Biomarker Testing in Lung Cancer

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Which biomarker tests are recommended in early lung cancer (Stage I-III) NSCLC?
Which biomarker tests are recommended in advanced/metastatic (Stage IV) NSCLC?
When do I test?
Biomarker testing and treatment guidelines

Biomarker testing can support HCPs to make treatment decisions in an approach known as personalised medicine; this ensures each patient receives the most appropriate treatment for their tumour. It has been shown that patients with biomarker results available at the time of their initial oncology consultation benefit from shorter times to treatment administration, compared with patients whose results are unavailable.¹

The aim of biomarker testing is to inform treatment decisions and provide optimal outcomes for patients.

The estimated biomarker prevalence for patients with NSCLC are listed in the table below:

Biomarker	Estimated prevalence in NSCLC cases (%)	Additional information
EGFR mutation^2-4	12-49	Highest prevalence in Asian patients, females, non-smokers and patients with adenocarcinoma
ALK fusions^4,5	3-6	Highest prevalence in young (median age ~55 years) patients and never/light smokers with adenocarcinoma
ROS1 rearrangements^4,6	1-2	Highest prevalence in never-smokers and those with adenocarcinoma
BRAF mutations^4,7-9	2-5	Highest prevalence in current/former smokers and patients with adenocarcinoma
KRAS G12C mutations^10,11	13	Highest prevalence in current/former smokers and patients with adenocarcinoma
MET exon 14 skipping mutations^4,10,12	2-3	Highest prevalence in elderly patients (median age 72.5 years), females, and patients with adenocarcinoma
RET rearrangements^4,10,13	1-2	Highest prevalence in younger patients and never-smokers
HER2 mutations^4,10,14	1-4	Highest prevalence in females, non-smokers and patients with adenocarcinoma
NTRK1/2/3 fusions^4,15	≤1	Rare alteration, without defining clinical or pathologic features
PD-L1 expression^16-19	50-68	Estimates depend on cut-off used

ABBREVIATIONS:

ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma virus; MET, MET proto-oncogene, receptor tyrosine kinase; NSCLC, non-small cell lung cancer; NTRK1/2/3, neurotrophic receptor tyrosine kinase 1/2/3; PD-L1, programmed cell death ligand-1; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1

Which biomarker tests are recommended in early lung cancer (Stage I–III) NSCLC?

For patients with early lung cancer*, guidelines commonly recommended testing for the following:^20–22

EGFR gene mutations

ALK gene fusions

PD-L1 protein expression

^*Per NCCN Guidelines^®, testing in early-stage NSCLC is recommended for Stages IB-IIIA, IIIB (T3,N2)

In the videos below, various experts share their perspectives on biomarker testing for patients with resectable (early-stage) NSCLC.

Biomarker testing in patients with resectable NSCLC: clinical staging and biopsy site selection

Description: Dr Neal Navani (Consultant Respiratory Physician, University College London Hospital, London, UK) provides a perspective on the guiding principles for clinical staging and optimal biopsy site selection.

Veeva ID: Z4-63486 | Date of preparation: July 2024

Biomarker testing in patients with resectable NSCLC: The evolving patient journey

Description: Professor Sanjay Popat (Consultant Medical Oncologist at The Royal Marsden and Professor of Thoracic Oncology, The Institute of Cancer Research, UK), Dr Neal Navani, and Dr Ángeles Montero-Fernández (Senior Consultant, Liverpool Clinical Laboratories, Liverpool, UK) share their perspectives on the evolving patient journey for resectable NSCLC.

Veeva ID: Z4-63484 | Date of preparation: April 2024

Biomarker testing in patients with resectable NSCLC: practical considerations to overcome challenges

Description: Professor Sanjay Popat, Dr Neal Navani, and Dr Ángeles Montero-Fernández discuss practical considerations and strategies to overcome the challenges of biomarker testing in the resectable setting.

Veeva ID: Z4-63488 | Date of preparation: July 2024

Aside from genetic and molecular analyses to inform treatment decisions in resectable NSCLC, there is increasing interest into the application of pathological markers to inform neoadjuvant treatment response. pCR and MPR are early endpoints being explored in neoadjuvant trials that may correlate with clinical outcomes in patients with resectable NSCLC.²³

The videos below provide an overview of pCR and MPR, including the calculations and technical considerations involved.

