Dissecting the clinicopathologic, genomic, and immunophenotypic correlates of KRASG12D-mutated non-small-cell lung cancer

被引：59

作者：

Ricciuti, B. ^{[1
]}

Alessi, J., V ^{[1
]}

Elkrief, A. ^{[2
]}

Wang, X. ^{[3
]}

Cortellini, A. ^{[4
]}

Li, Y. Y. ^{[5
,6
]}

Vaz, V. R. ^{[1
]}

Gupta, H. ^{[5
]}

Pecci, F. ^{[1
]}

Barrichello, A. ^{[1
]}

Lamberti, G. ^{[1
]}

Nguyen, T. ^{[1
]}

Lindsay, J. ^{[7
]}

Sharma, B. ^{[8
]}

Felt, K.

Rodig, S. J. ^{[8
,9
]}

Nishino, M. ^{[1
,10
]}

Sholl, L. M. ^{[9
]}

Barbie, D. A. ^{[1
]}

V. Negrao, M. ^{[11
]}

Zhang, J. ^{[11
]}

Cherniack, A. D. ^{[5
]}

V. Heymach, J. ^{[11
]}

Meyerson, M.

Ambrogio, C. ^{[12
]}

Jaenne, P. A. ^{[1
]}

Arbour, K. C. ^{[2
]}

Pinato, D. J.

Skoulidis, F. ^{[11
]}

Schoenfeld, A. J. ^{[2
,12
]}

Awadt, M. M. ^{[1
]}

Luo, J. ^{[1
,13
]}

机构：

[1] Lowe Ctr Thorac Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, Thorac Oncol Serv, New York, NY USA

[3] Harvard Sch Publ Hlth, Boston, MA USA

[4] Hammersmith Hosp, Imperial Coll London, Dept Surg & Canc, Div Canc, London, England

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA

[6] Broad Inst Harvard, Massachusetts Inst Technol MIT, Canc Program, Cambridge, England

[7] Dana Farber Canc Inst, Knowledge Syst Grp, Boston, MA USA

[8] Brigham & Women s Hosp, Dana Farber Canc Inst, ImmunoProfi, Boston, MA USA

[9] Brigham & Womens Hosp, Dept Pathol, Boston, MA USA

[10] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiol, Dept Imaging, Boston, MA USA

[11] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX USA

[12] Univ Turin, Mol Biotechnol & Hlth Sci, Turin, Italy

[13] Harvard Med Sch, 450 Brookline Ave LC4116, Boston, MA 02215 USA

来源：

ANNALS OF ONCOLOGY | 2022年 / 33卷 / 10期

关键词：

KRAS; G12D; PD-(L)1 blockade; NSCLC; KRAS MUTATIONS; K-RAS; ADENOCARCINOMA; SUPPRESSION; PROGRESSION; SMOKING; ASSAY;

D O I：

10.1016/j.annonc.2022.07.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRASMUT) non -small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRAS(G12C) NSCLC, KRAS(G12D) NSCLC is associated with low/never-smoking status and is largely uncharacterized. Patients and methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition +/- chemotherapy were analyzed according to KRAS mutation subtype.Results: Of 2327 patients with KRAS-mutated (KRAS(MUT)) NSCLC, 15% (n = 354) harbored KRAS(G12D). Compared to KRASnon-G12D NSCLC, KRAS(G12D) NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRAS(G12D) had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRASnon-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRAS(G12D) had lower intratumoral and total CD8+PD1+ T cells (P < 0.05). Among 850 patients with advanced KRASMUT NSCLC who received PD-(L)1-based therapies, KRAS(G12D) was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRASnon-G12D.Conclusions: KRAS(G12D )lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRASG12D lung cancers will have to take these differences into account.

引用

页码：1029 / 1040

页数：12

共 26 条

[1] Mutational signatures associated with tobacco smoking in human cancer [J].

Alexandrov, Ludmil B. ;

Ju, Young Seok ;

Haase, Kerstin ;

Van Loo, Peter ;

Martincorena, Inigo ;

Nik-Zainal, Serena ;

Totoki, Yasushi ;

Fujimoto, Akihiro ;

Nakagawa, Hidewaki ;

Shibata, Tatsuhiro ;

Campbell, Peter J. ;

Vineis, Paolo ;

Phillips, David H. ;

Stratton, Michael R. .

SCIENCE, 2016, 354 (6312) :618-622

[2] Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer [J].

Arbour, Kathryn C. ;

Jordan, Emmett ;

Kim, Hyunjae Ryan ;

Dienstag, Jordan ;

Yu, Helena A. ;

Sanchez-Vega, Francisco ;

Lito, Piro ;

Berger, Michael ;

Solit, David B. ;

Hellmann, Matthew ;

Kris, Mark G. ;

Rudin, Charles M. ;

Ni, Ai ;

Arcila, Maria ;

Ladanyi, Marc ;

Riely, Gregory J. .

CLINICAL CANCER RESEARCH, 2018, 24 (02) :334-340

[3] Quantitative Immunofluorescence Reveals the Signature of Active B-cell Receptor Signaling in Diffuse Large B-cell Lymphoma [J].

Bogusz, Agata M. ;

Baxter, Richard H. G. ;

Currie, Treeve ;

Sinha, Papiya ;

Sohani, Aliyah R. ;

Kutok, Jeffery L. ;

Rodig, Scott J. .

