Identifying patients suitable for targeted adjuvant therapy: advances in the field of developing biomarkers for tumor recurrence following irradiation

Figures & data

Figure 1. Current approaches to assessing tumor recurrence in the clinic involve clinical aspects (history, physical exam, patient-reported outcomes/toxicity assessments, laboratory assessments, and imaging).

Figure 2. Oncologic management modalities and their concurrent utilization over the course of malignancy illustrate the evolution of management components (surgery, radiation, systemic management) and existing biomarkers utilized in the clinic in relation to sample acquisition [4,5].

Figure 3. Existing and evolving biomarkers and their literature footprint. The biomarker literature footprint was determined based on a web of science literature search. Terms used in the search are ‘tumor recurrence and ‘radiation’ and the biomarker name [54].

Table 1. Existing and evolving biomarkers of tumor recurrence, radiation resistance, and stemness.

	Biomarker	Full Name	Details	Journal
Established biomarkers employed for clinical decision making	HER2	Human Epidermal Growth Factor Receptor 2	breast cancer	Zubair et al. 2021 [24]
	IDH-1	Isocitrate Dehydrogenase 1	gliomas	Stewart et al. 2022 [25]
	MGMT methylation	O6-Methylguanine-DNA Methyltransferase	gliomas	Wang et al. 2015 [26]
Established biomarkers used to detect recurrence	PSA	Prostate-Specific Antigen	prostate cancer	Wirth et al. 2005 [27]
	CA-125	Cancer Antigen-125	ovarian cancer	Giuliani et al. 2018 [28]
	AFP	Alpha-Fetoprotein	liver cancer	Xu et al. 2022 [29]
	CEA	Carcinoembryonic Antigen	Colorectal, lung, and Endometrial cancer	Lee et al. 2015 [20], Kozakiewicz et al. 2016 [30], Shintani et al. 2017 [31]
	CA 19–9	Cancer Antigen 19–9	Pancreatic cancer	Micke et al. 2003 [32]
	CA 15–3	Cancer Antigen 15–3	breast cancer	Zubair et al. 2021 [24]
	CA 27–29	Cancer Antigen 27–29	breast cancer	Zubair et al. 2021 [24]
Evolving biomarkers of radiation resistance	KRAS	Kirsten rat sarcoma viral oncogene homolog	Involved in uncontrolled cell proliferation	Toulany et al. 2023 [33]
	VEGF	Vascular Endothelial Growth Factor	Involved in angiogenesis	Mortexaee et al. 2019 [34]
	TP53	Tumor Protein 53	Tumor suppressor gene	Ho et al. 2022 [35]
	IL-6	Interleukin-6	Involved in immune and response	Tsai et al. 2019 [7]
	NRF2	Nuclear factor erythroid 2-related factor 2	Transcription factors involved in oxidative stress response	Jeong et al. 2017 [36]
	HiF-1a	Hypoxia-Inducible Factor 1α	Transcription factors involved in hypoxia response	Brown et al. 2020 [37]
	COX2	Cyclooxygenase-2	Enzymes involved in inflammation	Laube et al. 2016 [8]
	IGF-1R	Insulin-like Growth Factor 1 Receptor	Cell surface receptor; cell growth and survival	Breen et al. 2017 [38]
	CRP	C-reactive Protein	Acute phase reactant protein response to inflammation	Katano et al. 2017 [39]
	PD-L1	Programmed Death Ligand	Inhibiting immune response	Tsai et al. 2019 [7]
	TGF- β	Transforming growth factor-beta	Cellular proliferation	Wang et al. 2021 [6]
	EGFR	Epidermal growth factor receptor	Uncontrolled proliferation	Mortezaee et al. 2019 [34]
Markers of Cancer Stem Cells	CD44	Cell surface glycoprotein	Cell surface glycoprotein; tumor metastasis	Zhao et al. 2021 [40]
	CD133	Prominin-1	Cell surface marker; cell renewal and differentiation	Kamamoto et al. 2019 [41]
	ALDH1	Aldehyde Dehydrogenase 1	Enzymes involved in cellular detoxification	Arnold et al. 2020 [42]

Slidesgo. Project Management Infographics. 2022 [cited 2022 Jul 6]. Available from: https://slidesgo.com/theme/project-management-infographics#search-Infographics&position-1&results-982.

 Google Scholar

Slidesgo. Healthcare infographics. Human Icon And Test Tube Icon. 2022 [cited 2022 Jul 6]. Available from: https://slidesgo.com/theme/healthcare-infographics#search-healthcare&position-1&results-35.

 Google Scholar

Jagasia S. Literature search. Philadelphia, PA: Web of Science; 2023.

 Google Scholar

Zubair M, Wang S, Ali N. Advanced approaches to breast cancer classification and diagnosis. Front Pharmacol. 2021;11:11. doi: 10.3389/fphar.2020.632079

 Web of Science ®Google Scholar

Stewart J, Sahgal A, Chan AKM, et al. Pattern of recurrence of glioblastoma versus grade 4 IDH-Mutant astrocytoma following chemoradiation: a retrospective matched-cohort analysis. Technol Cancer Res Treat. 2022;21:21. doi: 10.1177/15330338221109650

 Web of Science ®Google Scholar

Wang Z, JIANG W, WANG Y, et al. MGMT promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma. Biomed Rep. 2015;3(4):543–548. doi: 10.3892/br.2015.462

