Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected Locally Advanced Non-Small Cell Lung Cancer treated with chemo- radiotherapy.

Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected Locally Advanced Non-Small Cell Lung Cancer treated with chemo- radiotherapy. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected Locally Advanced Non-Small Cell Lung Cancer treated with chemo- radiotherapy. Fiorella Pastena, Gregory Pond, Evangelia E. Tsakiridis, Andre Gouveia, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4266135/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Nov, 2024 Read the published version in Radiation Oncology → Version 1 posted 7 You are reading this latest preprint version Abstract Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard-of-care concurrent chemoradiotherapy (cCRT). Methods : Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60-66Gy), with or without metformin (2000mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. Results : Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively). Conclusions : GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets. Lung cancer biomarker GDF15 concurrent chemo-radiotherapy metformin Figures Figure 1 Figure 2 Figure 3 Figure 4 Highlights Analysis of plasma specimens of OCOG-ALMERA, a phase II clinical trial that investigated metformin in combination with standard of care concurrent chemoradiotherapy, suggests that the cytokine growth differentiation Factor 15 (GDF15) may be a promising biomarker in unresected locally advanced non-small cell lung cancer (LA-NSCLC). GDF15 levels increased during chemoradiotherapy, did more so in metformin-treated patients and corresponded with the radiotherapy clinical target volumes. Baseline plasma levels of GDF15 predicted overall and relapse-free survival. Validation of these results within larger clinical trials could lead to the establishment of an easily assessable plasma biomarker that could guide LA-NSCLC treatment in the future. INTRODUCTION Non-small cell lung cancer (NSCLC) represents 85% of all lung cancer cases[ 1 , 2 ] and is frequently diagnosed at a locally advanced (LA) stage that is inoperable and has a poor prognosis after standard of care treatment with concurrent chemoradiotherapy (cCRT)[ 3 – 5 ]. In recent years, consolidation immune checkpoint inhibitor therapy has been added to cCRT, but this provided only moderate improvements in survival[ 6 , 7 ]. Earlier, in human NSCLC models we observed that metabolic targeting with the anti-diabetic agent metformin activates the energy stress sensor AMP-activated kinase (AMPK)[ 8 ], inhibits the Akt - mammalian target of rapamycin (mTOR) pathway and suppresses tumor growth[ 9 ]. On this basis, we conducted a randomized phase II clinical trial, OCOG-ALMERA, to examine whether addition of metformin (2000mg/day) to standard cCRT could improve survival outcomes in LA-NSCLC. With 54 patients recruited from 7 Canadian centres, the OCOG-ALMERA was not able to demonstrate benefit[ 10 ]. Such results illustrate a need for effective biomarkers that could predict patient response to cCRT or investigational targeted therapies. Growth Differentiation Factor 15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1) or non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a member of the TGFβ superfamily[ 11 , 12 ], that is synthesized as a 308aa peptide[ 13 ]. After being processed to its mature form, GDF15 is released and circulates as a 25kDa dimer linked by a single interchain disulphide bond[ 14 ]. GDF15 mRNA is expressed at a low level in most human tissues except in abdominal and pelvic organs and the placenta. In healthy individuals, GDF15 serum content ranges from 200pg/ml to 1200pg/ml[ 15 – 17 ]. Circulating GDF15 is increased in several pathologies, including obesity, diabetes, cardiovascular diseases, and cancer[ 13 ]. The only described receptor for GDF15 is GFRAL-RET, expressed specifically in neurons of the area postrema and nucleus of the solitary tract (hindbrain) in mice and humans[ 18 ]. GDF15 was shown to help suppress appetite, reduce food intake and body weight[ 13 ], and to promote energy expenditure in muscle[ 19 ]. We and others found that cytotoxic treatments such as chemotherapy[ 20 ] and ionizing radiation[ 21 ], or metabolic therapies such as metformin[ 22 , 23 ], induce GDF15 expression. Further, efforts to develop radiation bio-dosimetry tools found that GDF15 belongs to a group of genes exhibiting a linear dose response relationship with radiation dose received in human peripheral blood cells[ 24 ]. Studies suggest that GDF15 may have diagnostic and prognostic value in lung cancer[ 25 , 26 ]. However, the modulation of this marker by cytotoxic therapy and its predictive or prognostic value have not been investigated systematically within lung cancer randomized trials. METHODS Patient population With appropriate institutional ethics approvals, OCOG-ALMERA (NCT02115464) accrued 54 patients from 7 Canadian centres. Full details of the trial were described earlier[ 10 ]. Briefly, the study accrued non-diabetic patients with pathologically or cytologically proven unresected stage IIIA or IIIB NSCLC (AJCC 7th edition) staged with conventional imaging, whole body fluorodeoxyglucose (FDG) positron emission tomography (PET) and Endobronchial Ultrasound (EBUS), as clinically indicated. Patients were randomized to either cCRT alone (n = 28) or combined with metformin (n = 26). Interventions Radiotherapy Chest radiotherapy of 60-66Gy was delivered in 30 daily fractions over six weeks concurrent with chemotherapy. Radiotherapy volume delineation followed ICRU-62 guidelines[ 27 ]. Gross tumor volume (GTV), including the primary tumor and involved lymph nodes only, was expanded to include respiratory tumor motion detected by 4-dimensional CT, fluoroscopy, or estimated (1 to 1.5cm expansion) for conventional CT simulation, respecting anatomic barriers to define internal target volume (ITV). Planned target volume (PTV) was generated with the expansion of ITV by 0.5 to 1.5cm. Normal tissue dose constraints followed standard Radiation Therapy Oncology Group (RTOG) guidelines. Systemic therapy Platinum-based chemotherapy was given in 2 cycles of 3–4 weeks concurrently with radiotherapy. Acceptable options included cisplatin–etoposide, or cisplatin-vinorelbine combinations. Carboplatin in combination with etoposide or paclitaxel was also permitted. Consolidation chemotherapy of 2 additional cycles was allowed in patients treated with the carboplatin/paclitaxel combination. Anti-programmed death receptor ligand 1 (PD-L1) immunotherapy was permitted after May 2018. See Table s1 for details of systemic therapy. Metformin Treatment started 2 weeks before the initiation of standard therapy at a dose of 1000mg/d orally; the dose was increased to 1500mg/d in week 2 and to 2000mg/d at the start of chemo-radiotherapy (week 3 of metformin treatment – week 1 of cCRT). Reduction of the dose escalation period to 1 week was permitted if clinically indicated. Metformin was given concurrently with cytotoxic therapy and as a consolidation treatment at 2000mg/d daily for up to 12 months unless dose de-escalation was required due to toxicity or disease progression. Biospecimen collection Blood specimens were submitted at baseline, 1 week into cCRT treatment (corresponding to the end of the first week of cCRT and the end of the third week of metformin treatment), the day of the last radiotherapy treatment (week 6 of cCRT, or week 8 from initiation of metformin treatment) and at 6 months (26 weeks) from the end of cCRT, while on metformin treatment or observation. EDTA plasma was extracted, preserved at -80 o C and shipped to the biospecimen storage site at Juravinski Cancer Center. Elisa assay GDF15 content was analysed by personnel blinded to the outcomes and data collected by the trial. Assays were performed using the GDF-15 Duo Set ELISA kit (Catalog #DY957, R&D Systems). Briefly, 96 well plates were coated with the capture antibody for human GDF15. After washing and blocking, 100µl of standard and samples were added to each well and incubated for two hours, followed by washing, incubation with detection antibody, streptavidin-horse radish peroxidase (HRP) and substrate solution. Assays were terminated with stop solution and optical density was measured with a microplate reader at 450nm (wavelength correction set to 540nm). Statistical analysis Descriptive statistics were used to summarise patient characteristics, laboratory measures, and outcomes. Kaplan-Meier method was used to estimate