Lung Cancer | Precision Medicine

Tumor Types & Biomarkers
Tumor Types & Biomarkers

Explore clinical guidelines on why, whom and how to test actionable biomarkers in lung, breast, ovarian and prostate cancers.
- Lung Tumor
  
  EGFR
  
  ERBB2 (HER2)
- Breast Tumor
  
  BRCA1/2
  
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  HRD
- Prostate Tumor
  
  HRRm
  
  PTEN
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Testing Recommendations
Biomarkers Informing Treatment Options
Actionable Biomarkers Prevalence
Considerations for Your Practice
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Biomarker Testing Is Transforming the Management of Lung Cancer

In the US, lung cancer is the leading cause of cancer mortality, causing 20% of cancer deaths.¹ Precision Medicine is improving survival rates for NSCLC through targeted therapies guided by biomarker testing.²

Overall survival doubled for patients with advanced NSCLC who had biomarker testing, compared with those who did not.^2,a

^aResults taken from a retrospective analysis including 48,857 patients diagnosed with advanced NSCLC (stage IIIB or IV) between January 1, 2011 and May 31, 2018. 17,555 eligible patients with non-squamous advanced NSCLC were then classified into either patients who had any actionable CDx test for one of the four driver mutations (ALK, BRAF, EGFR or ROS1 positive or negative) and/or PD-L1 expression (n=14,732) and those who did not have reported evidence of testing (n=2,823). Patients with CDx testing had a longer median survival than those without testing (median overall survival [95% CI], 13.04 [12.62–13.40] months vs 6.01 [5.72–6.24] months).²

ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene serine/threonine kinase; CDx, companion diagnostic; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

Lung Cancer Biomarker Testing Recommendations Are Integral to Treatment Decisions

Precision medicine in NSCLC relies on effective biomarker testing for optimal cancer care. NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines^®) recommend testing for all eligible patients.³

Resectable
Stages IB–IIIA,
IIIB (T3, N2)

Biomarker
testing^a–c

EGFR mutation
ALK rearrangement
PD-L1 status (IHC)

Test all eligible patients
with resectable NSCLC at
the earliest opportunity
to support critical systemic
treatment decisions

Establish
histology

ADC,
large-cell,
NSCLC
NOS

Metastatic
disease

Consider
molecular
testing for
SCC

Biomarker
testing

Molecular testing^b,d,e
(EGFR, ERBB2 [HER2],
ALK, KRAS, ROS1,
BRAF, MET exon 14
skipping, RET,
NTRK1/2/3, high-level
MET amplification)

Driver oncogene positive (actionable)

EGFR mutation positive^f
ERBB2 (HER2) mutation positive
ALK rearrangement positive
KRAS G12C mutation positive
ROS1 rearrangement positive
BRAF V600E mutation positive
MET exon 14 skipping mutation positive
RET rearrangement positive
NTRK1/2/3 gene fusion positive

Treatment selection
based on positive
actionable biomarker
status^g

Driver oncogene positive (emerging)

High-level MET amplification positive

Positive-emerging
biomarker status may
help inform clinical
decisions and clinical
trial eligibility⁴

PD-L1 IHC
testing^b

Driver oncogene negative

PD-L1 ≥1%
PD-L1 <1%

Treatment selection
based on driver
oncogene status
and PD-L1
expression level^h

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer V.11.2024. © 2024 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines^® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available.

Testing early, such as at preoperative biopsy, can guide critical systemic treatment decisions, inform potential trial eligibility, and support testing workflow efficiency. In the advanced or mNSCLC setting, when biopsy samples are insufficient or unavailable, consider using plasma ctDNA.³

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^aIn resectable NSCLC, a preoperative biopsy is recommended for patients with clinical Stage IB or higher who may be candidates for systemic therapy prior to surgery.³ ^bThe NCCN Guidelines^® for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific assays or commercial laboratories.³ ^cTesting is recommended for EGFR mutations, ALK rearrangements, and PD-L1 status for eligible patients with resectable Stage IB-IIIA, IIIB (T3, N2) NSCLC using a preoperative biopsy or surgical tissue.³ ^dNCCN Guidelines strongly advise broader molecular profiling for eligible patients with metastatic NSCLC with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is defined as molecular testing that identifies all recommended and emerging biomarkers in either a single assay or a combination of a limited number of assays.³ ^eIf there is insufficient tissue to allow testing for all of EGFR, ERBB2 (HER2), ALK, KRAS, ROS1, BRAF, MET exon 14 skipping, NTRK1/2/3, and RET, consider tissue rebiopsy or ctDNA testing.³ ^fIncludes exon 19 deletions, exon 21 L858R mutation, exon 20 insertion, p.S768I, p.L861Q, and/or p.G719X mutations. Certain patients with EGFR exon 20 insertion mutations should receive systemic treatment in 1L; targeted therapies are recommended as 2L treatment options.³ ^gIn patients with metastatic NSCLC, 1L treatment selection is based on driver mutation–positive status except in certain patients whose tumors harbor an EGFR exon 20 insertion mutation, a KRAS G12C mutation, or an ERBB2 (HER2) mutation as the sole driver mutation. Certain patients with an EGFR exon 20 insertion mutation, KRAS G12C mutation, or an ERBB2 mutation should receive systemic treatment in 1L; targeted therapies are recommended as 2L treatment options. Patients with EGFR exon 20 insertion mutations and nonsquamous histology can receive targeted therapy in the 1L.³ ^hIn patients with metastatic NSCLC, 1L treatment selection is based on PD-L1 expression level and molecular biomarker status except in certain patients whose tumors harbor an EGFR exon 20 insertion mutation, a KRAS G12C mutation, or an ERBB2 (HER2) mutation as the sole driver mutation. Certain patients with an EGFR exon 20 insertion mutation, a KRAS G12C mutation, or an ERBB2 (HER2) mutation should receive systemic treatment in 1L; targeted therapies are recommended as 2L treatment options. Patients with EGFR exon 20 insertion mutations and nonsquamous histology can receive targeted therapy in the 1L.³

