Biomarkers in Lung Cancer: Unlocking Precision Treatment

Lung cancer remains one of the most common and deadliest malignancies worldwide. Early detection and accurate molecular characterization are critical for improving survival. One of the most transformative advances in recent years is the integration of biomarker testing—the identification of measurable biological indicators that reveal a tumor’s molecular profile, behavior, and treatment vulnerabilities.

In modern thoracic oncology, biomarkers guide not only diagnosis and prognosis, but most importantly, the selection of targeted therapies and immunotherapies that have dramatically improved outcomes.

What Are Biomarkers and Why Do They Matter in Lung Cancer?

Biomarkers are biological molecules—such as DNA, RNA, proteins, or metabolites—found in tissue, blood, or other body fluids that signal normal or abnormal processes. In lung cancer, they can help:

• Detect cancer earlier, even before symptoms appear
• Distinguish between different cancer subtypes (e.g., NSCLC vs. SCLC)
• Predict how a patient will respond to a specific drug
• Monitor treatment response or disease recurrence

Molecular testing has made personalized medicine a reality in lung cancer—ensuring each patient receives therapy tailored to the genetic and immunologic makeup of their tumor.

Key Genetic and Molecular Biomarkers in Non-Small Cell Lung Cancer (NSCLC)

Most biomarker testing is performed in NSCLC, particularly in adenocarcinoma and never-smoker patients, though squamous histology is also being increasingly profiled when feasible.

Actionable Genetic Alterations (Driver Mutations and Fusions):

Biomarker	Molecular Type	Key Notes	Targeted Therapy
EGFR mutations	Point mutations/exon 19 deletions/exon 21 L858R	Common in non-smokers; exon 20 insertions have distinct therapies	Osimertinib, Amivantamab (for exon 20ins)
ALK rearrangements	Gene fusion	Younger non-smokers; sensitive to ALK inhibitors	Alectinib, Lorlatinib
ROS1 fusions	Gene fusion	~1–2% NSCLC	Entrectinib, Crizotinib
BRAF V600E	Point mutation	~2% NSCLC	Dabrafenib + Trametinib
MET exon 14 skipping	Splicing alteration	~3–4% NSCLC	Capmatinib, Tepotinib
RET fusions	Gene fusion	<2% NSCLC	Selpercatinib, Pralsetinib
NTRK fusions	Gene fusion	<1% but pan-cancer actionable	Entrectinib, Larotrectinib
KRAS G12C	Point mutation	Most common (~25–30%); smoking-related	Sotorasib, Adagrasib
HER2 mutations	Exon 20 insertions	2–4% of NSCLC	Trastuzumab Deruxtecan (T-DXd)
NRG1 fusions	Rare fusion	Under clinical evaluation	Experimental therapies (Afatinib, Seribantumab trials)

Testing methods: Next-Generation Sequencing (NGS) is now the preferred standard, as recommended by NCCN, ESMO, and CAP/IASLC/AMP guidelines, due to its ability to detect multiple actionable alterations simultaneously using minimal tissue.

PD-L1 Expression and Immunotherapy Response

PD-L1 (Programmed Death-Ligand 1) is a key immunohistochemical biomarker that helps predict response to immune checkpoint inhibitors (ICIs) such as pembrolizumab, nivolumab, or atezolizumab.

• PD-L1 expression is quantified using Immunohistochemistry (IHC) and reported as a Tumor Proportion Score (TPS).
• Patients with TPS ≥50% are often eligible for first-line single-agent immunotherapy.
• Even patients with lower PD-L1 expression (1–49%) may benefit from chemo-immunotherapy combinations.
• Absence of PD-L1 expression (TPS <1%) does not exclude immunotherapy but may influence regimen choice.

Protein Biomarkers Used in Clinical Practice

Although tissue and molecular tests are the gold standard, serum protein biomarkers continue to play a role in disease monitoring, especially when tissue sampling is difficult. They have a very limited role in the management of Lung Cancer.

Biomarker	Associated Subtype	Clinical Use
CEA (Carcinoembryonic Antigen)	Adenocarcinoma	Treatment response and recurrence monitoring
CYFRA 21-1	Squamous cell carcinoma	Disease monitoring; higher baseline levels correlate with poorer prognosis
SCC Antigen	Squamous carcinoma	Adjunctive diagnostic marker
NSE (Neuron-Specific Enolase)	Small Cell Lung Cancer (SCLC)	Disease activity monitoring
Pro-GRP (Progastrin-Releasing Peptide)	SCLC	Highly specific, often superior to NSE for diagnosis and follow-up

These markers are not diagnostic in isolation but provide valuable complementary data with imaging and histopathology.

Emerging Biomarkers: Liquid Biopsy and Circulating microRNAs

Liquid biopsy—testing circulating tumor DNA (ctDNA) or microRNAs (miRNAs) from plasma—is transforming the landscape of lung cancer diagnostics.

• ctDNA NGS can detect resistance mutations (e.g., EGFR T790M or C797S) non-invasively.
• Circulating microRNAs (c-miRNAs) such as miR-21, miR-155, and miR-210 show potential as early detection and prognostic tools, though they remain research-stage rather than clinical routine.
• Liquid biopsy is particularly useful when tissue biopsy is not feasible or for monitoring minimal residual disease (MRD).

Personalized Treatment Through Biomarker-Driven Medicine

Biomarker integration allows clinicians to design customized treatment pathways:

• Targeted Therapy: For tumors harboring actionable mutations (EGFR, ALK, ROS1, etc.).
• Immunotherapy: For tumors with PD-L1 expression or high Tumor Mutational Burden (TMB).
• Combination or Sequential Strategies: Guided by evolving biomarker profiles on re-biopsy or liquid biopsy.

This approach minimizes ineffective therapy exposure, reduces toxicity, and improves progression-free and overall survival.

Conclusion

Biomarkers have revolutionized the way we understand and treat lung cancer. From driver mutation detection to immune profiling and liquid biopsies, these molecular insights enable oncologists to move from a “one-size-fits-all” approach to precision oncology.

As research progresses, novel biomarkers—such as MET amplifications, KRAS co-mutations, TMB, and microRNA signatures—are expected to further refine therapy selection and prognostication.

If you or a loved one is diagnosed with lung cancer, discuss comprehensive biomarker testing with your oncologist or pathologist—it could define the most effective, personalized treatment strategy.

Frequently Asked Questions (FAQ)

Q1: Are biomarkers enough to diagnose lung cancer?

A: No. Biomarkers supplement, but do not replace, histopathological diagnosis based on tissue morphology.

Q2: When should biomarker testing be done?

A: Ideally at the time of initial diagnosis of NSCLC, particularly in advanced (stage III–IV) disease, before treatment initiation. Retesting may be indicated at progression.

Q3: Can biomarker profiles change over time?

A: Yes. Tumor heterogeneity and treatment pressure can lead to new resistance mutations; hence, repeat testing (tissue or liquid biopsy) may be necessary.

Q4: How are biomarkers tested?

A: Via tissue biopsy, blood-based assays, or pleural fluid samples using methods like NGS, PCR, or IHC.

Q5: Are biomarker tests accessible to all patients?

A: Most major cancer centers and tertiary hospitals offer biomarker testing. In India, government and private panels (e.g., FoundationOne CDx, OncoFocus) are increasingly available.

Q6: Are they expensive?

A: Costs have decreased substantially; guideline-recommended biomarker panels are often covered under insurance or institutional cancer care programs.