Table 1.
Correlation between GDF-15 serum and/or tumor levels with clinical outcome in different cancer types.
| Indication | Patient cohort | Patient numbers | GDF-15 plasma/ serum assay | Assay matrix | Plasma/Serum threshold | GDF-15 expression tumor (IHC or RNA) | Correlation with clinical outcome and disease markers | References |
|---|---|---|---|---|---|---|---|---|
| Breast cancer (BC) | Gustave Roussy Cancer Center, Villejuif, France | 605 BC patients | Not applicable | Not applicable | Not determined | GDF-15 IHC of 605 BC patients | Tumor GDF-15 expression correlates with ER-negative and HER2-positive status in patients with breast cancer | (109) |
| Colorectal cancer (CRC) | Nurses' Health Study (NHS), Health Professionals Follow-up Study (HPFS), USA | 616 CRC patients from 2 independent patient cohorts | GDF-15 ELISA (R&D Systems) | Plasma | 1,060 pg/mL | Not applicable | Plasma GDF-15 above threshold correlates with shorter OS | (87) |
| Zhejiang University Sir Run Run Shaw Hospital, China | 138 CRC patients | GDF-15 ELISA (not defined) | Serum | 1,150 pg/mL | Not applicable | Serum GDF-15 above threshold correlates with shorter OS | (110) | |
| Charles University and General University Hospital, Czech Republic | 97 metastatic CRC patients | GDF-15 ELISA (Biovendor-Laboratorni medicina) | Serum | 7,000 pg/mL | Not applicable | Serum levels of GDF-15 were significantly higher in patients with colorectal cancer compared to healthy controls. GDF-15 correlates with shorter OS. | (111) | |
| Nurses' Health Study (NHS), USA | 757 CRC patients | GDF-15 ELISA (R&D Systems) | Plasma | Not determined | Not applicable | Elevated levels of plasma GDF-15 were associated with higher risk of advanced colorectal cancer | (112) | |
| The Johns Hopkins Hospital, USA St. Vincent's Hospital, Australia | 525 CRC patients from 2 independent patient cohorts | GDF-15 ELISA (in-house) | Serum | 1,150 pg/mL | Not applicable | Serum levels of GDF-15 were significantly higher in patients with colorectal cancer compared to healthy controls. Serum GDF-15 above threshold correlates with disease progression and shorter OS | (113) | |
| Vasteras Hospital, Sweden | 320 CRC patients | GDF-15 SP-PLA | Plasma (60 patients) | 1,150 pg/mL | GDF-15 IHC of 274 CRC patients | Moderate or high tumor GDF-15 intensity correlates an increased risk of recurrence and with shorter OS | (114) | |
| Chinese Academy of Medical Sciences (CICAMS), | 473 CRC patients | GDF-15 ELISA (in-house) | Serum | 1,000 pg/mL | Not applicable | Serum GDF-15 is significantly higher in patients with stage IV CRC compared to stage I-III and healthy individuals. Patients with liver metastasis have elevated serum levels of GDF-15. Disease recurrence is associated with increase of serum GDF-15 levels. Patients with higher serum GDF-15 had a trend to poorer tumor-specific survival | (79) | |
| Endometrial Cancer | Oslo University Hospital & Haukeland University Hospital, Norway | 510 endometrial cancer patients | Immunoradiometric sandwich assay using a polyclonal, affinity chromatography– purified goat anti-human GDF-15 IgG antibody (R&D Systems) | Plasma | Upper tertile of GDF-15 level (median = 1,077 pg(mL) | Not applicable | High plasma GDF-15 is associated with metastatic disease. GDF-15 above threshold correlates with shorter PFS and OS | (104) |
| Haukeland University Hospital, Norway | 235 endometrial cancer patients | GDF-15 ELISA (R&D Systems) | Plasma | Upper tertile of GDF-15 level (median = 1,780 pg/mL (range 518–9,475 pg/mL) | Not applicable | High plasma level GDF-15 independently predicts recurrent disease and lymph node metastases. GDF-15 above threshold correlates with shorter PFS and OS | (115) | |
| Esophageal cancer | Chinese Academy of Medical Sciences (CICAMS), China | 286 ESCC patients | GDF-15 ELISA (in-house) | Serum | 1,000 pg/mL | GDF-15 IHC of 40 Patients | Serum GDF15 decreased after surgical removal and increased at relapse. GDF-15 above threshold correlates with shorter relapse-free survival and tumor-specific survival | (105) |
| Gastric cancer | Dankook University College of Medicine, Korea | 80 gastric cancer patients | GDF-15 ELISA (R&D Systems) | Serum (80 patients) | Not determined | 41 patients | Serum GDF-15 and tumor GDF-15 (protein and mRNA) expression is higher in patients with gastric cancer. Tumor GDF15 correlates with differentiation stage | (89) |
| Gastric cancer | Peking University Cancer Hospital, China | 384 gastric cancer patients | GDF-15 ELISA (in-house) | Serum (217 patients) | 1,120 pg/mL | Not applicable | Serum GDF-15 levels above threshold before chemotherapy and increased GDF-15 levels during chemotherapy correlate with shorter OS | (116) |