overall survival (OS) and relapse-free survival (RFS). Cox regression analyses were used to investigate the prognostic ability of GDF15. In univariable analysis GDF15 levels were stratified by intervention arm. In the multivariable model GDF15, as a continuous variable was adjusted for treatment and AJCC 7th edition overall stage (stage IIIA vs IIIB). OS and RFS, of all patients, are illustrated vs baseline GDF15 levels dichotomized at the median marker level, as well as the value of 1465pg/ml, suggested to have significant discriminatory value in other reports of NSCLC patients. An exploratory sensitivity analysis for optimal cutoff values was performed. The change in GDF15 over time was calculated as the absolute difference (= on treatment - baseline) and relative change (= (on treatment – baseline)/baseline*100%) and tested using the Wilcoxon rank sum test. Spearman correlation coefficients were used to explore the association between GDF15 and radiotherapy treatment volumes. Confidence intervals were constructed for selected outcomes of interest. All tests and confidence intervals were two-sided, and statistical significance was defined at the α = 0.05 level. All analyses were done blinded to patient outcomes. RESULTS Population Of the 54 patients accrued to the OCOG-ALMERA trial, 32 patients [16 of the control (cCRT) and 16 of the experimental arm (cCRT + metformin)] provided blood specimens to extract EDTA plasma at baseline and at least one of the subsequent time-points and were included in this analysis. There were no statistically significant differences in patient characteristics between treatment arms amongst the patients participating in this analysis ( Table 1 ). Further, there were no statistically significant differences in patient characteristics between trial patients with available biospecimens included in this analysis vs those that were not ( Table s1 ). Baseline GDF15 levels and kinetics during chemo-radiotherapy. GDF15 levels detected at baseline, were generally elevated, median=1030, (range=417-2445pg/ml), compared to reported normal plasma levels [28, 29] ( Figure 1A ). There was no statistically significant difference between GDF15 levels measured at baseline between the cCRT and the cCRT + metformin arms ( Figure 1B, Table s2 ). After only 1 week of cCRT, GDF15 levels increased, remained high until the end of cCRT (week 6), and returned to almost the pre-treatment levels at 6 months after completion of cCRT ( Figure 2A ). Interestingly, the addition of metformin to cCRT, in the experimental arm was associated with greater increase in GDF15 levels during cCRT, compared to cCRT alone ( Figure 2B, Table s2 ). Plasma GDF15 levels correlate with radiotherapy tumor volumes. Given the possible modulation of GDF15 by cCRT we analysed the relationship between the levels of this marker and radiotherapy tumor volumes: gross tumor volume (GTV) and planned tumor volume (PTV) (median and range values are shown in Table 1) . Using Spearman correlation coefficient, we detected positive, moderately significant, correlations between GDF15 and GTV at baseline (p<0.01), and between GDF15 and PTV at 1 week into cCRT (p<0.006) ( Figure 3 ). We did not detect any obvious difference in baseline GDF15 values when patients were separated per AJCC 7 th edition staging factors, including overall stage (IIIA vs IIIB), T stage (T1-2 vs T3), and N stage (N0-1 vs N2-3) ( Table s3A ). Prognostic analysis of baseline GDF15 levels. Kaplan-Meier survival curves illustrating the Overall Survival (OS) and the Relapse Free Survival (RFS) of patients included in the analysis are shown in Figure 4 . A statistically significant inverse association was observed between baseline GDF15 levels with OS and RFS. In univariate analysis, T- and N- stage score, but not overall stage or tumor volumes (GTV, PTV), could predict RFS (Table s3B). However, only baseline GDF15, was found to be significantly prognostic for both RFS [HR 1.11 (95% CI: 1.02, 1.22), p-value=0.016] and OS [HR 1.17 (95% CI: 1.04, 1.32), p-value=0.009]. Further, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) in multivariate analysis (p=0.005 and p=0.002, respectively, Table 2 ). Patients with baseline GDF15 above the median (1029.9pg/ml) demonstrated reduced OS (A) compared to below the median [HR=1.19, (95% CI:1.06,1.34), p=0.005] and similarly reduced RFS (B) [(HR=1.14 (95% CI:1.04, 1.27), p=0.005]. An exploratory sensitivity analysis suggested that GDF15 levels between 1000pg/ml - 1700pg/ml was the range of values which discriminated between better and worse OS and RFS (see Table s4 ). Indeed, the GDF15 baseline cut-off value of 1465pg/ml reported by Liu et al[29] dichotomized our patients also in two groups with significantly different OS (HR=5.29, (95% CI:1.46, 19.15), p=0.011) ( Figure 4C). DISCUSSION The key observation of this study is that baseline plasma GDF15 may be an independent prognostic biomarker in unresected LA-NSCLC patients managed with standard of care cCRT. Interestingly, in this analysis GDF15 was found to have improved prognostic value compared to AJCC tumor stage and tumor volumes defined for radiotherapy treatment. Earlier reports with lung cancer patients suggested the biomarker value of GDF15. Liu et al. (2016)[ 29 ] detected prognostic value for GDF15 in stage I and II NSCLC patients managed with surgery, and others reported similar observations in undifferentiated populations including all stages of NSCLC[ 30 ]. All studies reported elevated baseline GDF15 levels in lung cancer patients. Consistently, in the present study we detected elevated levels of GDF15 in stage III NSCLC patients at baseline. Our sensitivity analysis of cutoff values indicated that GDF15 levels > 1000pg/ml can predict poor survival outcomes in unresected LA-NSCLC treated with cCRT. Indeed, the median of our population (1029.9pg/ml) separated patients into two groups with significantly different overall survival (OS) independently of the treatment arm distribution (p = 0.005) and when adjusted for treatment arm (p = 0.0009). Further, our data validated the cutoff level of 1465pg/ml described by Liu et al. (2016)[ 29 ] to predict poor post-operative outcomes [ 29 ]. GDF15 values of > 1000pg/ml deserve further systematic investigation as a potentially poor prognostic marker in NSCLC. Given that elevated baseline GDF15 predicted poor RFS, it is possible that GDF15 may be associated with factors that determine the biological response of lung cancer to cCRT. Pre-clinical studies suggested that GDF15 could mediate radio-resistance through a variety of mechanisms, including promotion of endothelial to mesenchymal transition (EMT), regulation of reactive oxygen species, inhibition of apoptosis and induction of cell cycle arrest [ 21 , 31 – 33 ]. On the other hand, reports suggested that the pre-treatment tumor volume determines response to cytotoxic therapy[ 34 , 35 ]. In this analysis we could not detect an association of tumor volumes (GTV or PTV) with RFS but found a moderately significant association of baseline GDF15 with GTV. This indicates this circulating factor may be able to reflect the disease burden in LA-NSCLC. Currently, there is need for markers to monitor biological tumor response during cytotoxic therapy. It is possible that GDF15 could serve this role for NSCLC tumors during cCRT. To date, only few studies examined the modulation of GDF15 during cytotoxic treatment. Frey et al[ 36 ] described increased GDF15 in response to either intensity-modulated or stereotactic ablative radiotherapy treatment of prostate cancer. Consistent with this and other observation of GDF15 induction by chemotherapy and radiation[ 21 , 28 , 32 , 37 , 38 ], we found a significant increase in GDF15 levels measured at the end of weeks 1 and 6 of cCRT (Fig. 2 ). Remarkably, circulating GDF15 levels 1 week into cCRT correlated with PTV, indicating a potential relationship of this marker with volumes of irradiated tissues in the chest. The increase of GDF15 during cCRT observed in the present study was several-fold above baseline. However, at 6 months after completion of cCRT, GDF15 returned to values close to baseline. This is not dissimilar to other reports[ 28 , 36 ]. Studies suggested that GDF15 may contribute to the anti-hyperglycaemic effect of metformin[ 13 , 23 ]. In 2317 dysglycemic patients that were part of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, GDF15 circulating levels were strongly linked to metformin use[ 22 ]. Similar results were reported by Coll and colleagues in 2020 amongst the participants of CAMERA, a