CLINICAL CANCER RESEARCH, 2012, 18 (22) :6122-6135

[4] Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) A Hybridization Capture-Based Next-Generation Sequencing Clinical Assay for Solid Tumor Molecular Oncology [J].

Cheng, Donavan T. ;

Mitchell, Talia N. ;

Zehir, Ahmet ;

Shah, Ronak H. ;

Benayed, Ryma ;

Syed, Aijazuddin ;

Chandramohan, Raghu ;

Liu, Zhen Yu ;

Won, Helen H. ;

Scott, Sasinya N. ;

Brannon, A. Rose ;

O'Reilly, Catherine ;

Sadowska, Justyna ;

Casanova, Jacklyn ;

Yannes, Angela ;

Hechtman, Jaclyn F. ;

Yao, Jinjuan ;

Song, Wei ;

Ross, Dara S. ;

Oultache, Alifya ;

Dogan, Snjezana ;

Borsu, Laetitia ;

Hameed, Meera ;

Nafa, Khedoudja ;

Arcila, Maria E. ;

Ladanyi, Marc ;

Berger, Michael F. .

JOURNAL OF MOLECULAR DIAGNOSTICS, 2015, 17 (03) :251-264

[5] Comprehensive molecular profiling of lung adenocarcinoma [J].

Collisson, Eric A. ;

Campbell, Joshua D. ;

Brooks, Angela N. ;

Berger, Alice H. ;

Lee, William ;

Chmielecki, Juliann ;

Beer, David G. ;

Cope, Leslie ;

Creighton, Chad J. ;

Danilova, Ludmila ;

Ding, Li ;

Getz, Gad ;

Hammerman, Peter S. ;

Hayes, D. Neil ;

Hernandez, Bryan ;

Herman, James G. ;

Heymach, John V. ;

Jurisica, Igor ;

Kucherlapati, Raju ;

Kwiatkowski, David ;

Ladanyi, Marc ;

Robertson, Gordon ;

Schultz, Nikolaus ;

Shen, Ronglai ;

Sinha, Rileen ;

Sougnez, Carrie ;

Tsao, Ming-Sound ;

Travis, William D. ;

Weinstein, John N. ;

Wigle, Dennis A. ;

Wilkerson, Matthew D. ;

Chu, Andy ;

Cherniack, Andrew D. ;

Hadjipanayis, Angela ;

Rosenberg, Mara ;

Weisenberger, Daniel J. ;

Laird, Peter W. ;

Radenbaugh, Amie ;

Ma, Singer ;

Stuart, Joshua M. ;

Byers, Lauren Averett ;

Baylin, Stephen B. ;

Govindan, Ramaswamy ;

Meyerson, Matthew ;

Rosenberg, Mara ;

Gabriel, Stacey B. ;

Cibulskis, Kristian ;

Sougnez, Carrie ;

Kim, Jaegil ;

Stewart, Chip .

NATURE, 2014, 511 (7511) :543-550

[6] The origins and genetic interactions of KRAS mutations are allele- and tissue-specific [J].

Cook, Joshua H. ;

Melloni, Giorgio E. M. ;

Gulhan, Doga C. ;

Park, Peter J. ;

Haigis, Kevin M. .

NATURE COMMUNICATIONS, 2021, 12 (01)

[7] Molecular Epidemiology of EGFR and KRAS Mutations in 3,026 Lung Adenocarcinomas: Higher Susceptibility of Women to Smoking-Related KRAS-Mutant Cancers [J].

Dogan, Snjezana ;

Shen, Ronglai ;

Ang, Daphne C. ;

Johnson, Melissa L. ;

D'Angelo, Sandra P. ;

Paik, Paul K. ;

Brzostowski, Edyta B. ;

Riely, Gregory J. ;

Kris, Mark G. ;

Zakowski, Maureen F. ;

Ladanyi, Marc .

CLINICAL CANCER RESEARCH, 2012, 18 (22) :6169-6177

[8] New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [J].

Eisenhauer, E. A. ;

Therasse, P. ;

Bogaerts, J. ;

Schwartz, L. H. ;

Sargent, D. ;

Ford, R. ;

Dancey, J. ;

Arbuck, S. ;

Gwyther, S. ;

Mooney, M. ;

Rubinstein, L. ;

Shankar, L. ;

Dodd, L. ;

Kaplan, R. ;

Lacombe, D. ;

Verweij, J. .

EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) :228-247

[9] Characteristics and Outcomes of Patients With Metastatic KRAS-Mutant Lung Adenocarcinomas: The Lung Cancer Mutation Consortium Experience [J].

El Osta, Badi ;

Behera, Madhusmita ;

Kim, Sungjin ;

Berry, Lynne D. ;

Sica, Gabriel ;

Pillai, Rathi N. ;

Owonikoko, Taofeek K. ;

Kris, Mark G. ;

Johnson, Bruce E. ;

Kwiatkowski, David J. ;

Sholl, Lynette M. ;

Aisner, Dara L. ;

Bunn, Paul A. ;

Khuri, Fadlo R. ;

Ramalingam, Suresh S. .

JOURNAL OF THORACIC ONCOLOGY, 2019, 14 (05) :876-889

[10] KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma [J].

Gao, Ge ;

Liao, Weiting ;

Ma, Qizhi ;

Zhang, Benxia ;

Chen, Yue ;

Wang, Yongsheng .

LUNG CANCER, 2020, 149 :41-45

← 1 2 3 →