Veeva ID: Z4-60134 | Date of preparation: January 2024

Pathological assessments of resected lung cancers after neoadjuvant immunotherapy

Professor Keith Kerr (Department of Pathology Aberdeen Royal Infirmary and Aberdeen University School of Medicine, Aberdeen, UK) discusses how to assess resected tumours to understand the pathological response to neoadjuvant treatment.

Play video

Veeva ID: Z4-61371 | Date of preparation: March 2024

The role of pathological complete response (pCR) in lung cancer: expert perspectives on assessment and clinical implication

Professor Jarushka Naidoo (Consultant Medical Oncologist, Beaumont Hospital Dublin, Ireland) discusses how pCR can be used to assess response to neoadjuvant therapy. Professor Sanja Dacic (Vice Chair and Director of Anatomic Pathology, Yale School of Medicine, USA) shares a pathologist’s perspective on assessing pCR, and compares the IASLC and irPRC criteria for pathologic response.

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Veeva ID: Z4-66632 | Date of preparation: November 2024

Overview of pathological complete response and major pathological response in lung cancer

Dr Ángeles Montero-Fernández discusses practical considerations regarding the implementation of pCR and MPR in clinical practice. Dr Montero-Fernández provides an overview of the diagnostic journey, from the pCR request form to the management of specimens, as well as discussing how pCR and MPR may inform treatment decisions for patients with early-stage NSCLC.

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Another notable biomarker under investigation in early-stage NSCLC is the utility of ctDNA quantification, which is a proxy for MRD, to monitor likelihood of disease relapse.²⁴ Presence of ctDNA MRD early after complete resection is associated with increased risk of disease recurrence.²⁵ There are, however, some challenges to overcome before ctDNA MRD can be routinely used, including the limited application in patients with very early disease status (Stage I) due to the low frequency of detectable ctDNA.²⁴

Which biomarker tests are recommended in advanced/metastatic (Stage IV) NSCLC?

Guidelines commonly recommend testing for the following biomarkers in advanced lung cancer:^{21,22,26–33}

EGFR gene mutations
ALK gene fusions
ROS1 gene rearrangements
BRAF gene mutations
KRAS G12C mutations

MET exon 14 skipping mutations
RET gene rearrangements
HER2 mutations
NTRK1/2/3 gene fusions
PD-L1 protein expression

Assessment of other emerging biomarkers, including MET amplifications²¹, STK11 mutations, KEAP1 mutations, HER2 amplifications, TMB, and MSI are also often considered when using extended molecular panels or when routine testing is negative.³¹

EGFR mutation

EGFR mutations associated with NSCLC commonly occur between exons 18 and 21 of the EGFR gene. The two most prevalent EGFR mutations are an in-frame deletion of exon 19 and L858R point mutation in exon 21 (45% and 40% of samples from patients with EGFRm NSCLC, respectively). Less common EGFR mutations include point mutations: L861Q in exon 21, G719X in exon 18, and S768I in exon 20 (10% of samples from patients with EGFRm NSCLC). Tumours harbouring these mutations are sensitive to EGFR-TKI treatment.³⁴ Most EGFR exon 20 insertion mutation variants do not respond treatment with first-, second-, or third-generation EGFR-TKIs.²¹ Certain patients with EGFR exon 20 insertion mutations may receive treatment with a bispecific monoclonal EGFR and MET receptor-directed antibody.²¹

ALK fusions

ALK fusions occur when part of the ALK gene translocates to a partner gene, leading to the creation of a fusion oncogene. The most common partner gene implicated in NSCLC is EML4. Oncogenic EML4-ALK induces tumour formation in mice, which can be reduced after the administration of ALK-TKIs in vitro and in vivo.⁵

ROS1 rearrangements

ROS1 is a receptor tyrosine kinase of the insulin receptor family. Chromosomal rearrangements involving the ROS1 gene can lead to constitutive kinase activity and these mutations are associated with sensitivity to TKIs in vitro.⁶

BRAF mutations

BRAF is a protein kinase involved in the MAPK/ERK pathway, which is involved in cell growth, proliferation, survival and differentiation. Approximately 50% of BRAF mutations in NSCLC are due to a point mutation in exon 15 (V600E), with 50% due to non-V600E mutations. The BRAF V600E mutation results in oncogenic properties including enhanced ERK activity.³⁵