randomized placebo-control trial testing metformin in people without diabetes but with a history of cardiovascular disease[ 39 ]. Metformin treatment was significantly associated with increased levels of circulating GDF15 at 6, 12, and 18 months. Here, we observed a greater increase in plasma GDF15 levels in LA-NSCLC patients who received metformin treatment in addition to cCRT. Given the recent evidence generated by our group and others[ 40 , 41 ] that i) GDF15 mediates energy expenditure[ 19 ], ii) it is responsible for the chemotherapy-induced anorexia and weight loss[ 20 ] and iii) is associated with cachexia observed in lung cancer patients[ 40 ], it is possible that GDF15 could influence survival outcomes when metabolic targeting is added to cytotoxic therapy in patients of poor performance status. This notion requires careful investigation. Early industry trials investigate now GDF15-targeting antibody therapies as anti-cancer or anti-cachexia agents, alone or in combination with standard therapies (NCT04725474, NCT05397171, NCT05546476). This is the first study that investigated the prognostic value of GDF15 as a biomarker for tumor response to cCRT and overall survival within a prospective randomized clinical trial in LA-NSCLC. The use of a consistent methodology in biomarker analysis and strict guidelines for patient selection, specimen collection and handling as well as the consistent tumor delineation for radiotherapy planning within this trial may have contributed to the ability of this analysis to detect prognostic biomarker value for GDF15. Limitations of this analysis are the small sample size, the open-label nature of the OCOG-ALMERA trial and the heterogeneity of our population. It is possible that GDF15 modulation in this population may be affected by other interfering factors. The moderately significant associations between GDF15 levels and tumor volumes detected in this study are interesting but should be interpreted with caution. Further, the number of patients with samples at later timepoints was limited, and it is possible that observed results are biased by including only those with available data. Therefore, it is necessary to validate the results of our study in larger trials and datasets. Conclusions The results obtained in this study give insights into the potential role of GDF15 as a marker of prognosis and tumor response to cCRT in LA-NSCLC. GDF15 may be able to function also as a useful marker of systemic response to metabolic therapy in lung cancer patients. Our results warrant further validation in biospecimens of larger lung cancer randomized trials. Abbreviations GDF15: growth differentiation factor – 15; TGFβ: transforming growth factor beta; MIC-1: macrophage inhibitory cytokine 1; NAG-1: non-steroidal anti-inflammatory drug-activated gene-1; LA-NSCLC: locally advanced non-small cell lung cancer; cCRT : concurrent chemoradiotherapy; AMPK : AMP-activated kinase; AJCC: American Joint Committee on Cancer; FDG: 18-fluoro-deoxyglucose; PET: positron emission tomography; EBUS: Endobronchial Ultrasound; GTV: Gross tumor volume; PTV: Planned target volume; ITV: internal target volume; PD-L1: programmed death receptor ligand 1; Declarations Ethics Approvals The clinical trial protocol of OCOG-ALMERA including the section of biospecimen collection and corresponding consent forms, received Health Ethics approval from all institutional and provincial ethics boards of participating institutions. This included the Ontario Cancer Research Ethics Board (OCREB), McGill University Research Ethics Board (REB), University of Manitoba REB and Health Research Ethics Board of Alberta (HREBA). Consents All patients willing to provide biospecimen signed the ethics board approved informed-consent forms before donating their biospecimen. This consent form clearly stated that biospecimen will be collected, shipped to Juravinski Cancer Centre, Hamilton, Ontario, and will be used for the purpose of biomarker analysis, in combination with clinical data, in an anonymized fashion. Data Availability The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Funding Funding for this work was provided by the Hamilton Health Science Foundation and the Canadian Institutes for Health Research to T.T. and the Canadian Institutes for Health Research to G.S. 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Li H, Tong CW, Leung Y, Wong MH, To KK, Leung KS. Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer. Front Oncol. 2017;7:288. Taugner J, Kasmann L, Karin M, Eze C, Florsch B, Guggenberger J, Li M, Tufman A, Reinmuth N, Duell T, et al. Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition. Invest New Drugs. 2022;40(1):163–71. Karin M, Taugner J, Kasmann L, Eze C, Roengvoraphoj O, Tufman A, Belka C, Manapov F. Association of Planning Target Volume with Patient Outcome in Inoperable Stage III NSCLC Treated with Chemoradiotherapy: A Comprehensive Single-Center Analysis. Cancers (Basel) 2020, 12(10). Frey B, Mika J, Jelonek K, Cruz-Garcia L, Roelants C, Testard I, Cherradi N, Lumniczky K, Polozov S, Napieralska A, et al. Systemic modulation of stress and immune parameters in patients treated for prostate adenocarcinoma by intensity-modulated radiation therapy or stereotactic ablative body radiotherapy. Strahlenther Onkol. 2020;196(11):1018–33. Park H, Nam KS, Lee HJ, Kim KS. Ionizing Radiation-Induced GDF15 Promotes Angiogenesis in Human Glioblastoma Models by Promoting VEGFA Expression Through p-MAPK1/SP1 Signaling. Front Oncol. 2022;12:801230. Demissei BG, Freedman G, Feigenberg SJ, Plastaras JP, Maity A, Smith AM, McDonald C, Sheline K, Simone CB 2nd, Lin LL, et al. Early Changes in Cardiovascular Biomarkers with Contemporary Thoracic Radiation Therapy for Breast Cancer, Lung Cancer, and Lymphoma. Int J Radiat Oncol Biol Phys. 2019;103(4):851–60. Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444–8. Al-Sawaf O, Weiss J, Skrzypski M, Lam JM, Karasaki T, Zambrana F, Kidd AC, Frankell AM, Watkins TBK, Martinez-Ruiz C, et al. Body composition and lung cancer-associated cachexia in TRACERx. Nat Med. 2023;29(4):846–58. Borner T, Wald HS, Ghidewon MY, Zhang B, Wu Z, De Jonghe BC, Breen D, Grill HJ. GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss. Cell Rep. 2020;31(3):107543. Tables Table 1. Patient Characteristics. Clinical, disease s tage, histological and treatment characteristics of the OCOG-ALMERA patients included in this analysis. CRT alone (standard) CRT+Metformin (experimental) p-values N 16 16 Stage N (%) 3B 8 (50.0) 6 (37.5) 0.72 Stratum Treatment N (%) Carboplatin 2 (12.5) 0 0.34 Cisplatin 4 (25.0) 4 (25.0) No stratum listed 10 (62.5) 12 (75.0) Sex N (%) Female 8 (50.0) 10 (62.5) 0.72 ECOG 0 7 (43.8) 10 (62.5) 0.48 1 9 (56.3) 6 (37.5) Age Mean (sd) 64.4 (8.5) 65.0 (5.6) 1.00 BMI Mean (sd) 25.6 (4.5) 26.5 (5.4) 0.65 Histology SCC 8 (50.0) 4 (25.0) 0.25 Adenocarcinoma 8 (50.0) 11 (68.8) NOS 0 1 (6.3) Cycles of Chemo 1 0 2 (12.5) 0.33 2 10 (62.5) 8 (50.0) Missing 6 (37.5) 6 (37.5) Duration of Chemo Median (Range) days 35 (28, 44) 35 (4, 42) 0.094 N (%) >=35 days 14 (87.5) 10 (62.5) 0.22 Immunotherapy N (%) Yes 4 (25.0) 2 (12.5) 0.65 Radiation Dose 60 8 (50.0) 6 (37.5) GTV Median (IQR) 113 (64, 172) 124 (46, 166) 0.84 ITV Median (IQR) 156 (95, 323) 154 (52, 249) 0.74 PTV Median (IQR) 437 (309, 540) 411 (252, 540) 0.60 Table 2. Prognostic value of baseline GDF15 compared to tumor volume and stage factors ( Univariate analysis ). Hazard Ratio (HR), confidence interval (95%CI) and p values are illustrated for Relapse Free (RFS) and overall (OS) survival. Additional Declarations No competing interests reported. Supplementary Files SupplementalTablesandFiguresFrontiers.docx Cite Share Download PDF Status: Published Journal Publication published 07 Nov, 2024 Read the published version in Radiation Oncology → Version 1 posted Editorial decision: Revision requested 25 Jul, 2024 Reviews received at journal 27 Jun, 2024 Reviewers agreed at journal 10 Jun, 2024 Reviewers invited by journal 06 May, 2024 Editor assigned by journal 22 Apr, 2024 Submission checks completed at journal 16 Apr, 2024 First submitted to journal 14 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4266135","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":291770133,"identity":"b591a0f8-d31c-40f4-9b27-c11f8ae586a1","order_by":0,"name":"Fiorella Pastena","email":"","orcid":"","institution":"McMaster University","correspondingAuthor":false,"prefix":"","firstName":"Fiorella","middleName":"","lastName":"Pastena","suffix":""},{"id":291770134,"identity":"11f0ecab-9ee1-4cf2-af4f-9c270d6430f4","order_by":1,"name":"Gregory Pond","email":"","orcid":"","institution":"McMaster University","correspondingAuthor":false,"prefix":"","firstName":"Gregory","middleName":"","lastName":"Pond","suffix":""},{"id":291770135,"identity":"aa2a3ab1-a60f-4de3-8792-7f18e9580843","order_by":2,"name":"Evangelia E. 