| La Coruña Biomedical Research Institute (INIBIC), Spain | 52 gastric cancer patients | GDF-15 ELISA (R&D Systems) | Serum | 493 pg/mL | Not applicable | Serum GDF-15 above threshold correlates with shorter PFS and OS | (90) | |
| Glioblastoma | Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland | 33 patients with glioblastoma | GDF-15 ELISA (in-house) | Plasma Cerebrospinal fluid (CSF) | 156 pg/mL | Not applicable | GDF-15 (CSF) above threshold correlates with shorter OS | (106) |
| TCGA database (http://cancergenome.nih.gov), | 540 glioblastoma patients (TCGA) | Not applicable | Not applicable | Not determined | GDF-15 tumor mRNA expression obtained from TCGA | Low GDF-15 tumor mRNA expression correlate with better outcome in glioblastoma | (107) | |
| Head and neck cancer (HNSCC) | Johannes Gutenberg-University Mainz, Germany | 64 OSCC patients | GDF-15 ELISA (R&D Systems) | Serum | 875 pg/ml | Not applicable | Serum GDF-15 above threshold correlates with shorter OS and tumor load | (98) |
| Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China | 256 stage III and IV OSCC patients | Not applicable | Not applicable | Not determined | GDF-15 IHC of 256 patients | Elevated tumor tissue expression of GDF-15 correlates with shorter PFS and OS. Docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy is beneficial for patients with elevated tumor GDF-15 expression | ||
| Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, China | 60 OSCC patients | GDF-15 ELISA (R&D Systems) | Serum | 364 pg/mL | Not applicable | GDF-15 above threshold did not significantly correlate with shorter OS | (117) | |
| Melanoma | University Hospital Tubingen, Germany | 761 stage III/IV melanoma patients | GDF-15 ELISA (R&D Systems) | Serum | 1,500 pg/mL | Not applicable | Elevated GDF-15 correlates with shorter OAS | (94) |
| Melanoma | Oslo University Hospital The Norwegian Radium Hospital, Norway | 69 patients with unresectable or metastatic malignant melanoma were treated with ipilimumab (Phase IV study (NCT0268196/EudraCT2013-002408-15) | GDF-15 ELISA (R&D Systems) | Serum (56 patients) | 517 pg/mL | Not applicable | In univariable analysis baseline GDF-15 above threshold correlated with shorter survival. The association between survival and GDF-15 was markedly attenuated by multivariable adjustment and was no longer significantly associated with death under subsequent ipilimumab treatment | (118) |
| Pennsylvania State University, USA | 29 melanoma patients | GDF-15 ELISA (R&D Systems) | Serum (10 patients) | Not determined | 22 patients | Primary melanoma biopsies expressing low levels of GDF-15. Metastatic melanoma patients having elevated GDF-15 expression in tumors also had high levels of GDF-15 in serum | (119) | |
| Queensland Institute of Medical Research and Princess Alexandra Hospital | 22 primary melanoma and 16 metastatic melanoma patients | Not applicable | Not applicable | Not determined | 38 patients | Elevated GDF-15 tissue expression, detected by IHC, was significantly associated with metastatic melanoma and not primary melanoma | (120) | |
| Hepato-cellular Carcinoma (HCC) | Chinese Academy of Medical Sciences (CICAMS), China | 223 HCC patients | GDF-15 ELISA (R&D Systems) | Serum | 2.463 ng/mL | GDF-15 IHC of 20 HCC patients | Tumor GDF15 protein expression in HCC was significantly higher than that in the corresponding adjacent paracarcinomatous tissue and normal liver. Serum GDF15 level is elevated in patients with HCC | (92) |
| Multiple myeloma | Franccophone du Myelome treatment trials, France | 131 multiple myeloma patients | GDF-15 ELISA (R&D Systems) | Plasma | 500 pg/mL | GDF-15 correlates with shorter event-free survival and OS and β2-microglobulin level and disease stage | (121) | |
| University Hospital Malmo, Sweden | 138 multiple myeloma patients | GDF-15 MILLIPLEX MAP Human Panel (Millipore) | Serum | 1,008 pg/mL | GDF-15 above threshold correlates with shorter OS | (97) | ||
| The Johns Hopkins Hospital, USA | 15 multiple myeloma patients | GDF-15 ELISA (R&D Systems) | Serum | Not determined | Not applicable | Increased serum GDF-15 levels correlate with shorter OS | (96) | |
| Non-small cell lung cancer (NSCLC) | Nanjing Medical University Jiangsu, China | 46 stage I/II and 20 stage III/IV NSCLC patients | Not applicable | Not determined | Not determined | GDF15 mRNA by qRT-PCR of 66 NSCLC patients | Downregulated GDF15 mRNA in NSCLC tissues is correlated with poor clinical outcomes in NSCLC | (122) |