1L, first-line; 2L, second-line; ADC, adenocarcinoma; ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; ctDNA, circulating tumor deoxyribonucleic acid; EGFR, epidermal growth factor receptor; ERBB2, erb-B2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; N, node; NCCN, National Comprehensive Cancer Network^® (NCCN^®); NOS, not otherwise specified; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; PD-L1, programmed death-ligand 1; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1, tyrosine receptor kinase; SCC, squamous cell carcinoma; T, tumor; TAT, test turnaround time.

Comprehensive Biomarker Testing May Inform Treatment Eligibility^3,5

NCCN Guidelines strongly advise broad molecular profiling in eligible patients with advanced or mNSCLC with the goal of identifying actionable biomarkers to ensure that the most appropriate treatment can be selected, or to appropriately counsel individuals regarding the availability of clinical trials.^3,a

NCCN Guidelines recommend the use of tissue and ctDNA specimens.^3,b–d Testing can be performed concurrently or in a sequence. Consider concurrent testing to help improve turnaround time. If certain clinically actionable biomarkers are identified via either method, biomarker-based therapy may be initiated.³

Setting	Biomarker type	Biomarker	NGS	PCR	ISH/FISH	IHC	Sanger sequencing
Resectable	Actionable³	ALK
		EGFR
		PD-L1 status
Advanced or mNSCLC	Actionable³	ALK
		BRAF
		EGFR
		ERBB2 (HER2) mutation
		HER2 overexpression
		KRAS
		MET exon 14 skipping
		NTRK1/2/3
		PD-L1 status
		RET
		ROS1
	Emerging^3,5	High-level MET amplification

^aThe NCCN Guidelines for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories. ^bPlasma ctDNA specimen.³ ^cctDNA should not be used to test for PD-L1.³ ^dctDNA should not be used in lieu of a histologic tissue diagnosis.³

ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; ERBB2, erb-B2 receptor tyrosine kinase 2; FISH, fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; NCCN, National Comprehensive Cancer Network^® (NCCN^®); NGS, next-generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; PCR, polymerase chain reaction; PD-L1, programmed death-ligand 1; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1, tyrosine receptor kinase.

Over Half of Patients With NSCLC May Carry an Actionable Mutation, Highlighting the Importance of Accurate Biomarker Testing^6–11

ACTIONABLE BIOMARKERS

EGFR sensitizing 19.4%^6,a
EGFR T790M 5.5%^6,a
EGFR exon 20 2.1%^6,a
KRAS G12C 13.8%^7,b
ALK fusion 3.8%^6,a
MET splice (MET exon 14) 3.0%^6,a
ROS1 fusion 2.6%^6,a
ERBB2 (HER2) mutation 2.3%^6,a
HER2 overexpression (IHC 3+) 1-5%^8–10
BRAF V600E 2.1%^6,a
RET fusion 1.7%^6,a
NTRK1/2/3 <1%^11,c

EGFR and ERBB2 (HER2) mutations are two actionable biomarkers with significant impact in NSCLC^6,12,13; EGFR mutations are the most common oncogenic drivers.⁶ Although ERBB2 (HER2) mutations are less common, those with this targetable oncogenic driver are unlikely to have any other oncogenic driver mutation.¹³

EMERGING BIOMARKERS

MET amplification ~1.4%^6,a

OTHER MUTATIONS

Other driver mutations 2.9%⁶

UNKNOWN

Unknown mitogenic driver/no driver ~13%^6,a

^aJordan et al (2017) prospectively analyzed a total of 915 tumors from 860 patients with recurrent or metastatic lung adenocarcinoma for mutations using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, a hybridization capture-based, next-generation sequencing platform.⁶ ^bNassar et al (2021) extracted data from the registry of the American Association for Cancer Research project Genomics Evidence Neoplasia Information Exchange (GENIE) version 8.0 to study the distribution of KRAS mutations in 32,138 patients with cancer across race and sex. KRAS mutations were identified in 1,867 samples, most frequently in patients with NSCLC (1,443 of 10,444).⁷ Stage of disease was not disclosed. ^cFarago et al (2018) examined data on 4,872 patients to determine a frequency of 0.23% (n=11) for NTRK gene fusions in NSCLC.¹¹ ^dOther driver mutations are defined as all mutations excluding actionable, emerging, and unknown driver mutations.

ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; ERBB2, erb-B2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-epithelial transition; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; RET, rearranged during transfection; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

Help Inform Clinical Decisions with Biomarker Testing in Eligible Patients

Test for DNA alterations in EGFR and ERBB2 (HER2) – as two clinically impactful targetable mutations – to inform eligibility for targeted treatment options.¹²

Why test for EGFR Why test for ERBB2 (HER2)

Novel prognostic and predictive biomarkers (e.g., STK11, KEAP1, and SMARCA4) are an evolving area of research and could help better inform treatment planning for patients with newly diagnosed metastatic NSCLC, including for PD-L1 expression <1%.^14–16

Explore novel biomarkers in mNSCLC

Two scientists, one looking through a microscope, and one looking at a lab samples

DNA, deoxyribonucleic acid; EGFR, epidermal growth factor receptor; ERBB2, erb-B2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; KEAP1, kelch-like ECH-associated protein 1; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; SMARCA4, SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4; STK11, serine/threonine kinase 11.

Considerations for Your Practice

Investigate, action, or review multidisciplinary team (MDT) protocols for identifying individuals eligible for biomarker testing, such as EGFR and ERBB2 (HER2):

Perform biomarker testing as recommended across clinical guidelines in eligible patients with NSCLC to help inform clinical decisions
Find a testing lab* which can perform biomarker testing
Standardize biomarker testing protocols with your MDT
Discover novel biomarkers

EGFR, epidermal growth factor receptor; ERBB2, erb-B2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; MDT, multidisciplinary team; NSCLC, non-small cell lung cancer.

*This information is intended as educational and is not intended as a complete list of available testing options. AstraZeneca is not responsible for any test provider and does not endorse any particular diagnostic test. The accuracy and results of diagnostic tests vary, and AstraZeneca shall have no liability arising from such testing. Information provided herein should in no way be considered a guarantee of coverage, reimbursement, or patient assistance. Providers should contact third-party laboratories for information on their patient assistance programs. While diagnostic testing may assist providers in identifying appropriate treatment for patients, the decision and action should be decided by a provider in consultation with the patient. All products are trademarks of their respective holders, all rights reserved.

Helpful Resources

Check out these featured resources on biomarker testing in lung cancer.

View more resources

American Cancer Society. Cancer Facts & Figures 2024. Accessed 15 June, 2024. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.html
John A, et al. Oncologist. 2020;25(11):e1743–e1752.
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 22, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org
Planchard D, et al. Ann Oncol. 2018;29(suppl 4):iv192–iv237.
Schubart C, et al. Cancers. 2021;13:5023.
Jordan EJ, et al. Cancer Discov. 2017;7(6):596–609.
Nassar AH, et al. N Engl J Med. 2021;384(2):185–187.
Yan M, et al. Cancer Metastasis Rev. 2015;34(1):157–164.
Heinmoller P, et al. Clin Cancer Res. 2003;9(14):5238–5244.
Zinner RG, et al. Lung Cancer. 2004;44(1):99–110.
Farago AF, et al. JCO Precis Oncol. 2018;2018:PO.18.00037.
Le X, et al. Cancers (Basel). 2023;15(11):2917.
Pillai RN, et al. Cancer. 2017;123(21):4099–4105.
Sholl LM. Mod Pathol. 2022;35:66–74.
Shang X, et al. Lung Cancer. 2021;154:105–112.
Skoulidis F, et al. Cancer Discov. 2018;8(7):822–835.

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.

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Precision Medicine for Lung Cancer

Biomarker Testing Is Transforming the Management of Lung Cancer

Footnotes

Lung Cancer Biomarker Testing Recommendations Are Integral to Treatment Decisions

Footnotes

Comprehensive Biomarker Testing May Inform Treatment Eligibility3,5

Footnotes

Over Half of Patients With NSCLC May Carry an Actionable Mutation, Highlighting the Importance of Accurate Biomarker Testing6–11

Footnotes

Help Inform Clinical Decisions with Biomarker Testing in Eligible Patients

Considerations for Your Practice

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Comprehensive Biomarker Testing May Inform Treatment Eligibility^3,5

Over Half of Patients With NSCLC May Carry an Actionable Mutation, Highlighting the Importance of Accurate Biomarker Testing^6–11