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University","correspondingAuthor":true,"prefix":"","firstName":"Theodoros","middleName":"","lastName":"Tsakiridis","suffix":""}],"badges":[],"createdAt":"2024-04-14 19:29:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4266135/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4266135/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13014-024-02546-y","type":"published","date":"2024-11-07T15:57:54+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55250437,"identity":"456ed180-c35b-45ed-b55a-5ac9acccbfd2","added_by":"auto","created_at":"2024-04-24 17:33:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":92152,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of baseline plasma GDF15 levels. A. \u003c/strong\u003eDistribution of individual baseline GDF15 levels for all patients. \u003cstrong\u003eB.\u003c/strong\u003eComparison of baseline GDF15 levels between the concurrent chemo-radiotherapy (cCRT) and the cCRT + metformin arms (Wilcoxon rank sum test p-value=0.44: [median=963.5pg/ml (475.98-2072.85pg/ml) vs. 1094.2pg/ml (417.23-2444.59pg/ml), respectively].\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4266135/v1/bc3b77f3e1da5e21a619c04c.jpg"},{"id":55250438,"identity":"ce607915-cfed-4d1a-984c-13ccba4421c0","added_by":"auto","created_at":"2024-04-24 17:33:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":90725,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eModulation of plasma GDF15 levels by treatments. \u003c/strong\u003eLevels of GDF15 over the first 26 weeks (6 months) from starting cCRT (assessments on weeks 1, 6 and 26 of cCRT or weeks 3, 8 and 26 of metformin treatment). \u003cstrong\u003eA.\u003c/strong\u003eFor all patients included in this analysis. \u003cstrong\u003eB.\u003c/strong\u003e For patients based on treatment arm (cCRT: Control, cCRT + Metformin: Metformin). Statistical significance compared to average baseline plasma GDF15 levels, *p \u0026lt; 0.05, ** p\u0026lt; 0.01, *** p \u0026lt; 0.001. Statistical significance compared to average plasma GDF15 level of the Control (cCRT) arm patients at the same timepoint: # p \u0026lt; 0.05, ## p\u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4266135/v1/020a8fb93e8fb947c40ab8a0.jpg"},{"id":55251673,"identity":"13c935f3-1019-41ef-ac7b-b12cad7c4fc9","added_by":"auto","created_at":"2024-04-24 17:41:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":72862,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociation of plasma GDF15 with tumor volumes. A. \u003c/strong\u003eCorrelation of baseline GDF15 levels with Gross Tumor Volume (GTV)\u003cstrong\u003e. \u003c/strong\u003e\u0026nbsp;\u003cstrong\u003eB.\u003c/strong\u003e Correlation of circulating GDF15 levels at the end of week 1 of concurrent chemoradiotherapy (cCRT) with Planned Tumor Volume (PTV).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4266135/v1/7573ca35fcad58eff1c4dbca.jpg"},{"id":55250441,"identity":"c162e93e-deb5-4a46-8fcd-a7609a2f303e","added_by":"auto","created_at":"2024-04-24 17:33:58","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":110323,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier survival curves of Overall (OS) and Relapse Free (RFS) survival in relation to baseline GDF15 levels for the entire population.\u003c/strong\u003e \u003cstrong\u003eA.\u003c/strong\u003e OS of patients based on baseline GDF15 levels (black line: below the median of the entire population; red dotted line: above the median). \u003cstrong\u003eB.\u003c/strong\u003eRFS of patients based on median baseline GDF15 levels (black line: below the median of the entire population; red dotted line: above the median). \u003cstrong\u003eC.\u003c/strong\u003eOverall survival (OS) of patients based on baseline GDF15 levels using the cutoff value of 1465pg/ml reported by Liu et al (2016).\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4266135/v1/8efc775dc3683edc2b9698d7.jpg"},{"id":68750001,"identity":"b656a865-8a86-41a1-b876-11853281f983","added_by":"auto","created_at":"2024-11-11 16:08:21","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1067608,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4266135/v1/c2508105-3305-4050-92be-775467eb3081.pdf"},{"id":55250442,"identity":"d7737069-cf8e-4bce-a575-65b6768fa9bc","added_by":"auto","created_at":"2024-04-24 17:33:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":281631,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTablesandFiguresFrontiers.docx","url":"https://assets-eu.researchsquare.com/files/rs-4266135/v1/5404f7313f639311d0f71905.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected Locally Advanced Non-Small Cell Lung Cancer treated with chemo- radiotherapy.","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003eAnalysis of plasma specimens of OCOG-ALMERA, a phase II clinical trial that investigated metformin in combination with standard of care concurrent chemoradiotherapy, suggests that the cytokine growth differentiation Factor 15 (GDF15) may be a promising biomarker in unresected locally advanced non-small cell lung cancer (LA-NSCLC).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGDF15 levels increased during chemoradiotherapy, did more so in metformin-treated patients and corresponded with the radiotherapy clinical target volumes.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBaseline plasma levels of GDF15 predicted overall and relapse-free survival.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eValidation of these results within larger clinical trials could lead to the establishment of an easily assessable plasma biomarker that could guide LA-NSCLC treatment in the future.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eNon-small cell lung cancer (NSCLC) represents 85% of all lung cancer cases[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and is frequently diagnosed at a locally advanced (LA) stage that is inoperable and has a poor prognosis after standard of care treatment with concurrent chemoradiotherapy (cCRT)[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In recent years, consolidation immune checkpoint inhibitor therapy has been added to cCRT, but this provided only moderate improvements in survival[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEarlier, in human NSCLC models we observed that metabolic targeting with the anti-diabetic agent metformin activates the energy stress sensor AMP-activated kinase (AMPK)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], inhibits the Akt - mammalian target of rapamycin (mTOR) pathway and suppresses tumor growth[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. On this basis, we conducted a randomized phase II clinical trial, OCOG-ALMERA, to examine whether addition of metformin (2000mg/day) to standard cCRT could improve survival outcomes in LA-NSCLC. With 54 patients recruited from 7 Canadian centres, the OCOG-ALMERA was not able to demonstrate benefit[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Such results illustrate a need for effective biomarkers that could predict patient response to cCRT or investigational targeted therapies.