KRAS G12C mutations

KRAS is an oncogene of the RAS family. The KRAS gene encodes for the KRAS protein, a GTPase that regulates cell signalling, and can drive tumour growth, differentiation and survival. The KRAS protein was previously thought to be ‘undruggable’ due to its smooth surface, however the discovery of a pocket in G12C-mutated KRAS allowed for the development of a selective KRAS G12C inhibitor. The G12C mutation is found in a third of patients with KRAS-mutated NSCLC.³⁶

MET exon 14 skipping mutations

MET is a proto-oncogene that encodes a receptor tyrosine kinase. MET exon 14 skipping, caused by molecular alterations in the surrounding introns, leads to the mis-splicing of the exon. The resulting MET protein is abnormal and causes oncogenic signalling. Patients with MET mutations are sensitive to MET-TKIs.³⁷

RET rearrangements

RET rearrangements occur when part of the RET gene translocates to a partner gene, leading to the creation of a fusion oncogene. Partner genes implicated in NSCLC include KIF5B, NCOA4, and CCDC6. RET rearrangements cause constitutive activation of RET signalling pathways, leading to tumour cell proliferation and survival.^13,21,38

HER2 mutations

The HER2 gene encodes for a tyrosine kinase receptor. Mutations in the HER2 gene most frequently occur in exons 18–21. HER2 activating mutations are linked with responsiveness to anti-HER2 agents.¹⁴

NTRK1/2/3 fusions

Fusions in the NTRK1/2/3 genes lead to the expression of a constitutively active protein, and abnormal TRK signalling. NTRK1/2/3 gene fusions are associated with responsiveness to oral TRK inhibitors.¹⁵

STK11 and KEAP1 mutations

Mutations in tumour suppressor gene STK11 can be found in up to 5–30% of patients with mNSCLC.³⁹ KEAP1 mutations have been reported to be present 10–30% of NSCLC tumours.³⁹ Current data suggest that outcomes for patients with non-squamous NSCLC that harbour mutations in STK11 or KEAP1 are worse than those for patients with STK11- and KEAP1-wild-type tumours.^40,41

PD-L1 expression

The PD-1/PD-L1 pathway is an important checkpoint used by tumour cells to inhibit antitumour immune responses.⁴² In-vitro assessment suggests that PD-L1 can be overexpressed by lung cancer cells through the actions of surrounding cytokines, which prevents T-cell-mediated tumour cell elimination.^43–45 PD-1/PD-L1 inhibitors are effective therapies in tumours with high PD-L1 expression since the interaction between immune cell PD-1 and tumour cell PD-L1 is prevented, thus promoting a natural immune response against the tumour.⁴³

Veeva ID: Z4-60139 | Date of preparation: January 2024

The role of PD-L1 testing for immunotherapy

Professor Patrick Pauwels (Professor of Molecular Oncopathology, University of Antwerp, Belgium) discusses how PD-L1 testing can be used to predict response to immunotherapy.

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Mechanism of action of anti-PD-L1 therapy

PD-L1 expression leads to immune cell evasion

Anti-PD-1/PD-L1 reverses immune suppression

Mechanism of action of anti-PD-L1 therapy

PD-L1 expression leads to immune cell evasion

Anti-PD-1/PD-L1 reverses immune suppression

Figure adapted from Peters, et al. 2019⁴²

PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1

PD-L1 expression leads to immune cell evasion

Anti-PD-1/PD-L1 reverses immune suppression

Figure adapted from Peters, et al. 2019⁴²

PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1

When do I test?

It is recommended that biomarker testing should occur at the initial disease diagnosis and during disease progression.^21,28 Typically, biomarker testing is oncologist-led, and occurs following the establishment of a pathological diagnosis and an MDT discussion. However, with the agreement of the MDT, a pathologist may initiate biomarker testing; this practice is referred to as reflex testing.⁴⁶ Reflex testing is recommended as an optimal strategy to ensure that patients are tested in a timely manner.^{46, 47}

For more information on the clinical utility, considerations, and challenges associated with reflex testing in NSCLC, watch the panel discussions below to hear from experts Prof. Brendon Stiles (Professor and Chief, Thoracic Surgery and Surgical Oncology, Department of Cardiothoracic & Vascular Surgery at Montefiore-Einstein, New York, US), Prof. Marina Garassino (Professor of Medicine at the University of Chicago, Chicago, US), Prof. John Gosney (Professor of Thoracic Pathology, Royal Liverpool University Hospital and University of Liverpool, Liverpool, UK), and Dr Juan Botero (Interventional Pulmonologist, Clínica Cardio VID, Medellín, Colombia).