 PubMedGoogle Scholar

Wirth MP, Engelhardt FM. PSA recurrence after primary curative therapy — local or systemic? Urologe. 2005;44(9):997–1008. doi: 10.1007/s00120-005-0879-4

 Web of Science ®Google Scholar

Giuliani M, Gui B, Valentini AL, et al. Early detection of recurrence or progression disease in patients with ovarian cancer after primary debulking surgery. Correlation between CT findings and. CA 125 levels. Minerva Obstet Gynecol. 2017;69(6):538–547. doi: 10.23736/S0026-4784.17.04062-X

 Google Scholar

Xu Y, Yang Y, Li L, et al. The α-RECIST (RECIST 1.1 combined with alpha fetoprotein): a novel tool for identifying tumor response of conversion-radiotherapy for Unresectable Hepatocellular carcinoma before hepatectomy. Front Oncol. 2022;12:12. doi: 10.3389/fonc.2022.905260

 Web of Science ®Google Scholar

Lee JH, Kim DY, Kim SH, et al. Carcinoembryonic antigen has prognostic value for tumor downstaging and recurrence in rectal cancer after preoperative chemoradiotherapy and curative surgery: a multi-institutional and case-matched control study of KROG 14-12. Radiother Oncol. 2015;116(2):202–208. doi: 10.1016/j.radonc.2015.07.049

 PubMed Web of Science ®Google Scholar

Kozakiewicz B, Chadzynska M, Dmoch-Gajzlerska E, et al. Monitoring the treatment outcome in endometrial cancer patients by CEA and TATI. Tumor Biol. 2016;37(7):9367–9374. doi: 10.1007/s13277-016-4784-9

 PubMedGoogle Scholar

Shintani T, Matsuo Y, Iizuka Y, et al. Prognostic significance of serum CEA for non-small cell lung cancer patients receiving stereotactic body radiotherapy. Anticancer Res. 2017;37(9):5161–5167.

 PubMed Web of Science ®Google Scholar

Micke O, Bruns F, Kurowski R, et al. Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy. Int J Radiat Oncol Biol Phys. 2003;57(1):90–97. doi: 10.1016/S0360-3016(03)00524-8

 PubMed Web of Science ®Google Scholar

Toulany M. Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives. Clin Transl Radiat Oncol. 2023;38:6–14. doi: 10.1016/j.ctro.2022.10.004

 PubMed Web of Science ®Google Scholar

Mortezaee K, Parwaie W, Motevaseli E, et al. Targets for improving tumor response to radiotherapy. Int Immunopharmacol; 2019;76: 76.

 Web of Science ®Google Scholar

Ho V, Chung L, Lim SH, et al. Prognostic impact of TP53 mutations and tumor mutational load in colorectal cancer. Gastrointestinal Disorders. 2022;4(3):165–179. doi: 10.3390/gidisord4030016

 Google Scholar

Tsai MS, Chen WC, Lu CH, et al. The prognosis of head and neck squamous cell carcinoma related to immunosuppressive tumor microenvironment regulated by IL-6 signaling. Oral Oncol. 2019;91:47–55. doi: 10.1016/j.oraloncology.2019.02.027

 PubMed Web of Science ®Google Scholar

Jeong Y, Hoang NT, Lovejoy A, et al. Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer Discovery. 2017;7(1):86–101. doi: 10.1158/2159-8290.CD-16-0127

 PubMed Web of Science ®Google Scholar

Brown JM. Radiation damage to tumor vasculature initiates a program that promotes tumor recurrences. Int J Radiat Oncol Biol Phys. 2020;108(3):734–744. doi: 10.1016/j.ijrobp.2020.05.028

 PubMed Web of Science ®Google Scholar

Laube M, Kniess T, Pietzsch J. Development of antioxidant COX-2 inhibitors as Radioprotective agents for radiation therapy—A hypothesis-driven review. Antioxidants. 2016;5(2):14. doi: 10.3390/antiox5020014

 Web of Science ®Google Scholar

Breen KJ, O’Neill A, Murphy L, et al. Investigating the role of the IGF axis as a predictor of biochemical recurrence in prostate cancer patients post-surgery. Prostate. 2017;77(12):1288–1300. doi: 10.1002/pros.23389

 PubMed Web of Science ®Google Scholar

Katano A, Takahashi W, Yamashita H, et al. The impact of elevated C-reactive protein level on the prognosis for oro-hypopharynx cancer patients treated with radiotherapy. Sci Rep. 2017;7(1):17805.

 PubMedGoogle Scholar

Wang J, Xu Z, Wang Z, et al. TGF-beta signaling in cancer radiotherapy. Cytokine. 2021;148:155709. doi: 10.1016/j.cyto.2021.155709

 PubMed Web of Science ®Google Scholar

Zhao Y, Kang J-H, Yoo K-C, et al. K-RAS acts as a critical regulator of CD44 to promote the invasiveness and stemness of GBM in response to ionizing radiation. Int J Mol Sci. 2021;22(20):10923. doi: 10.3390/ijms222010923

 PubMed Web of Science ®Google Scholar

Kamamoto D, Saga I, Ohara K, et al. Association between CD133, CD44, and nestin expression and prognostic factors in high-grade meningioma. World Neurosurg. 2019;124:E188–E196. doi: 10.1016/j.wneu.2018.12.067

 Web of Science ®Google Scholar

Arnold CR, Mangesius J, Skvortsova II, et al. The role of cancer stem cells in radiation resistance. Front Oncol. 2020;10:164. doi: 10.3389/fonc.2020.00164

 PubMedGoogle Scholar