\u003c/p\u003e \u003cp\u003eGrowth Differentiation Factor 15 (GDF15), also known as macrophage inhibitory cytokine 1 (MIC-1) or non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) is a member of the TGFβ superfamily[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], that is synthesized as a 308aa peptide[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. After being processed to its mature form, GDF15 is released and circulates as a 25kDa dimer linked by a single interchain disulphide bond[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. GDF15 mRNA is expressed at a low level in most human tissues except in abdominal and pelvic organs and the placenta. In healthy individuals, GDF15 serum content ranges from 200pg/ml to 1200pg/ml[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Circulating GDF15 is increased in several pathologies, including obesity, diabetes, cardiovascular diseases, and cancer[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The only described receptor for GDF15 is GFRAL-RET, expressed specifically in neurons of the area postrema and nucleus of the solitary tract (hindbrain) in mice and humans[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGDF15 was shown to help suppress appetite, reduce food intake and body weight[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and to promote energy expenditure in muscle[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. We and others found that cytotoxic treatments such as chemotherapy[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and ionizing radiation[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], or metabolic therapies such as metformin[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], induce GDF15 expression. Further, efforts to develop radiation bio-dosimetry tools found that GDF15 belongs to a group of genes exhibiting a linear dose response relationship with radiation dose received in human peripheral blood cells[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies suggest that GDF15 may have diagnostic and prognostic value in lung cancer[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, the modulation of this marker by cytotoxic therapy and its predictive or prognostic value have not been investigated systematically within lung cancer randomized trials.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003eWith appropriate institutional ethics approvals, OCOG-ALMERA (NCT02115464) accrued 54 patients from 7 Canadian centres. Full details of the trial were described earlier[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Briefly, the study accrued non-diabetic patients with pathologically or cytologically proven unresected stage IIIA or IIIB NSCLC (AJCC 7th edition) staged with conventional imaging, whole body fluorodeoxyglucose (FDG) positron emission tomography (PET) and Endobronchial Ultrasound (EBUS), as clinically indicated. Patients were randomized to either cCRT alone (n\u0026thinsp;=\u0026thinsp;28) or combined with metformin (n\u0026thinsp;=\u0026thinsp;26).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eRadiotherapy\u003c/strong\u003e \u003cp\u003eChest radiotherapy of 60-66Gy was delivered in 30 daily fractions over six weeks concurrent with chemotherapy. Radiotherapy volume delineation followed ICRU-62 guidelines[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Gross tumor volume (GTV), including the primary tumor and involved lymph nodes only, was expanded to include respiratory tumor motion detected by 4-dimensional CT, fluoroscopy, or estimated (1 to 1.5cm expansion) for conventional CT simulation, respecting anatomic barriers to define internal target volume (ITV). Planned target volume (PTV) was generated with the expansion of ITV by 0.5 to 1.5cm. Normal tissue dose constraints followed standard Radiation Therapy Oncology Group (RTOG) guidelines.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSystemic therapy\u003c/strong\u003e \u003cp\u003ePlatinum-based chemotherapy was given in 2 cycles of 3\u0026ndash;4 weeks concurrently with radiotherapy. Acceptable options included cisplatin\u0026ndash;etoposide, or cisplatin-vinorelbine combinations. Carboplatin in combination with etoposide or paclitaxel was also permitted. Consolidation chemotherapy of 2 additional cycles was allowed in patients treated with the carboplatin/paclitaxel combination. Anti-programmed death receptor ligand 1 (PD-L1) immunotherapy was permitted after May 2018. See Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003es1\u003c/span\u003e for details of systemic therapy.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eMetformin\u003c/strong\u003e \u003cp\u003eTreatment started 2 weeks before the initiation of standard therapy at a dose of 1000mg/d orally; the dose was increased to 1500mg/d in week 2 and to 2000mg/d at the start of chemo-radiotherapy (week 3 of metformin treatment \u0026ndash; week 1 of cCRT). Reduction of the dose escalation period to 1 week was permitted if clinically indicated. Metformin was given concurrently with cytotoxic therapy and as a consolidation treatment at 2000mg/d daily for up to 12 months unless dose de-escalation was required due to toxicity or disease progression.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eBiospecimen collection\u003c/h2\u003e \u003cp\u003eBlood specimens were submitted at baseline, 1 week into cCRT treatment (corresponding to the end of the first week of cCRT and the end of the third week of metformin treatment), the day of the last radiotherapy treatment (week 6 of cCRT, or week 8 from initiation of metformin treatment) and at 6 months (26 weeks) from the end of cCRT, while on metformin treatment or observation. EDTA plasma was extracted, preserved at -80\u003csup\u003eo\u003c/sup\u003eC and shipped to the biospecimen storage site at Juravinski Cancer Center.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eElisa assay\u003c/h2\u003e \u003cp\u003eGDF15 content was analysed by personnel blinded to the outcomes and data collected by the trial. Assays were performed using the GDF-15 Duo Set ELISA kit (Catalog #DY957, R\u0026amp;D Systems). Briefly, 96 well plates were coated with the capture antibody for human GDF15. After washing and blocking, 100\u0026micro;l of standard and samples were added to each well and incubated for two hours, followed by washing, incubation with detection antibody, streptavidin-horse radish peroxidase (HRP) and substrate solution. Assays were terminated with stop solution and optical density was measured with a microplate reader at 450nm (wavelength correction set to 540nm).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eDescriptive statistics were used to summarise patient characteristics, laboratory measures, and outcomes. Kaplan-Meier method was used to estimate overall survival (OS) and relapse-free survival (RFS). Cox regression analyses were used to investigate the prognostic ability of GDF15. In univariable analysis GDF15 levels were stratified by intervention arm. In the multivariable model GDF15, as a continuous variable was adjusted for treatment and AJCC 7th edition overall stage (stage IIIA vs IIIB). OS and RFS, of all patients, are illustrated vs baseline GDF15 levels dichotomized at the median marker level, as well as the value of 1465pg/ml, suggested to have significant discriminatory value in other reports of NSCLC patients. An exploratory sensitivity analysis for optimal cutoff values was performed. The change in GDF15 over time was calculated as the absolute difference (=\u0026thinsp;on treatment - baseline) and relative change (= (on treatment \u0026ndash; baseline)/baseline*100%) and tested using the Wilcoxon rank sum test. Spearman correlation coefficients were used to explore the association between GDF15 and radiotherapy treatment volumes. Confidence intervals were constructed for selected outcomes of interest. All tests and confidence intervals were two-sided, and statistical significance was defined at the α\u0026thinsp;=\u0026thinsp;0.05 level. All analyses were done blinded to patient outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cem\u003ePopulation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOf the 54 patients accrued to the OCOG-ALMERA trial, 32 patients [16 of the control (cCRT) and 16 of the experimental arm (cCRT + metformin)] provided blood specimens to extract EDTA plasma at baseline and at least one of the subsequent time-points and were included in this analysis. There were no statistically significant differences in patient characteristics between treatment arms amongst the patients participating in this analysis (\u003cstrong\u003eTable 1\u003c/strong\u003e). Further, there were no statistically significant differences in patient characteristics between trial patients with available biospecimens included in this analysis vs those that were not (\u003cstrong\u003eTable s1\u003c/strong\u003e). \u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eBaseline GDF15 levels and kinetics during chemo-radiotherapy. \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eGDF15 levels detected at baseline, were generally elevated, median=1030, (range=417-2445pg/ml), compared to reported normal plasma levels [28, 29] (\u003cstrong\u003eFigure 1A\u003c/strong\u003e). There was no statistically significant difference between GDF15 levels measured at baseline between the cCRT and the cCRT + metformin arms (\u003cstrong\u003eFigure 1B, Table s2\u003c/strong\u003e). \u003c/p\u003e\n\u003cp\u003eAfter only 1 week of cCRT, GDF15 levels increased, remained high until the end of cCRT (week 6), and returned to almost the pre-treatment levels at 6 months after completion of cCRT (\u003cstrong\u003eFigure 2A\u003c/strong\u003e). Interestingly, the addition of metformin to cCRT, in the experimental arm was associated with greater increase in GDF15 levels during cCRT, compared to cCRT alone (\u003cstrong\u003eFigure 2B, Table s2\u003c/strong\u003e). \u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003ePlasma GDF15 levels correlate with radiotherapy tumor volumes.