INSTIGO Trial: Evaluation of a Plasma Protein Profile as a Predictive Biomarker for Metastatic Relapse of Triple Negative Breast Cancer
Hugo Veyssière, Sejdi Lusho, Ioana Molnar, Myriam Kossai, Maureen Bernadach, Catherine Abrial, Yannick Bidet, Nina Radosevic-Robin, Xavier Durando, Hugo Veyssière, Sejdi Lusho, Ioana Molnar, Myriam Kossai, Maureen Bernadach, Catherine Abrial, Yannick Bidet, Nina Radosevic-Robin, Xavier Durando
Abstract
Background: Triple negative breast cancer (TNBC) accounts for 10-20% of breast cancers but has no specific therapy. While TNBC may be more sensitive to chemotherapy than other types of breast cancer, it has a poor prognosis. Most TNBC relapses occur during the five years following treatment, however predictive biomarkers of metastatic relapse are still lacking. High tumour-infiltrating lymphocytes (TILs) levels before and after neo-adjuvant chemotherapy (NAC) are associated with lower relapse risk and longer survival but TILs assessment is highly error-prone and still not introduced into the clinic. Therefore, having reliable biomarker of relapse, but easier to assess, remains essential for TNBC management. Searching for such biomarkers among serum/plasma proteins, circulating tumoral DNA (ctDNA) and blood cells appear relevant.
Methods: This single-centre and prospective study aims to discover predictive biomarkers of TNBC relapse and particularly focuses on plasma proteins. Blood samples will be taken at diagnosis, on the day of first-line or post-NAC surgery, on the day of radiotherapy start, then 6 months and one year after radiotherapy. A blood sample will be taken at the time of metastatic relapse diagnosis. Blood samples will be used for circulating protein quantification, blood cell counts and circulating tumour DNA quantification. A tumour RNA signature, based on the analysis of the RNA expression of 6 genes, will also be tested from the initial biopsy taken routinely. In NAC patients, TILs quantity will be assessed on TNBC pre-treatment biopsy and surgical specimen.
Ethics and dissemination: INSTIGO belongs to category 2 interventional research on humans. This study has been approved by the SUD-EST IV ethics committee and is conducted in accordance with the Declaration of Helsinki and General Data Protection Regulation (GDPR). Study findings will be published in peer-reviewed medical journals.
Clinical trial registration: ClinicalTrials.gov, identifier NCT04438681.
Keywords: RNA signature; TILs; blood cells; ctDNA; metastatic relapse; plasma proteins; predictive biomarker; triple negative breast cancer.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Copyright © 2021 Veyssière, Lusho, Molnar, Kossai, Bernadach, Abrial, Bidet, Radosevic-Robin and Durando.
Figures
References
- Lee J, Kim D-M, Lee A. Prognostic Role and Clinical Association of Tumor-Infiltrating Lymphocyte, Programmed Death Ligand-1 Expression With Neutrophil-Lymphocyte Ratio in Locally Advanced Triple-Negative Breast Cancer. Cancer Res Treat (2019) 51:649–63. 10.4143/crt.2018.270
- Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. . Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence. Clin Cancer Res (2007) 13:4429–34. 10.1158/1078-0432.CCR-06-3045
- Foulkes WD, Smith IE, Reis-Filho JS. Triple-Negative Breast Cancer. N Engl J Med (2010) 363:1938–48. 10.1056/NEJMra1001389
- Garrido-Castro AC, Lin NU, Polyak K. Insights Into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov (2019) 9:176–98. 10.1158/-18-1177
- Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. . Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers. J Clin Oncol (2019) 37:559–69. 10.1200/JCO.18.01010
- Luen SJ, Salgado R, Dieci MV, Vingiani A, Curigliano G, Gould RE, et al. . Prognostic Implications of Residual Disease Tumor-Infiltrating Lymphocytes and Residual Cancer Burden in Triple-Negative Breast Cancer Patients After Neoadjuvant Chemotherapy. Ann Oncol (2019) 30:236–42. 10.1093/annonc/mdy547
- Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, et al. . Update on Tumor-Infiltrating Lymphocytes (Tils) in Breast Cancer, Including Recommendations to Assess TILs in Residual Disease After Neoadjuvant Therapy and in Carcinoma in Situ: A Report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol (2018) 52:16–25. 10.1016/j.semcancer.2017.10.003
- Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. . The Evaluation of Tumor-Infiltrating Lymphocytes (Tils) in Breast Cancer: Recommendations by an International Tils Working Group 2014. Ann Oncol (2015) 26:259–71. 10.1093/annonc/mdu450
- von Minckwitz G, Untch M, Blohmer J-U, Costa SD, Eidtmann H, Fasching PA, et al. . Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. J Clin Oncol (2012) 30:1796–804. 10.1200/JCO.2011.38.8595
- Ghajar CM. Metastasis Prevention by Targeting the Dormant Niche. Nat Rev Cancer (2015) 15:238–47. 10.1038/nrc3910
- Redig AJ, McAllister SS. Breast Cancer as a Systemic Disease: A View of Metastasis. J Intern Med (2013) 274:113–26. 10.1111/joim.12084
- Benoy IH, Salgado R, Dam PV, Geboers K, Marck EV, Scharpé S, et al. . Increased Serum Interleukin-8 in Patients With Early and Metastatic Breast Cancer Correlates With Early Dissemination and Survival. Clin Cancer Res (2004) 10:7157–62. 10.1158/1078-0432.CCR-04-0812
- Endo M, Yamamoto Y, Nakano M, Masuda T, Odagiri H, Horiguchi H, et al. . Serum ANGPTL2 Levels Reflect Clinical Features of Breast Cancer Patients: Implications for the Pathogenesis of Breast Cancer Metastasis. Int J Biol Markers (2014) 29:239–45. 10.5301/jbm.5000080
- Noman AS, Uddin M, Chowdhury AA, Nayeem MJ, Raihan Z, Rashid MI, et al. . Serum Sonic Hedgehog (SHH) and Interleukin-(IL-6) as Dual Prognostic Biomarkers in Progressive Metastatic Breast Cancer. Sci Rep (2017) 7. 10.1038/s41598-017-01268-4
- Bahhnassy A, Mohanad M, Shaarawy S, Ismail MF, El-Bastawisy A, Ashmawy AM, et al. . Transforming Growth Factor-β, Insulin-Like Growth Factor I/insulin-like Growth Factor I Receptor and Vascular Endothelial Growth Factor-a: Prognostic and Predictive Markers in Triple-Negative and non-Triple-Negative Breast Cancer. Mol Med Rep (2015) 12:851–64. 10.3892/mmr.2015.3560
- Ethier J-L, Desautels D, Templeton A, Shah PS, Amir E. Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Breast Cancer: A Systematic Review and Meta-Analysis. Breast Cancer Res BCR (2017) 19. 10.1186/s13058-016-0794-1
- Huszno J, Kołosza Z, Mrochem-Kwarciak J, Zajusz A. Prognostic Value of the Neutrophil-Lymphocyte, Platelet-Lymphocyte, and Monocyte-Lymphocyte Ratios in Male Breast Cancer Patients. Oncology (2020) 98:1–6. 10.1159/000505627
- Chae S, Kang KM, Kim HJ, Kang E, Park SY, Kim JH, et al. . Neutrophil–Lymphocyte Ratio Predicts Response to Chemotherapy in Triple-Negative Breast Cancer. Curr Oncol (2018) 25:e113–9. 10.3747/co.25.3888
- Patel DA, Xi J, Luo J, Hassan B, Thomas S, Ma CX, et al. . Neutrophil-to-Lymphocyte Ratio as a Predictor of Survival in Patients With Triple-Negative Breast Cancer. Breast Cancer Res Treat (2019) 174:443–52. 10.1007/s10549-018-05106-7
- Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov (2016) 6:479–91. 10.1158/-15-1483
- Beddowes E, Sammut SJ, Gao M, Caldas C. Predicting Treatment Resistance and Relapse Through Circulating DNA. Breast (2017) 34:S31–5. 10.1016/j.breast.2017.06.024
- Fernandez-Garcia D, Hills A, Page K, Hastings RK, Toghill B, Goddard KS, et al. . Plasma Cell-Free DNA (cfDNA) as a Predictive and Prognostic Marker in Patients With Metastatic Breast Cancer. Breast Cancer Res BCR (2019) 21. 10.1186/s13058-019-1235-8
- Chia SK, Bramwell VH, Tu D, Shepherd LE, Jiang S, Vickery T, et al. . A 50-Gene Intrinsic Subtype Classifier for Prognosis and Prediction of Benefit From Adjuvant Tamoxifen. Clin Cancer Res (2012) 18:4465–72. 10.1158/1078-0432.CCR-12-0286
- Vieira AF, Schmitt F. An Update on Breast Cancer Multigene Prognostic Tests—Emergent Clinical Biomarkers. Front Med (2018) 5:248. 10.3389/fmed.2018.00248
- Wallden B, Storhoff J, Nielsen T, Dowidar N, Schaper C, Ferree S, et al. . Development and Verification of the PAM50-based Prosigna Breast Cancer Gene Signature Assay. BMC Med Genomics (2015) 8:54. 10.1186/s12920-015-0129-6
- Soliman H, Shah V, Srkalovic G, Mahtani R, Levine E, Mavromatis B, et al. . MammaPrint Guides Treatment Decisions in Breast Cancer: Results of the IMPACt Trial. BMC Cancer (2020) 20:81. 10.1186/s12885-020-6534-z
- Mittempergher L, Delahaye LJ, Witteveen AT, Snel MH, Mee S, Chan BY, et al. . Performance Characteristics of the BluePrint® Breast Cancer Diagnostic Test. Transl Oncol (2020) 13:100756. 10.1016/j.tranon.2020.100756
Source: PubMed