Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

被引:136
作者
Parsons, Heather A. [1 ]
Rhoades, Justin [2 ]
Reed, Sarah C. [2 ]
Gydush, Gregory [2 ]
Ram, Priyanka [1 ]
Exman, Pedro [1 ]
Xiong, Kan [2 ]
Lo, Christopher C. [2 ,3 ]
Li, Tianyu [4 ]
Fleharty, Mark [2 ]
Kirkner, Gregory J. [1 ]
Rotem, Denisse [2 ]
Cohen, Ofir [1 ,2 ]
Yu, Fangyan [5 ,6 ]
Fitarelli-Kiehl, Mariana [5 ,6 ]
Leong, Ka Wai [5 ,6 ]
Hughes, Melissa E. [1 ]
Rosenberg, Shoshana M. [1 ]
Collins, Laura C. [7 ,8 ]
Miller, Kathy D. [9 ]
Blumenstiel, Brendan [2 ]
Trippa, Lorenzo [4 ]
Cibulskis, Carrie [2 ]
Neuberg, Donna S. [4 ]
DeFelice, Matthew [2 ]
Freeman, Samuel S. [2 ]
Lennon, Niall J. [2 ]
Wagle, Nikhil [1 ]
Ha, Gavin [10 ]
Stover, Daniel G. [11 ]
Choudhury, Atish D. [1 ]
Getz, Gad [2 ]
Winer, Eric P. [1 ]
Meyerson, Matthew [1 ,2 ]
Lin, Nancy U. [1 ]
Krop, Ian [1 ]
Love, J. Christopher [2 ,12 ]
Makrigiorgos, G. Mike [2 ]
Partridge, Ann H. [1 ]
Mayer, Erica L. [1 ]
Golub, Todd R. [2 ,13 ,14 ]
Adalsteinsson, Viktor A. [2 ,12 ]
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[2] Broad Inst MIT & Harvard, Cambridge, MA USA
[3] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA
[4] Dana Farber Canc Inst, Div Biostat, Dept Data Sci, Boston, MA 02115 USA
[5] Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA
[6] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA
[7] Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave, Boston, MA 02215 USA
[8] Harvard Med Sch, Boston, MA 02115 USA
[9] Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA
[10] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Serv, 1124 Columbia St, Seattle, WA 98104 USA
[11] Ohio State Univ, Comprehens Canc Ctr, Med Oncol, Columbus, OH 43210 USA
[12] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
[13] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[14] Howard Hughes Med Inst, Chevy Chase, MD USA
关键词
LUNG-CANCER; THERAPY;
D O I
10.1158/1078-0432.CCR-19-3005
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing. Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples. Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% (n = 13/16) in newly diagnosed MBC, 23% (n = 7/30) at postoperative and 19% (n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months). Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
引用
收藏
页码:2556 / 2564
页数:9
相关论文
共 22 条
[1]   Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution [J].
Abbosh, Christopher ;
Birkbak, Nicolai J. ;
Wilson, Gareth A. ;
Jamal-Hanjani, Mariam ;
Constantin, Tudor ;
Salari, Raheleh ;
Le Quesne, John ;
Moore, David A. ;
Veeriah, Selvaraju ;
Rosenthal, Rachel ;
Marafioti, Teresa ;
Kirkizlar, Eser ;
Watkins, Thomas B. K. ;
McGranahan, Nicholas ;
Ward, Sophia ;
Martinson, Luke ;
Riley, Joan ;
Fraioli, Francesco ;
Al Bakir, Maise ;
Gronroos, Eva ;
Zambrana, Francisco ;
Endozo, Raymondo ;
Bi, Wenya Linda ;
Fennessy, Fiona M. ;
Sponer, Nicole ;
Johnson, Diana ;
Laycock, Joanne ;
Shafi, Seema ;
Czyzewska-Khan, Justyna ;
Rowan, Andrew ;
Chambers, Tim ;
Matthews, Nik ;
Turajlic, Samra ;
Hiley, Crispin ;
Lee, Siow Ming ;
Forster, Martin D. ;
Ahmad, Tanya ;
Falzon, Mary ;
Borg, Elaine ;
Lawrence, David ;
Hayward, Martin ;
Kolvekar, Shyam ;
Panagiotopoulos, Nikolaos ;
Janes, Sam M. ;
Thakrar, Ricky ;
Ahmed, Asia ;
Blackhall, Fiona ;
Summers, Yvonne ;
Hafez, Dina ;
Naik, Ashwini .
NATURE, 2017, 545 (7655) :446-+
[2]   Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors [J].