| Cancer Institute and Hospital Beijing, China | 152 stage I and II NCSCL patients | GDF-15 ELISA (in-house) | Serum | 1,465 pg/mL | Serum GDF-15 above threshold correlates with shorter OS | (81) | ||
| Esophageal adeno-carcinoma (OAC) | St. Vincent's Hospital, Australia & PROBE-NET study, Australia | 138 OAC patients | GDF-15 ELISA (in-house) | Plasma | 1,140 pg/mL | GDF15 mRNA by MT-PCR of 138 OAC patients | GDF15 mRNA tissue expression is higher in esophageal adenocarcinoma compared to healthy individuals. Plasma GDF-15 above threshold correlates with shorter OS in OAC | (123) |
| Pancreatic cancer | Arthur G. James Comprehensive Cancer Center, USA | 27 PDAC patients, 183 PDAC patients from the TCGA database. | GDF-15 ELISA (R&D Systems) | Serum | Not determined | Not applicable | GDF15 mRNA expression shows trend for shorter OS | (108) |
| Ovarian cancer | Xijing Hospital, China, | 145 EOC patients | GDF-15 ELISA (USCNLIFE) | Serum (120 patients) | 748 pg/mL | 145 patients | High GDF-15 expression in EOC tissue showed shorter PFS and OS. Serum GDF-15 levels where higher in EOC patients resistant to first-line chemotherapy | (103) |
| National Cancer Center/Cancer Hospital, China | 122 EOC patients | GDF-15 ELISA (CICAMS) | Serum | 960 pg/mL | Not applicable | Serum GDF-15 above threshold correlates with PFS and platinum-refractory disease | (80) | |
| Oslo University Hospital, Ulleval, Norway | 312 ovarian cancer patients | Immunoradiometric sandwich assay) | Plasma | 1,242 pg/mL | Not applicable | Plasma GDF-15 above threshold correlates with shorter OS | (102) | |
| Ovarian Cancer | Federal University of Triângulo Mineiro, Uberaba, Brazil | 38 ovarian cancer patients | GDF-15 ELISA (Aviscera Bioscience Inc.) | Serum | Not determined | 59 patients | Serum GDF-15 levels were higher in the patients with malignant neoplasms than in the patients with benign tumors, yet the difference was not statistically significant. GDF-15 immunostaining was significantly more frequent in the stroma of the malignant tumors than in the stroma of the benign tumors | (124) |
| Prostate cancer | Cancer Prostate, Sweden | 1,442 prostate cancer patients | GDF-15 ELISA (in-house) | Serum | 1,466 pg/mL | Not applicable | Serum GDF-15 above threshold correlates with shorter OS | (100) |
| King George's Medical University, Lucknow, Center of Biomedical Research, SGPGIMS Campus Lucknow, India | 85 prostate cancer patients | GDF-15 ELISA (in-house) | Serum | Not determined | Not applicable | GDF-15 correlates with PSA and Gleason score | (85) | |
| University Hospital Munster, Germany | 38 prostate cancer patients | GDF-15 ELISA (R&D Systems) | Serum | 1,300 pg/mL | Not applicable | Serum GDF-15 levels were higher in metastatic than in non-metastatic patients. Serum GDF-15 above threshold correlates with shorter OS | (125) | |
| Renal Cell Cancer (RCC) | University Hospital Munster, Germany | 94 RCC patients | GDF-15 ELISA (R&D Systems) | Serum | 1,200 pg/mL | Not applicable | Serum GDF-15 is linked to metastases and relapse. Serum GDF-15 above threshold correlates with shorter OS | (93) |
| Urothelial carcinoma (UUTUC) | University Hospital Munster, Germany | 38 UUTUC patients | GDF-15 ELISA (R&D Systems) | Serum | 1,200 pg/mL | Not applicable | Serum GDF-15 is linked to metastases and relapse. Serum GDF-15 above threshold correlates with shorter OS | (93) |
| Uveal melanoma (UM) | University Hospital Tubingen, Germany | 188 uveal melanoma patients | GDF-15 ELISA (R&D Systems) | Serum | Not determined | GDF-15 IHC of 44 UM patients | Patients with clinically detectable metastases had significantly higher GDF-15 serum levels compared to those without clinically detectable metastases as well as to healthy individuals | (101) |
| The Johns Hopkins Hospital, USA | 48 uveal melanoma patients + 36 healthy controls | GDF-15 Bio-Plex (BioRad) | Serum | Not determined | Not applicable | GDF-15 + MIA proposed to discriminate between patients with metastatic uveal melanoma and disease-free patients [AUC = 0.85 (0.68–1.00), n.s.] | (126) | |
| Solid vs. non-solid treatment-naïve malignancies | Vienna General Hospital | 555 treatment-naive cancer patients (breast cancer, lung cancer, gastrointestinal cancer and hematological cancers) | GDF-15 ELISA (R&D Systems) | Serum | Tertiles of GDF-15 level | Not applicable | GDF-15 is significantly associated with outcome for solid tumors as breast cancer, lung cancer or gastrointestinal cancer; however, no association with outcome could be shown for hematological cancers as myelodysplastic or myeloproliferative diseases | (127) |