Implementation of reflex testing may enhance patient care, and improve ways of working in clinical institutions

Veeva ID: Z4-61368 | Date of preparation: January 2024

Reflex testing: what it is & the clinical utility it provides

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The panel provide an introduction to reflex testing, and share how the implementation of reflex testing may enhance patient care, and improve ways of working in clinical institutions.

The experts discuss how the multidisciplinary team can work together to implement effective sample acquisition, and tissue stewardship practices.

Veeva ID: Z4-61369 | Date of preparation: January 2024

Reflex testing: practical considerations around implementation

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The panel reflect on their experience with implementing reflex testing in their institutions. With a focus on the use of reflex testing in early-stage NSCLC, the experts discuss how the multidisciplinary team can work together to implement effective sample acquisition, and tissue stewardship practices.

Discussion on how to overcome challenges related to reflex testing, including sample acquisition, and test reimbursement

Veeva ID: Z4-61370 | Date of preparation: January 2024

Reflex testing: challenges and solutions

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The experts conclude the discussion by sharing their perspectives on how to overcome challenges related to reflex testing, including sample acquisition, and test reimbursement.

ctDNA from blood (plasma) may be considered if a tumour sample cannot be obtained.²¹

In some cases, such as patients with EGFR mutations, a tumour rebiopsy at disease progression is recommended in order to guide future treatment decisions.²⁸

Two stages of disease management that use biomarker testing to inform treatment decisions

Initial testing (diagnosis)

Used to identify tumours with biomarkers that would make them more sensitive to certain treatments^{21, 28}

Patients with NSCLC harbouring a targetable biomarker may derive a greater benefit from targeted therapies (e.g. IO) compared with non-targeted therapies (e.g. CTx)²¹

Testing on progression

Used to identify resistance biomarkers in patients who progress on treatment

Identification of resistance biomarkers at disease progression can inform the next treatment decision²⁸

ABBREVIATIONS:

CTx, chemotherapy; IO, immunotherapy, NSCLC, non-small cell lung cancer

Results of such biomarker tests inform treatment decisions, therefore notifying the patient of results should be done in a timely manner. For example, it is suggested that the turnaround time to get available results from a requested mutational test should be less than ten working days.²⁶

Biomarker testing and treatment guidelines

NSCLC biomarker testing and treatment guidelines, including those from ASCO, an Asian expert consensus, CAP-IASLC-AMP, CSCO-ESMO, ESMO, National Comprehensive Cancer Network^® (NCCN^®) and SEOM-SEAP suggest that all patients with advanced/metastatic NSCLC should undergo biomarker testing.^{21,22,27-29,31–33,48} Some guidelines, including those from an Asian expert consensus, ESMO, NCCN and SEOM-SEAP recommend biomarker testing for early-stage NSCLC.^20–22,31

Treatment recommendations for a patient with NSCLC reflect the benefit of targeting the genetic abnormality driving the disease, where any is detected.^21,28 It has been shown that some tumours harbouring genetic mutations also express PD-L1 and treatment with PD-1/PD-L1 inhibitors in these patients is associated with low response rates.⁴⁹ Therefore, it is recommended that targeted therapy against the genetic abnormality should take precedence over treatment with PD-1/PD-L1 therapies.²¹
Establishing the status of all relevant lung biomarkers before initiating treatment is essential.

Veeva ID: Z4-60054 | Date of preparation: December 2023

The importance of obtaining all biomarker test results before starting treatment for NSCLC

Dr Federico Cappuzzo (Department of Oncology-Hematology, AUSL della Romagna, Ravenna, Italy) discusses the importance of obtaining all biomarker test results before starting treatment for NSCLC.