Adalsteinsson, Viktor A. ;
Ha, Gavin ;
Freeman, Samuel S. ;
Choudhury, Atish D. ;
Stover, Daniel G. ;
Parsons, Heather A. ;
Gydush, Gregory ;
Reed, Sarah C. ;
Rotem, Denisse ;
Rhoades, Justin ;
Loginov, Denis ;
Livitz, Dimitri ;
Rosebrock, Daniel ;
Leshchiner, Ignaty ;
Kim, Jaegil ;
Stewart, Chip ;
Rosenberg, Mara ;
Francis, Joshua M. ;
Zhang, Cheng-Zhong ;
Cohen, Ofir ;
Oh, Coyin ;
Ding, Huiming ;
Polak, Paz ;
Lloyd, Max ;
Mahmud, Sairah ;
Helvie, Karla ;
Merrill, Margaret S. ;
Santiago, Rebecca A. ;
O'Connor, Edward P. ;
Jeong, Seong H. ;
Leeson, Rachel ;
Barry, Rachel M. ;
Kramkowski, Joseph F. ;
Zhang, Zhenwei ;
Polacek, Laura ;
Lohr, Jens G. ;
Schleicher, Molly ;
Lipscomb, Emily ;
Saltzman, Andrea ;
Oliver, Nelly M. ;
Marini, Lori ;
Waks, Adrienne G. ;
Harshman, Lauren C. ;
Tolaney, Sara M. ;
Van Allen, Eliezer M. ;
Winer, Eric P. ;
Lin, Nancy U. ;
Nakabayashi, Mari ;
Taplin, Mary-Ellen ;
Johannessen, Cory M. .
NATURE COMMUNICATIONS, 2017, 8
[3]   Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials [J].
Albain, K. ;
Anderson, S. ;
Arriagada, R. ;
Barlow, W. ;
Bergh, J. ;
Bliss, J. ;
Buyse, M. ;
Cameron, D. ;
Carrasco, E. ;
Clarke, M. ;
Correa, C. ;
Coates, A. ;
Collins, R. ;
Costantino, J. ;
Cutter, D. ;
Cuzick, J. ;
Darby, S. ;
Davidson, N. ;
Davies, C. ;
Davies, K. ;
Delmestri, A. ;
Di Leo, A. ;
Dowsett, M. ;
Elphinstone, P. ;
Evans, V. ;
Ewertz, M. ;
Gelber, R. ;
Gettins, L. ;
Geyer, C. ;
Goldhirsch, A. ;
Godwin, J. ;
Gray, R. ;
Gregory, C. ;
Hayes, D. ;
Hill, C. ;
Ingle, J. ;
Jakesz, R. ;
James, S. ;
Kaufmann, M. ;
Kerr, A. ;
MacKinnon, E. ;
McGale, P. ;
McHugh, T. ;
Norton, L. ;
Ohashi, Y. ;
Paik, S. ;
Pan, H. C. ;
Perez, E. ;
Peto, R. ;
Piccart, M. .
LANCET, 2012, 379 (9814) :432-444
[4]   Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update [J].
Burstein, Harold J. ;
Lacchetti, Christina ;
Anderson, Holly ;
Buchholz, Thomas A. ;
Davidson, Nancy E. ;
Gelmon, Karen A. ;
Giordano, Sharon H. ;
Hudis, Clifford A. ;
Solky, Alexander J. ;
Stearns, Vered ;
Winer, Eric P. ;
Griggs, Jennifer J. .
JOURNAL OF CLINICAL ONCOLOGY, 2019, 37 (05) :423-+
[5]   Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling [J].
Chaudhuri, Aadel A. ;
Chabon, Jacob J. ;
Lovejoy, Alexander F. ;
Newman, Aaron M. ;
Stehr, Henning ;
Azad, Tej D. ;
Khodadoust, Michael S. ;
Esfahani, Mohammad Shahrokh ;
Liu, Chih Long ;
Zhou, Li ;
Scherer, Florian ;
Kurtz, David M. ;
Say, Carmen ;
Carter, Justin N. ;
Merriott, David J. ;
Dudley, Jonathan C. ;
Binkley, Michael S. ;
Modlin, Leslie ;
Padda, Sukhmani K. ;
Gensheimer, Michael F. ;
West, Robert B. ;
Shrager, Joseph B. ;
Neal, Joel W. ;
Wakelee, Heather A. ;
Loo, Billy W., Jr. ;
Alizadeh, Ash A. ;
Diehn, Maximilian .
CANCER DISCOVERY, 2017, 7 (12) :1394-1403
[6]   Tumor fraction in cell-free DNA as a biomarker in prostate cancer [J].