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eGiven the possible modulation of GDF15 by cCRT we analysed the relationship between the levels of this marker and radiotherapy tumor volumes: gross tumor volume (GTV) and planned tumor volume (PTV) (median and range values are shown in \u003cstrong\u003eTable 1)\u003c/strong\u003e. Using Spearman correlation coefficient, we detected positive, moderately significant, correlations between GDF15 and GTV at baseline (p\u0026lt;0.01), and between GDF15 and PTV at 1 week into cCRT (p\u0026lt;0.006) (\u003cstrong\u003eFigure 3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eWe did not detect any obvious difference in baseline GDF15 values when patients were separated per AJCC 7\u003csup\u003eth\u003c/sup\u003e edition staging factors, including overall stage (IIIA vs IIIB), T stage (T1-2 vs T3), and N stage (N0-1 vs N2-3) (\u003cstrong\u003eTable s3A\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrognostic analysis of baseline GDF15 levels.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKaplan-Meier survival curves illustrating the Overall Survival (OS) and the Relapse Free Survival (RFS) of patients included in the analysis are shown in \u003cstrong\u003eFigure 4\u003c/strong\u003e. A statistically significant inverse association was observed between baseline GDF15 levels with OS and RFS. In univariate analysis, T- and N- stage score, but not overall stage or tumor volumes (GTV, PTV), could predict RFS (Table s3B). However, only baseline GDF15, was found to be significantly prognostic for both RFS [HR 1.11 (95% CI: 1.02, 1.22), p-value=0.016] and OS [HR 1.17 (95% CI: 1.04, 1.32), p-value=0.009]. Further, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) in multivariate analysis (p=0.005 and p=0.002, respectively, \u003cstrong\u003eTable 2\u003c/strong\u003e). \u003c/p\u003e\n\u003cp\u003ePatients with baseline GDF15 above the median (1029.9pg/ml) demonstrated reduced OS \u003cstrong\u003e(A)\u003c/strong\u003e compared to below the median [HR=1.19, (95% CI:1.06,1.34), p=0.005] and similarly reduced RFS \u003cstrong\u003e(B)\u003c/strong\u003e [(HR=1.14 (95% CI:1.04, 1.27), p=0.005]. An exploratory sensitivity analysis suggested that GDF15 levels between 1000pg/ml - 1700pg/ml was the range of values which discriminated between better and worse OS and RFS (see \u003cstrong\u003eTable s4\u003c/strong\u003e). Indeed, the GDF15 baseline cut-off value of 1465pg/ml reported by Liu et al[29] dichotomized our patients also in two groups with significantly different OS (HR=5.29, (95% CI:1.46, 19.15), p=0.011) (\u003cstrong\u003eFigure 4C).\u003c/strong\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe key observation of this study is that baseline plasma GDF15 may be an independent prognostic biomarker in unresected LA-NSCLC patients managed with standard of care cCRT. Interestingly, in this analysis GDF15 was found to have improved prognostic value compared to AJCC tumor stage and tumor volumes defined for radiotherapy treatment.\u003c/p\u003e \u003cp\u003eEarlier reports with lung cancer patients suggested the biomarker value of GDF15. Liu et al. (2016)[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] detected prognostic value for GDF15 in stage I and II NSCLC patients managed with surgery, and others reported similar observations in undifferentiated populations including all stages of NSCLC[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. All studies reported elevated baseline GDF15 levels in lung cancer patients. Consistently, in the present study we detected elevated levels of GDF15 in stage III NSCLC patients at baseline. Our sensitivity analysis of cutoff values indicated that GDF15 levels\u0026thinsp;\u0026gt;\u0026thinsp;1000pg/ml can predict poor survival outcomes in unresected LA-NSCLC treated with cCRT. Indeed, the median of our population (1029.9pg/ml) separated patients into two groups with significantly different overall survival (OS) independently of the treatment arm distribution (p\u0026thinsp;=\u0026thinsp;0.005) and when adjusted for treatment arm (p\u0026thinsp;=\u0026thinsp;0.0009). Further, our data validated the cutoff level of 1465pg/ml described by Liu et al. (2016)[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] to predict poor post-operative outcomes [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. GDF15 values of \u0026gt;\u0026thinsp;1000pg/ml deserve further systematic investigation as a potentially poor prognostic marker in NSCLC.\u003c/p\u003e \u003cp\u003eGiven that elevated baseline GDF15 predicted poor RFS, it is possible that GDF15 may be associated with factors that determine the biological response of lung cancer to cCRT. Pre-clinical studies suggested that GDF15 could mediate radio-resistance through a variety of mechanisms, including promotion of endothelial to mesenchymal transition (EMT), regulation of reactive oxygen species, inhibition of apoptosis and induction of cell cycle arrest [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. On the other hand, reports suggested that the pre-treatment tumor volume determines response to cytotoxic therapy[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In this analysis we could not detect an association of tumor volumes (GTV or PTV) with RFS but found a moderately significant association of baseline GDF15 with GTV. This indicates this circulating factor may be able to reflect the disease burden in LA-NSCLC.\u003c/p\u003e \u003cp\u003eCurrently, there is need for markers to monitor biological tumor response during cytotoxic therapy. It is possible that GDF15 could serve this role for NSCLC tumors during cCRT. To date, only few studies examined the modulation of GDF15 during cytotoxic treatment. Frey et al[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] described increased GDF15 in response to either intensity-modulated or stereotactic ablative radiotherapy treatment of prostate cancer. Consistent with this and other observation of GDF15 induction by chemotherapy and radiation[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], we found a significant increase in GDF15 levels measured at the end of weeks 1 and 6 of cCRT (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Remarkably, circulating GDF15 levels 1 week into cCRT correlated with PTV, indicating a potential relationship of this marker with volumes of irradiated tissues in the chest. The increase of GDF15 during cCRT observed in the present study was several-fold above baseline. However, at 6 months after completion of cCRT, GDF15 returned to values close to baseline. This is not dissimilar to other reports[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies suggested that GDF15 may contribute to the anti-hyperglycaemic effect of metformin[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In 2317 dysglycemic patients that were part of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, GDF15 circulating levels were strongly linked to metformin use[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similar results were reported by Coll and colleagues in 2020 amongst the participants of CAMERA, a randomized placebo-control trial testing metformin in people without diabetes but with a history of cardiovascular disease[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Metformin treatment was significantly associated with increased levels of circulating GDF15 at 6, 12, and 18 months.\u003c/p\u003e \u003cp\u003eHere, we observed a greater increase in plasma GDF15 levels in LA-NSCLC patients who received metformin treatment in addition to cCRT. Given the recent evidence generated by our group and others[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] that i) GDF15 mediates energy expenditure[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], ii) it is responsible for the chemotherapy-induced anorexia and weight loss[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and iii) is associated with cachexia observed in lung cancer patients[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], it is possible that GDF15 could influence survival outcomes when metabolic targeting is added to cytotoxic therapy in patients of poor performance status. This notion requires careful investigation. Early industry trials investigate now GDF15-targeting antibody therapies as anti-cancer or anti-cachexia agents, alone or in combination with standard therapies (NCT04725474, NCT05397171, NCT05546476).