The role of biomarkers in stage III non-small cell lung cancer

ABSTRACT

Introduction

Stage III non-small cell lung cancer (NSCLC) is a composite of the regional spread of lung cancer with different levels of potential lymph node involvement and tumor size that often deem the stage at time of diagnosis to be unresectable and suitable for chemoradiation plus consolidation immunotherapy with durvalumab for 12 months. Chemoradiation plus durvalumab consolidation yielded a landmark 49.2% 5-year overall survival in unresectable NSCLC.

Areas covered

Sub-optimal results lead us to focus on the mechanisms of resistance responsible for intractability in a significant proportion of cases that fail with chemoradiation and immunotherapy. In stage III NSCLC it is opportune to explore the accumulated evidence on ferroptosis resistance that can lead to cancer progression and metastasis. Strong data shows that three anti-ferroptosis pathways are principally involved in resistance to chemotherapy, radiation, and immunotherapy.

Expert opinion

Because a large part of stage III NSCLCs is resistant to chemoradiation and durvalumab consolidation, a ferroptosis-based therapeutic approach, combined with standard-of-care therapy, can lead to improved clinical outcomes in patients diagnosed with stage III and possibly stage IV NSCLCs.

KEYWORDS:

• Stage III NSCLC
• ferroptosis
• Durvalumab, SLC17A11
• DHODH
• p53
• KEAP1
• NRF2
• chemoradiation

Article highlights

• Locally advanced NSCLC, or stage III, encompasses different tumor sizes and regional spread lymph node metastasis, without lung or distant metastasis, and is often deemed as unresectable disease.

• Chemoradiation followed by immunotherapy and consolidation therapy with durvalumab is current standard-of-care. Five-year progression-free-survival achieved in one-third of patients. In majority of stage III NSCLCs patients, lung cancer is impervious to most forms of cancer management.

• Identification of biomarkers could help sub-classify prognostic groups with countermeasures to neutralize mechanisms of resistance to either chemoradiation or immunotherapy.

• To date, sub-group analysis in stage 3 trials with chemoradiation and consolidation immunotherapy in unresectable stage III NSCLC have not identified any significant differences according to histology, programmed cell death ligand 1 (PD-L1), tumor mutation burden, or others.

• P53 mutations or p53 deficiency is observed in more than 50% of NSCLC patients, hampering effect of chemoradiation by reducing ferroptosis, leading to upregulation of the cystine transporter SLC17A11 and synthesis of strong anti-ferroptotic metabolites (GPX4). Other transcriptional factors (NFE2L2 or NRF2) induce overexpression of SLC17A11.

• Targeting antiferroptosis biomarkers (SLC17A11-GPX4 or de novo pyrimidine biosynthesis DHODH gatekeeper, for example) could help maneuver the standard-of-care treatment of chemoradiation and immunotherapy with the addition of ferroptosis inducers.

Acknowledgments

The authors thank Lourdes Franquet and Stephanie Davis for their help in the preparation of this manuscript

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.