Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Ellen L Goode; Matthew S Block; Kimberly R Kalli; Robert A Vierkant; Wenqian Chen; Zachary C Fogarty; Aleksandra Gentry-Maharaj; Aleksandra Tołoczko; Alexander Hein; Aliecia L Bouligny; Allan Jensen; Ana Osorio; Andreas Hartkopf; Andy Ryan; Anita Chudecka-Głaz; Anthony M Magliocco; Arndt Hartmann; Audrey Y Jung; Bo Gao; Brenda Y Hernandez; Brooke L Fridley; Bryan M McCauley; Catherine J Kennedy; Chen Wang; Chloe Karpinskyj; Christiani B de Sousa; Daniel G Tiezzi; David L Wachter; Esther Herpel; Florin Andrei Taran; Francesmary Modugno; Gregg Nelson; Jan Lubiński; Janusz Menkiszak; Jennifer Alsop; Jenny Lester; Jesús García-Donas; Jill Nation; Jillian Hung; José Palacios; Joseph H Rothstein; Joseph L Kelley; Jurandyr M de Andrade; Luis Robles-Díaz; Maria P Intermaggio; Martin Widschwendter; Matthias W Beckmann; Matthias Ruebner; Estrid Høgdall; Susanne K Kjaer; Ovarian Tumor Tissue Analysis (OTTA) Consortium

doi:10.1001/jamaoncol.2017.3290

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Ellen L Goode, Matthew S Block, Kimberly R Kalli, Robert A Vierkant, Wenqian Chen, Zachary C Fogarty, Aleksandra Gentry-Maharaj, Aleksandra Tołoczko, Alexander Hein, Aliecia L Bouligny, Allan Jensen, Ana Osorio, Andreas Hartkopf, Andy Ryan, Anita Chudecka-Głaz, Anthony M Magliocco, Arndt Hartmann, Audrey Y Jung, Bo Gao, Brenda Y HernandezBrooke L Fridley, Bryan M McCauley, Catherine J Kennedy, Chen Wang, Chloe Karpinskyj, Christiani B de Sousa, Daniel G Tiezzi, David L Wachter, Esther Herpel, Florin Andrei Taran, Francesmary Modugno, Gregg Nelson, Jan Lubiński, Janusz Menkiszak, Jennifer Alsop, Jenny Lester, Jesús García-Donas, Jill Nation, Jillian Hung, José Palacios, Joseph H Rothstein, Joseph L Kelley, Jurandyr M de Andrade, Luis Robles-Díaz, Maria P Intermaggio, Martin Widschwendter, Matthias W Beckmann, Matthias Ruebner, Estrid Høgdall, Susanne K Kjaer, Ovarian Tumor Tissue Analysis (OTTA) Consortium

285 Citationer (Scopus)

Abstract

IMPORTANCE: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.

OBJECTIVE: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.

DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.

EXPOSURES: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.

MAIN OUTCOMES AND MEASURES: Overall survival time.

RESULTS: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.

CONCLUSIONS AND RELEVANCE: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Originalsprog	Engelsk
Tidsskrift	JAMA Oncology
Vol/bind	3
Udgave nummer	12
Sider (fra-til)	e173290
ISSN	2374-2437
DOI	https://doi.org/10.1001/jamaoncol.2017.3290
Status	Udgivet - 1 dec. 2017
Udgivet eksternt	Ja

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10.1001/jamaoncol.2017.3290

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Goode, E. L., Block, M. S., Kalli, K. R., Vierkant, R. A., Chen, W., Fogarty, Z. C., Gentry-Maharaj, A., Tołoczko, A., Hein, A., Bouligny, A. L., Jensen, A., Osorio, A., Hartkopf, A., Ryan, A., Chudecka-Głaz, A., Magliocco, A. M., Hartmann, A., Jung, A. Y., Gao, B., ... Ovarian Tumor Tissue Analysis (OTTA) Consortium (2017). Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer. JAMA Oncology, 3(12), e173290. https://doi.org/10.1001/jamaoncol.2017.3290

Goode, EL, Block, MS, Kalli, KR, Vierkant, RA, Chen, W, Fogarty, ZC, Gentry-Maharaj, A, Tołoczko, A, Hein, A, Bouligny, AL, Jensen, A, Osorio, A, Hartkopf, A, Ryan, A, Chudecka-Głaz, A, Magliocco, AM, Hartmann, A, Jung, AY, Gao, B, Hernandez, BY, Fridley, BL, McCauley, BM, Kennedy, CJ, Wang, C, Karpinskyj, C, de Sousa, CB, Tiezzi, DG, Wachter, DL, Herpel, E, Taran, FA, Modugno, F, Nelson, G, Lubiński, J, Menkiszak, J, Alsop, J, Lester, J, García-Donas, J, Nation, J, Hung, J, Palacios, J, Rothstein, JH, Kelley, JL, de Andrade, JM, Robles-Díaz, L, Intermaggio, MP, Widschwendter, M, Beckmann, MW, Ruebner, M, Høgdall, E , Kjaer, SK & Ovarian Tumor Tissue Analysis (OTTA) Consortium 2017, 'Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer', JAMA Oncology, bind 3, nr. 12, s. e173290. https://doi.org/10.1001/jamaoncol.2017.3290

