, Scott
    Issai, Vanan Magimairajan
    Constantini, Shlomi
    Toledano, Helen
    Elhasid, Ronit
    Farah, Roula
    Dvir, Rina
    Dirks, Peter
    Huang, Annie
    Galati, Melissa A.
    Chung, Jiil
    Ramaswamy, Vijay
    Irwin, Meredith S.
    Aronson, Melyssa
    [J]. CELL, 2017, 171 (05) : 1042 - +
  • [4] Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice
    Campesato, Luis Felipe
    Barroso-Sousa, Romualdo
    Jimenez, Leandro
    Correa, Bruna R.
    Sabbaga, Jorge
    Hoff, Paulo M.
    Reis, Luiz F. L.
    Galante, Pedro Alexandre F.
    Camargo, Anamaria A.
    [J]. ONCOTARGET, 2015, 6 (33) : 34221 - 34227
  • [5] Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic
    Chan, T. A.
    Yarchoan, M.
    Jaffee, E.
    Swanton, C.
    Quezada, S. A.
    Stenzinger, A.
    Peters, S.
    [J]. ANNALS OF ONCOLOGY, 2019, 30 (01) : 44 - 56
  • [6] Cohen WL, 2017, CURR PERSP HOLISTIC, P77
  • [7] Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy
    Cristescu, Razvan
    Mogg, Robin
    Ayers, Mark
    Albright, Andrew
    Murphy, Erin
    Yearley, Jennifer
    Sher, Xinwei
    Liu, Xiao Qiao
    Lu, Hongchao
    Nebozhyn, Michael
    Zhang, Chunsheng
    Lunceford, Jared
    Joe, Andrew
    Cheng, Jonathan
    Webber, Andrea L.
    Ibrahim, Nageatte
    Plimack, Elizabeth R.
    Ott, Patrick A.
    Seiwert, Tanguy
    Ribas, Antoni
    McClanahan, Terrill K.
    Tomassini, Joanne E.
    Loboda, Andrey
    Kaufman, David
    [J]. SCIENCE, 2018, 362 (6411) : 197 - +
  • [8] Expression of tumour-specific antigens underlies cancer immunoediting
    DuPage, Michel
    Mazumdar, Claire
    Schmidt, Leah M.
    Cheung, Ann F.
    Jacks, Tyler
    [J]. NATURE, 2012, 482 (7385) : 405 - U1512
  • [9] The impact of tumor profiling approaches and genomic data strategies for cancer precision medicine
    Garofalo, Andrea
    Sholl, Lynette
    Reardon, Brendan
    Taylor-Weiner, Amaro
    Amin-Mansour, Ali
    Miao, Diana
    Liu, David
    Oliver, Nelly
    MacConaill, Laura
    Ducar, Matthew
    Rojas-Rudilla, Vanesa
    Giannakis, Marios
    Ghazani, Arezou
    Gray, Stacy
    Janne, Pasi
    Garber, Judy
    Joffe, Steve
    Lindeman, Neal
    Wagle, Nikhil
    Garraway, Levi A.
    Van Allen, Eliezer M.
    [J]. GENOME MEDICINE, 2016, 8
  • [10] Giannakis M, 2016, CELL REP, V15, P857, DOI 10.1016/j.celrep.2016.03.075