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Please refer to your local guidelines for guidance on treatment and management options in NSCLC

North America
ASCO
CAP-ACP
CAP-IASLC-AMP
NCCN

Europe
ESMO
SEOM-SEAP

ABBREVIATIONS:
ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; BRAF, B-Raf proto-oncogene; CAP, College of American Pathologists; CAP-ACP, Canadian Association of Pathologists-Association Canadienne Des Pathologistes; CSCO, Chinese Society of Clinical Oncology; CTx, chemotherapy; ctDNA, circulating tumour DNA; EGFR(m), epidermal growth factor receptor (mutation-positive); EML4, EMAP like 4; ERK, extracellular signal-regulated kinase; ESMO, European Society for Medical Oncology; GTP, guanosine triphosphate; HER2, human epidermal growth factor receptor 2; IASLC, International Association for the Study of Lung Cancer; IO, immunotherapy; KEAP1, Kelch-like ECH-associated protein 1; KRAS, Kirsten rat sarcoma virus; MAPK, mitogen activated protein kinase; MDT, multidisciplinary team; MET, MET proto-oncogene, receptor tyrosine kinase; mNSCLC, metastatic non-small cell lung cancer; MPR, major pathological response; MRD, minimal residual disease; MSI, microsatellite instability; NCCN, National Comprehensive Cancer Network; NSCLC, non-small cell lung cancer; NTRK1/2/3, neurotrophic receptor tyrosine kinase 1/2/3; pCR, pathological complete response; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1; SEAP, Spanish Society of Pathology; SEOM, Spanish Society of Medical Oncology; STK11, serine/threonine kinase 11; TKI, tyrosine kinase inhibitor; TMB, tumour mutational burden

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Awad MM, et al. MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression. J Clin Oncol 2016;34:721–30.
Wang R, et al. RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer. J Clin Oncol 2012;30:4352–9.
Garrido-Castro AC, Felip E. HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches. Transl Lung Cancer Res 2013;2:122–7.
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Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer V.11.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 28, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Mitsudomi T, et al. Expert Consensus Recommendations on Biomarker Testing in Metastatic and Nonmetastatic NSCLC in Asia. J Thorac Oncol 2023;18:436–46.
Blumenthal GM, et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol 2018;13:1818–31.
Xia J, et al. Circulating tumor DNA minimal residual disease in clinical practice of non-small cell lung cancer. Expert Rev Mol Diagn 2023;23:913–24.
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Why do I test?

Jump to section:

ABBREVIATIONS:

Which biomarker tests are recommended in early lung cancer (Stage I–III) NSCLC?

Biomarker testing in patients with resectable NSCLC: clinical staging and biopsy site selection

Biomarker testing in patients with resectable NSCLC: The evolving patient journey

Biomarker testing in patients with resectable NSCLC: practical considerations to overcome challenges

Pathological assessments of resected lung cancers after neoadjuvant immunotherapy

The role of pathological complete response (pCR) in lung cancer: expert perspectives on assessment and clinical implication

Overview of pathological complete response and major pathological response in lung cancer

Which biomarker tests are recommended in advanced/metastatic (Stage IV) NSCLC?

EGFR mutation

ALK fusions

ROS1 rearrangements

BRAF mutations

KRAS G12C mutations

MET exon 14 skipping mutations

RET rearrangements

HER2 mutations

NTRK1/2/3 fusions

STK11 and KEAP1 mutations

PD-L1 expression

The role of PD-L1 testing for immunotherapy

Mechanism of action of anti-PD-L1 therapy

PD-L1 expression leads to immune cell evasion

Anti-PD-1/PD-L1 reverses immune suppression

PD-L1 expression leads to immune cell evasion

Anti-PD-1/PD-L1 reverses immune suppression

PD-L1 expression leads to immune cell evasion

Anti-PD-1/PD-L1 reverses immune suppression

When do I test?

Reflex testing: what it is & the clinical utility it provides

Reflex testing: practical considerations around implementation

Reflex testing: challenges and solutions

Two stages of disease management that use biomarker testing to inform treatment decisions

Initial testing (diagnosis)

Testing on progression

ABBREVIATIONS:

Biomarker testing and treatment guidelines

The importance of obtaining all biomarker test results before starting treatment for NSCLC

Please refer to your local guidelines for guidance on treatment and management options in NSCLC

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Reflex testing: practical considerations around implementation

Two stages of disease management that use biomarker testing to inform treatment decisions