Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy

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Abstract

Background

Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO.

Methods

We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient’s histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology.

Results

The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node ( n = 58), liver ( n = 40), lung ( n = 37), bone ( n = 24), and brain ( n = 8). Most patients (80.7%) were RMH good risk. Most patients ( n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17–0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41–1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048).

Conclusions

Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.

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Most cited references 29

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Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.

Y. Fong, J. Fortner, R Sun … (1999)

There is a need for clearly defined and widely applicable clinical criteria for the selection of patients who may benefit from hepatic resection for metastatic colorectal cancer. Such criteria would also be useful for stratification of patients in clinical trials for this disease. Clinical, pathologic, and outcome data for 1001 consecutive patients undergoing liver resection for metastatic colorectal cancer between July 1985 and October 1998 were examined. These resections included 237 trisegmentectomies, 394 lobectomies, and 370 resections encompassing less than a lobe. The surgical mortality rate was 2.8%. The 5-year survival rate was 37%, and the 10-year survival rate was 22%. Seven factors were found to be significant and independent predictors of poor long-term outcome by multivariate analysis: positive margin (p = 0.004), extrahepatic disease (p = 0.003), node-positive primary (p = 0.02), disease-free interval from primary to metastases 1 (p = 0.0004), largest hepatic tumor >5 cm (p = 0.01), and carcinoembryonic antigen level >200 ng/ml (p = 0.01). When the last five of these criteria were used in a preoperative scoring system, assigning one point for each criterion, the total score was highly predictive of outcome (p < 0.0001). No patient with a score of 5 was a long-term survivor. Resection of hepatic colorectal metastases may produce long-term survival and cure. Long-term outcome can be predicted from five criteria that are readily available for all patients considered for resection. Patients with up to two criteria can have a favorable outcome. Patients with three, four, or five criteria should be considered for experimental adjuvant trials. Studies of preoperative staging techniques or of adjuvant therapies should consider using such a score for stratification of patients.

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High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation.

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The immunohistochemical analysis was used to evaluate the expression of PD-L1 in 109 non-small cell lung cancer (NSCLC) tissues and para-tumor tissues. Associations between expressed PD-L1 and tumor histological types, degree of differentiation, and lymph node metastasis were calculated, and overall survival was assessed. Meanwhile, immunohistochemistry and immunofluorescence double labeling technique were performed to detect the expressions of PD-L1, CD1α, and CD83 on TIDC of 20 lung cancer tissues, and the expression of PD-L1 in CD1α+DCs and CD83+DCs and their significances were also explored. We found that the expression rate of PD-L1 in NSCLC was associated with histological types and overall survival. Patients with either adenocarcinoma or survival time after surgery less than 3 years showed higher expression rate of PD-L1. Furthermore, Cox model analysis indicated that PD-L1 might be regarded as a poor prognostic factor. PD-L1 could be also detected in CD1α+ immature DC in NSCLC, indicating that as a class of key anti-tumor immunocyte in tumor microenvironment, DC expressing PD-L1 itself might play an important role in keeping its immature status and contributing to tumor cells immune escape and disease progression.

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Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.

R Thompson, Michael D Gillett, John Cheville … (2004)

Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94-10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.

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Author and article information

Contributors

Mehmet Asim Bilen:

ORCID: http://orcid.org/0000-0003-4003-1103

404-778-3693 , mehmet.a.bilen@emory.edu

Julie M. Shabto: Julie.mara.shabto@emory.edu

Dylan J. Martini: dylan.martini@emory.edu

Yuan Liu: yliu31@emory.edu

Colleen Lewis: colleen.lewis@emoryhealthcare.org

Hannah Collins: hannah.collins@emoryhealthcare.org

Mehmet Akce: mehmet.akce@emory.edu

Haydn Kissick: haydn.kissick@emory.edu

Bradley C. Carthon: bradley.c.carthon@emory.edu

Walid L. Shaib: walid.shaib@emory.edu

Olatunji B. Alese: olatunji.alese@emory.edu

Conor E. Steuer: csteuer@emory.edu

Christina Wu: christina.wu@emoryhealthcare.org

David H. Lawson: dlawson@emory.edu

Ragini Kudchadkar: rkudcha@emory.edu

Viraj A. Master: vmaster@emory.edu

Bassel El-Rayes: bassel.el-rayes@emoryhealthcare.org

Suresh S. Ramalingam: ssramal@emory.edu

Taofeek K. Owonikoko: towonik@emory.edu

R. Donald Harvey: rdharve@emory.edu

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 29 August 2019

Publication date PMC-release: 29 August 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 857

Affiliations

[1 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Hematology and Medical Oncology, , Emory University School of Medicine, ; Atlanta, GA USA

[2 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Hematology and Medical Oncology, , Winship Cancer Institute of Emory University, ; 1365 Clifton Rd, Atlanta, GA USA

[3 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Departments of Biostatistics and Bioinformatics, , Emory University, ; 1518 Clifton Rd, Atlanta, GA USA

[4 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Urology, , Emory University, ; 5673 Peachtree, Dunwoody Rd, Atlanta, GA USA

[5 ]ISNI 0000 0001 0941 6502, GRID grid.189967.8, Department of Pharmacology, , Emory University School of Medicine, ; 1365 Clifton Rd, Atlanta, GA USA

Author information

Mehmet Asim Bilen http://orcid.org/0000-0003-4003-1103

Article

Publisher ID: 6073

DOI: 10.1186/s12885-019-6073-7

PMC ID: 6716879

PubMed ID: 31464611

SO-VID: 1f4b4523-7d10-4cc5-983b-d61ae0830739

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 September 2018

Date accepted : 22 August 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100011621, Winship Cancer Institute;

Award ID: P30CA138292

Award Recipient : Mehmet Asim Bilen

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: immunotherapy,phase 1 clinical trials,sites of metastasis,liver metastasis,clinical outcomes,tumor immunology,tumor microenvironment,immune checkpoint blockade

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: immunotherapy, phase 1 clinical trials, sites of metastasis, liver metastasis, clinical outcomes, tumor immunology, tumor microenvironment, immune checkpoint blockade

Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy

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Cancer Immunotherapy

Most cited references 29

Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.

High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation.

Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target.

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