\u003c/p\u003e \u003cp\u003eThis is the first study that investigated the prognostic value of GDF15 as a biomarker for tumor response to cCRT and overall survival within a prospective randomized clinical trial in LA-NSCLC. The use of a consistent methodology in biomarker analysis and strict guidelines for patient selection, specimen collection and handling as well as the consistent tumor delineation for radiotherapy planning within this trial may have contributed to the ability of this analysis to detect prognostic biomarker value for GDF15.\u003c/p\u003e \u003cp\u003eLimitations of this analysis are the small sample size, the open-label nature of the OCOG-ALMERA trial and the heterogeneity of our population. It is possible that GDF15 modulation in this population may be affected by other interfering factors. The moderately significant associations between GDF15 levels and tumor volumes detected in this study are interesting but should be interpreted with caution. Further, the number of patients with samples at later timepoints was limited, and it is possible that observed results are biased by including only those with available data. Therefore, it is necessary to validate the results of our study in larger trials and datasets.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe results obtained in this study give insights into the potential role of GDF15 as a marker of prognosis and tumor response to cCRT in LA-NSCLC. GDF15 may be able to function also as a useful marker of systemic response to metabolic therapy in lung cancer patients. Our results warrant further validation in biospecimens of larger lung cancer randomized trials.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGDF15: growth differentiation factor \u0026ndash; 15; \u0026nbsp;TGF\u0026beta;: transforming growth factor beta; MIC-1: macrophage inhibitory cytokine 1; NAG-1: non-steroidal anti-inflammatory drug-activated gene-1; LA-NSCLC: locally advanced non-small cell lung cancer; cCRT : concurrent chemoradiotherapy; AMPK : AMP-activated kinase; AJCC: American Joint Committee on Cancer; FDG: 18-fluoro-deoxyglucose; \u0026nbsp;PET: positron emission tomography; EBUS: Endobronchial Ultrasound; GTV: Gross tumor volume; PTV: Planned target volume; ITV: internal target volume; PD-L1: programmed death receptor ligand 1;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approvals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical trial protocol of OCOG-ALMERA including the section of biospecimen collection and corresponding consent forms, received Health Ethics approval from all institutional and provincial ethics boards of participating institutions. This included the Ontario Cancer Research Ethics Board (OCREB), McGill University Research Ethics Board (REB), University of Manitoba REB and Health Research Ethics Board of Alberta (HREBA). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsents\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients willing to provide biospecimen signed the ethics board approved informed-consent forms before donating their biospecimen. This consent form clearly stated that biospecimen will be collected, shipped to Juravinski Cancer Centre, Hamilton, Ontario, and will be used for the purpose of biomarker analysis, in combination with clinical data, in an anonymized fashion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding for this work was provided by the Hamilton Health Science Foundation and the Canadian Institutes for Health Research to T.T. and the Canadian Institutes for Health Research to G.S.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFDP: Investigation, Visualization,\u0026nbsp;Writing, Data Curation, Original Draft\u003c/p\u003e\n\u003cp\u003eGP: Formal analysis, Data Curation\u003c/p\u003e\n\u003cp\u003eEET: Visualization, Writing - Original Draft, Data Curation\u003c/p\u003e\n\u003cp\u003eAG: Writing - Original Draft\u003c/p\u003e\n\u003cp\u003eEA: Investigation\u003c/p\u003e\n\u003cp\u003eODB: Investigation\u003c/p\u003e\n\u003cp\u003eAA: Investigation\u003c/p\u003e\n\u003cp\u003eAS: Investigation\u003c/p\u003e\n\u003cp\u003eGO: Investigation\u003c/p\u003e\n\u003cp\u003ePME: Investigation\u003c/p\u003e\n\u003cp\u003eBA: Investigation\u003c/p\u003e\n\u003cp\u003eNA: Investigation\u003c/p\u003e\n\u003cp\u003eAR: Investigation\u003c/p\u003e\n\u003cp\u003eWR: Investigation,\u003c/p\u003e\n\u003cp\u003eMV: Investigation,\u003c/p\u003e\n\u003cp\u003ePK: Methodology\u003c/p\u003e\n\u003cp\u003eMW: Methodology\u003c/p\u003e\n\u003cp\u003eJW: Investigation, methodology\u003c/p\u003e\n\u003cp\u003eGS: Methodology, Resources, Writing - Original Draft, Supervision,\u003c/p\u003e\n\u003cp\u003eTT: Conceptualization, Methodology, Investigation, Resources, Writing - Original Draft,\u003c/p\u003e\n\u003cp\u003eSupervision, Project administration, Funding acquisition\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGovindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, Spitznagel EL, Piccirillo J. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24(28):4539\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBradley JD, Hu C, Komaki RR, Masters GA, Blumenschein GR, Schild SE, Bogart JA, Forster KM, Magliocco AM, Kavadi VS, et al. Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer. 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GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates. Cell Metab. 2020;32(6):938\u0026ndash;e950936.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandor N, Schilling-Toth B, Kis E, Benedek A, Lumniczky K, Safrany G, Hegyesi H. Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity. Mutat Res Genet Toxicol Environ Mutagen. 2015;793:142\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerstein HC, Pare G, Hess S, Ford RJ, Sjaarda J, Raman K, McQueen M, Lee S, Haenel H, Steinberg GR, Investigators O. Growth Differentiation Factor 15 as a Novel Biomarker for Metformin. Diabetes Care. 2017;40(2):280\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDay EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR, Gutgesell RM, Lu R, Raphenya AR, Kabiri M, McArthur AG, et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab. 2019;1(12):1202\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi L, Jiang L, Wang Y, Zhao Y, Zhang XJ, Wu G, Zhou X, Sun J, Bai J, Ren B, et al. Combination of Metformin and Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patients with EGFR Mutations: A Randomized, Double-Blind Phase II Trial. Clin Cancer Res. 2019;25(23):6967\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWischhusen J, Melero I, Fridman WH. Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol. 2020;11:951.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan M, Dai D, Yousafzai NA, Wang F, Wang H, Zhou Q, Lu H, Xu W, Feng L, Jin H, Wang X. CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer. 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Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer. Front Oncol. 2017;7:288.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaugner J, Kasmann L, Karin M, Eze C, Florsch B, Guggenberger J, Li M, Tufman A, Reinmuth N, Duell T, et al. Planning target volume as a predictor of disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition. Invest New Drugs. 2022;40(1):163\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarin M, Taugner J, Kasmann L, Eze C, Roengvoraphoj O, Tufman A, Belka C, Manapov F. Association of Planning Target Volume with Patient Outcome in Inoperable Stage III NSCLC Treated with Chemoradiotherapy: A Comprehensive Single-Center Analysis. Cancers (Basel) 2020, 12(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrey B, Mika J, Jelonek K, Cruz-Garcia L, Roelants C, Testard I, Cherradi N, Lumniczky K, Polozov S, Napieralska A, et al. Systemic modulation of stress and immune parameters in patients treated for prostate adenocarcinoma by intensity-modulated radiation therapy or stereotactic ablative body radiotherapy. Strahlenther Onkol. 2020;196(11):1018\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePark H, Nam KS, Lee HJ, Kim KS. Ionizing Radiation-Induced GDF15 Promotes Angiogenesis in Human Glioblastoma Models by Promoting VEGFA Expression Through p-MAPK1/SP1 Signaling. Front Oncol. 2022;12:801230.