Choudhury, Atish D. ;
Werner, Lillian ;
Francini, Edoardo ;
Wei, Xiao X. ;
Ha, Gavin ;
Freeman, Samuel S. ;
Rhoades, Justin ;
Reed, Sarah C. ;
Gydush, Gregory ;
Rotem, Denisse ;
Lo, Christopher ;
Taplin, Mary-Ellen ;
Harshman, Lauren C. ;
Zhang, Zhenwei ;
O'Connor, Edward P. ;
Stover, Daniel G. ;
Parsons, Heather A. ;
Getz, Gad ;
Meyerson, Matthew ;
Love, J. Christopher ;
Hahn, William C. ;
Adalsteinsson, Viktor A. .
JCI INSIGHT, 2018, 3 (21)
[7]   Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma [J].
Christensen, Emil ;
Birkenkamp-Demtroder, Karin ;
Sethi, Himanshu ;
Shchegrova, Svetlana ;
Salari, Raheleh ;
Nordentoft, Iver ;
Wu, Hsin-Ta ;
Knudsen, Michael ;
Lamy, Philippe ;
Lindskrog, Sia Viborg ;
Taber, Ann ;
Balcioglu, Mustafa ;
Vang, Soren ;
Assaf, Zoe ;
Sharma, Shruti ;
Tin, Antony S. ;
Srinivasan, Ramya ;
Hafez, Dina ;
Reinert, Thomas ;
Navarro, Samantha ;
Olson, Alexander ;
Ram, Rosalyn ;
Dashner, Scott ;
Rabinowitz, Matthew ;
Billings, Paul ;
Sigurjonsson, Styrmir ;
Andersen, Claus Lindbjerg ;
Swenerton, Ryan ;
Aleshin, Alexey ;
Zimmermann, Bernhard ;
Agerbaek, Mads ;
Lin, Cheng-Ho Jimmy ;
Jensen, JOrgen Bjerggaard ;
Dyrskjot, Lars .
JOURNAL OF CLINICAL ONCOLOGY, 2019, 37 (18) :1547-1557
[8]   Personalized Detection of Circulating Tumor DNA Antedates Breast Cancer Metastatic Recurrence [J].
Coombes, Raoul Charles ;
Page, Karen ;
Salari, Raheleh ;
Hastings, Robert K. ;
Armstrong, Anne ;
Ahmed, Samreen ;
Ali, Simak ;
Cleator, Susan ;
Kenny, Laura ;
Stebbing, Justin ;
Rutherford, Mark ;
Sethi, Himanshu ;
Boydell, Anna ;
Swenerton, Ryan ;
Fernandez-Garcia, Daniel ;
Gleason, Kelly L. T. ;
Goddard, Katie ;
Guttery, David S. ;
Assaf, Zoe J. ;
Wu, Hsin-Ta ;
Natarajan, Prashanthi ;
Moore, David A. ;
Primrose, Lindsay ;
Dashner, Scott ;
Tin, Antony S. ;
Balcioglu, Mustafa ;
Srinivasan, Ramya ;
Shchegrova, Svetlana V. ;
Olson, Alexander ;
Hafez, Dina ;
Billings, Paul ;
Aleshin, Alexey ;
Rehman, Farah ;
Toghill, Bradley J. ;
Hills, Allison ;
Louie, Maggie C. ;
Lin, Cheng-Ho Jimmy ;
Zimmermann, Bernhard G. ;
Shaw, Jaqueline A. .
CLINICAL CANCER RESEARCH, 2019, 25 (14) :4255-4263
[9]   Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials [J].
Dowsett, M. ;
Forbes, J. F. ;
Bradley, R. ;
Ingle, J. ;
Aihara, T. ;
Bliss, J. ;
Boccardo, F. ;
Coates, A. ;
Coombes, R. C. ;
Cuzick, J. ;
Dubsky, P. ;
Gnant, M. ;
Kaufmann, M. ;
Kilburn, L. ;
Perrone, F. ;
Rea, D. ;
Thuerlimann, B. ;
van de Velde, C. ;
Pan, H. ;
Peto, R. ;
Davies, C. ;
Gray, R. ;
Baum, M. ;
Buzdar, A. ;
Sestak, I. ;
Markopoulos, C. ;
Fesl, C. ;
Jakesz, R. ;
Colleoni, M. ;
Gelber, R. ;
Regan, M. ;
von Minckwitz, G. ;
Snowdon, C. ;
Goss, P. ;
Pritchard, K. ;
Anderson, S. ;
Costantino, J. ;
Mamounas, E. ;
Ohashi, Y. ;
Watanabe, T. ;
Bastiaannet, E. .
LANCET, 2015, 386 (10001) :1341-1352
[10]   Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods [J].
Ferlay, J. ;
Colombet, M. ;
Soerjomataram, I. ;
Mathers, C. ;
Parkin, D. M. ;
Pineros, M. ;
Znaor, A. ;
Bray, F. .
INTERNATIONAL JOURNAL OF CANCER, 2019, 144 (08) :1941-1953