@article{0cadb33603764a6eb2c872bb3121314a,

title = "Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer",

abstract = "IMPORTANCE: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.OBJECTIVE: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.EXPOSURES: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.MAIN OUTCOMES AND MEASURES: Overall survival time.RESULTS: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.CONCLUSIONS AND RELEVANCE: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.",

keywords = "BRCA2 Protein/genetics, CD8 Antigens/metabolism, Carcinoma, Ovarian Epithelial/drug therapy, Cohort Studies, Cystadenocarcinoma, Serous/genetics, Female, Humans, Lymphocytes, Tumor-Infiltrating/immunology, Middle Aged, Mutation, Neoplasm Grading, Ovarian Neoplasms/genetics, Prospective Studies, Survival Analysis, Treatment Outcome",

author = "Goode, {Ellen L} and Block, {Matthew S} and Kalli, {Kimberly R} and Vierkant, {Robert A} and Wenqian Chen and Fogarty, {Zachary C} and Aleksandra Gentry-Maharaj and Aleksandra To{\l}oczko and Alexander Hein and Bouligny, {Aliecia L} and Allan Jensen and Ana Osorio and Andreas Hartkopf and Andy Ryan and Anita Chudecka-G{\l}az and Magliocco, {Anthony M} and Arndt Hartmann and Jung, {Audrey Y} and Bo Gao and Hernandez, {Brenda Y} and Fridley, {Brooke L} and McCauley, {Bryan M} and Kennedy, {Catherine J} and Chen Wang and Chloe Karpinskyj and {de Sousa}, {Christiani B} and Tiezzi, {Daniel G} and Wachter, {David L} and Esther Herpel and Taran, {Florin Andrei} and Francesmary Modugno and Gregg Nelson and Jan Lubi{\'n}ski and Janusz Menkiszak and Jennifer Alsop and Jenny Lester and Jes{\'u}s Garc{\'i}a-Donas and Jill Nation and Jillian Hung and Jos{\'e} Palacios and Rothstein, {Joseph H} and Kelley, {Joseph L} and {de Andrade}, {Jurandyr M} and Luis Robles-D{\'i}az and Intermaggio, {Maria P} and Martin Widschwendter and Beckmann, {Matthias W} and Matthias Ruebner and Estrid H{\o}gdall and Kjaer, {Susanne K} and {Ovarian Tumor Tissue Analysis (OTTA) Consortium}",

year = "2017",

month = dec,

day = "1",

doi = "10.1001/jamaoncol.2017.3290",

language = "English",

volume = "3",

pages = "e173290",

journal = "JAMA Oncology",

issn = "2374-2437",

publisher = "American Medical Association",

number = "12",

}

TY - JOUR

T1 - Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

AU - Goode, Ellen L

AU - Block, Matthew S

AU - Kalli, Kimberly R

AU - Vierkant, Robert A

AU - Chen, Wenqian

AU - Fogarty, Zachary C

AU - Gentry-Maharaj, Aleksandra

AU - Tołoczko, Aleksandra

AU - Hein, Alexander

AU - Bouligny, Aliecia L

AU - Jensen, Allan

AU - Osorio, Ana

AU - Hartkopf, Andreas

AU - Ryan, Andy

AU - Chudecka-Głaz, Anita

AU - Magliocco, Anthony M

AU - Hartmann, Arndt

AU - Jung, Audrey Y

AU - Gao, Bo

AU - Hernandez, Brenda Y

AU - Fridley, Brooke L

AU - McCauley, Bryan M

AU - Kennedy, Catherine J

AU - Wang, Chen

AU - Karpinskyj, Chloe

AU - de Sousa, Christiani B

AU - Tiezzi, Daniel G

AU - Wachter, David L

AU - Herpel, Esther

AU - Taran, Florin Andrei

AU - Modugno, Francesmary

AU - Nelson, Gregg

AU - Lubiński, Jan

AU - Menkiszak, Janusz

AU - Alsop, Jennifer

AU - Lester, Jenny

AU - García-Donas, Jesús

AU - Nation, Jill

AU - Hung, Jillian

AU - Palacios, José

AU - Rothstein, Joseph H

AU - Kelley, Joseph L

AU - de Andrade, Jurandyr M

AU - Robles-Díaz, Luis

AU - Intermaggio, Maria P

AU - Widschwendter, Martin

AU - Beckmann, Matthias W

AU - Ruebner, Matthias

AU - Høgdall, Estrid

AU - Kjaer, Susanne K

AU - Ovarian Tumor Tissue Analysis (OTTA) Consortium

PY - 2017/12/1

Y1 - 2017/12/1

N2 - IMPORTANCE: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.OBJECTIVE: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.EXPOSURES: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.MAIN OUTCOMES AND MEASURES: Overall survival time.RESULTS: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.CONCLUSIONS AND RELEVANCE: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

AB - IMPORTANCE: Cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.OBJECTIVE: To define the prognostic role of CD8+ TILs in epithelial ovarian cancer.DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.EXPOSURES: Following immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.MAIN OUTCOMES AND MEASURES: Overall survival time.RESULTS: The final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.CONCLUSIONS AND RELEVANCE: This study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

KW - BRCA2 Protein/genetics

KW - CD8 Antigens/metabolism

KW - Carcinoma, Ovarian Epithelial/drug therapy

KW - Cohort Studies

KW - Cystadenocarcinoma, Serous/genetics

KW - Female

KW - Humans

KW - Lymphocytes, Tumor-Infiltrating/immunology

KW - Middle Aged

KW - Mutation

KW - Neoplasm Grading

KW - Ovarian Neoplasms/genetics

KW - Prospective Studies

KW - Survival Analysis

KW - Treatment Outcome

U2 - 10.1001/jamaoncol.2017.3290

DO - 10.1001/jamaoncol.2017.3290

M3 - Journal article

C2 - 29049607

SN - 2374-2437

VL - 3

SP - e173290

JO - JAMA Oncology

JF - JAMA Oncology

IS - 12

ER -

Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

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