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDemissei BG, Freedman G, Feigenberg SJ, Plastaras JP, Maity A, Smith AM, McDonald C, Sheline K, Simone CB 2nd, Lin LL, et al. Early Changes in Cardiovascular Biomarkers with Contemporary Thoracic Radiation Therapy for Breast Cancer, Lung Cancer, and Lymphoma. Int J Radiat Oncol Biol Phys. 2019;103(4):851\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColl AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAl-Sawaf O, Weiss J, Skrzypski M, Lam JM, Karasaki T, Zambrana F, Kidd AC, Frankell AM, Watkins TBK, Martinez-Ruiz C, et al. Body composition and lung cancer-associated cachexia in TRACERx. Nat Med. 2023;29(4):846\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorner T, Wald HS, Ghidewon MY, Zhang B, Wu Z, De Jonghe BC, Breen D, Grill HJ. GDF15 Induces an Aversive Visceral Malaise State that Drives Anorexia and Weight Loss. Cell Rep. 2020;31(3):107543.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patient Characteristics.\u0026nbsp;\u003c/strong\u003eClinical, disease \u003cstrong\u003es\u003c/strong\u003etage, histological and treatment characteristics of the OCOG-ALMERA patients included in this analysis.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"627\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003eCRT alone (standard)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003eCRT+Metformin (experimental)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003ep-values\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eN (%) 3B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\" rowspan=\"3\"\u003e\n \u003cp\u003eStratum Treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eN (%) Carboplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003eCisplatin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003eNo stratum listed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e10 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e12 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eN (%) Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e10 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\" rowspan=\"2\"\u003e\n \u003cp\u003eECOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e7 (43.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e10 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e9 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eMean (sd)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e64.4 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e65.0 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eMean (sd)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e25.6 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e26.5 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\" rowspan=\"3\"\u003e\n \u003cp\u003eHistology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eSCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e11 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003eNOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e1 (6.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\" rowspan=\"3\"\u003e\n \u003cp\u003eCycles of Chemo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e10 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\" rowspan=\"2\"\u003e\n \u003cp\u003eDuration of Chemo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eMedian (Range) days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e35 (28, 44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e35 (4, 42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.094\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003eN (%) \u0026gt;=35 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e14 (87.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e10 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eImmunotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eN (%) Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e4 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\" rowspan=\"3\"\u003e\n \u003cp\u003eRadiation Dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003e\u0026lt;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e2 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"25.8%\"\u003e\n \u003cp\u003e\u0026gt;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.4%\"\u003e\n \u003cp\u003e8 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.6%\"\u003e\n \u003cp\u003e6 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eGTV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e113 (64, 172)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e124 (46, 166)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003eITV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e156 (95, 323)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e154 (52, 249)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.12779552715655%\"\u003e\n \u003cp\u003ePTV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.60702875399361%\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.482428115015974%\"\u003e\n \u003cp\u003e437 (309, 540)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.447284345047922%\"\u003e\n \u003cp\u003e411 (252, 540)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.335463258785943%\" valign=\"top\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. \u0026nbsp; Prognostic value of baseline GDF15 compared to tumor volume and stage factors\u003c/strong\u003e (\u003cem\u003eUnivariate analysis\u003c/em\u003e). Hazard Ratio (HR), confidence interval (95%CI) and p values are illustrated for Relapse Free (RFS) and overall (OS) survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003cimg 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\" 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Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Lung cancer biomarker, GDF15, concurrent chemo-radiotherapy, metformin","lastPublishedDoi":"10.21203/rs.3.rs-4266135/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4266135/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGrowth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard-of-care concurrent chemoradiotherapy (cCRT).\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods\u003c/b\u003e: Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60-66Gy), with or without metformin (2000mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes.\u003c/p\u003e \u003cp\u003e \u003cb\u003eResults\u003c/b\u003e: Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the addition of metformin was associated with a further increase (week 6, p\u0026thinsp;=\u0026thinsp;0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p\u0026thinsp;\u0026lt;\u0026thinsp;0.006). In multivariate analysis, baseline plasma GDF15 was prognostic poor relapse-free (RFS) and overall survival (OS) (p\u0026thinsp;=\u0026thinsp;0.005 and p\u0026thinsp;=\u0026thinsp;0.002, respectively).\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusions\u003c/b\u003e: GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.\u003c/p\u003e","manuscriptTitle":"Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected Locally Advanced Non-Small Cell Lung Cancer treated with chemo- radiotherapy.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-24 17:33:53","doi":"10.21203/rs.3.rs-4266135/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-25T12:13:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-27T14:47:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223390341909807748175957983433531795600","date":"2024-06-10T07:00:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-06T10:15:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-22T08:49:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-16T08:37:26+00:00","index":"","fulltext":""},{"type":"submitted","content":"Radiation Oncology","date":"2024-04-14T19:22:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"deffb389-be11-4640-8c9d-6bff681984f0","owner":[],"postedDate":"April 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-11-11T16:02:36+00:00","versionOfRecord":{"articleIdentity":"rs-4266135","link":"https://doi.org/10.1186/s13014-024-02546-y","journal":{"identity":"radiation-oncology","isVorOnly":false,"title":"Radiation Oncology"},"publishedOn":"2024-11-07 15:57:54","publishedOnDateReadable":"November 7th, 2024"},"versionCreatedAt":"2024-04-24 17:33:53","video":"","vorDoi":"10.1186/s13014-024-02546-y","vorDoiUrl":"https://doi.org/10.1186/s13014-024-02546-y","workflowStages":[]},"version":"v1","identity":"rs-4266135","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4266135","identity":"rs-4266135","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}