KEYWORDS: NGS testing for cancer, tumour profiling, liquid biopsy for cancer, tissue biopsy NGS, comprehensive genomic profiling, ctDNA test, cancer biomarker testing, precision oncology, molecular testing for cancer

 

Compare tissue and liquid biopsy for NGS cancer testing. Learn what each method detects, when both may be needed and how results may guide treatment.

 

For patients with advanced, metastatic, recurrent or treatment-resistant cancer, identifying the name and location of the tumour may not be enough. Two cancers that appear similar under a microscope can contain different molecular alterations and may respond differently to treatment.

 

Next-generation sequencing, commonly called NGS, can examine many cancer-related genes and molecular changes within a single test. Depending on the cancer type, sample quality and clinical situation, testing may be performed using tumour tissue, blood-based liquid biopsy or a combination of both.

 

However, tissue biopsy and liquid biopsy are not interchangeable in every case. Each provides different information, and each has important limitations.

 

This guide explains how the two approaches differ, when one may be preferred and why some patients may benefit from testing both.

 

 

What Is NGS Testing for Cancer?

 

NGS is a laboratory technology that can analyse many genes simultaneously. Instead of checking one mutation at a time, an NGS panel may examine dozens or hundreds of cancer-related genes from the same sample.

 

Depending on the test, NGS may detect:

 

- Single-nucleotide variants

- Small insertions and deletions

- Gene amplifications

- Gene losses

- Gene rearrangements and fusions

- Microsatellite instability

- Tumour mutational burden

- Other molecular features relevant to a specific cancer

 

The objective is not simply to produce a long genetic report. The clinically important question is whether the test identifies information that could influence diagnosis, prognosis, treatment selection or eligibility for a clinical trial.

 

A detected alteration may be:

 

- Associated with an approved treatment for that cancer type

- Associated with a treatment approved for another tumour type

- Relevant to a clinical trial

- Linked to resistance against a particular treatment

- Potentially inherited and in need of confirmatory germline testing

- A variant of uncertain significance with no established treatment implication

 

Not every alteration is medically actionable, and the presence of a biomarker does not guarantee that the corresponding treatment will work.

 

 

Why NGS May Be Considered in Advanced Cancer

 

NGS is most commonly considered when the result has a realistic possibility of influencing a treatment decision.

 

Situations may include:

 

- Newly diagnosed advanced or metastatic cancer

- Cancer that has returned after treatment

- Disease that has progressed despite standard therapy

- A rare tumour with limited established treatment options

- Insufficient information from individual biomarker tests

- The need to investigate resistance to a previous targeted treatment

- Consideration of a biomarker-selected clinical trial

- A tumour type in which professional guidelines recommend broad molecular profiling

 

Updated ESMO recommendations support routine tumour NGS in several advanced cancers, including advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma and ovarian cancer. Testing may also be appropriate in other cancers when clinically relevant biomarkers or trial opportunities are available.

 

The decision should be made by an oncologist who understands the patient’s diagnosis, previous treatment and current clinical condition.

 

 

What Is Tissue-Based NGS?

 

Tissue-based NGS analyses DNA—and sometimes RNA—extracted from tumour tissue.

 

The sample may come from:

 

- A previous operation

- A core-needle biopsy

- An endoscopic biopsy

- A lymph-node biopsy

- A biopsy of a metastatic lesion

- Another suitable tumour-containing specimen

 

Archived paraffin blocks or unstained pathology slides may sometimes be used, provided that the sample contains sufficient tumour material of adequate quality.

 

 

Advantages of Tissue Biopsy

 

It establishes the pathological diagnosis

Tissue allows the pathologist to examine tumour cells directly. This is essential for confirming the type of cancer, evaluating its morphology and performing immunohistochemistry.

 

Liquid biopsy cannot usually replace tissue when the diagnosis itself has not been established.

 

 

It may provide a stronger tumour signal

A suitable tissue sample may contain a higher proportion of tumour DNA than a blood sample, particularly when the cancer releases little DNA into the bloodstream.

 

 

It can support DNA and RNA analysis

RNA-based testing can be particularly useful for detecting certain gene fusions and rearrangements. Whether RNA testing is required depends on the tumour type and the molecular question.

 

 

It supports additional laboratory testing

The same tissue may be used for:

 

- Immunohistochemistry

- PD-L1 testing

- HER2 assessment

- Mismatch-repair protein testing

- In-situ hybridization

- Other tumour-specific examinations

 

 

Limitations of Tissue Biopsy

 

A new biopsy may be invasive

Obtaining tissue can involve pain, bleeding, infection, sedation or other procedure-related risks. The risk depends on the location of the tumour and the type of biopsy.

 

The available sample may be insufficient

Small biopsies may contain too few tumour cells. Previous processing, decalcification or long-term storage can also reduce DNA or RNA quality.

 

Older tissue may not reflect the current disease

Cancer changes over time and under treatment pressure. An archived sample collected years earlier may not show newly developed resistance mechanisms.

 

One biopsy samples only one area

Different tumour sites may contain different molecular alterations. A biopsy from one location may not fully represent the biological diversity of metastatic disease.

 

 

What Is a Liquid Biopsy?

 

A liquid biopsy usually analyses circulating cell-free DNA from a blood sample. A fraction of this material may originate from tumour cells and is known as circulating tumour DNA, or ctDNA.

 

The test looks for tumour-related molecular alterations released into the bloodstream.

 

Liquid biopsy should not be confused with a standard blood tumour-marker test. Tests such as CEA, CA 19-9, CA 125 or PSA measure particular proteins or substances. A liquid-biopsy NGS panel examines genetic material.

 

 

Advantages of Liquid Biopsy

 

It requires only a blood sample

Liquid biopsy is minimally invasive and may be useful when the tumour is difficult or unsafe to biopsy.

 

It may be performed more quickly

Collecting blood is generally easier than scheduling an invasive biopsy. Actual reporting time depends on the laboratory, test and sample logistics.

 

It may capture alterations from different tumour sites

Because tumour DNA may enter the bloodstream from more than one cancer location, liquid biopsy can sometimes provide information about the molecular diversity of metastatic disease.

 

It may identify resistance mechanisms

When cancer progresses during targeted therapy, liquid biopsy may help identify new alterations associated with treatment resistance.

 

It can be repeated

Blood-based testing may be used at different stages of treatment when repeat tissue biopsy would be difficult. Whether repeat testing is clinically useful depends on the cancer and the treatment decision being considered.

 

Limitations of Liquid Biopsy

 

A negative result does not necessarily mean that no mutation exists

Some tumours release very little DNA into the bloodstream. This is sometimes called low tumour shedding.

 

A blood test may therefore produce a false-negative or non-informative result even when an important alteration is present in the tumour.

 

When liquid biopsy is negative and the result would affect treatment, tissue testing should be considered if a biopsy is clinically feasible.

 

 

It does not normally establish the full diagnosis

Liquid biopsy generally cannot replace pathological examination when the cancer type, tumour origin or histological subtype remains uncertain.

 

Some alterations may be more difficult to detect

The performance of a liquid-biopsy test varies according to:

 

- Tumour fraction in the blood

- Cancer type

- Disease location

- Disease burden

- Previous treatment

- Gene and alteration being investigated

- Laboratory platform

- Technical sensitivity of the assay

 

Blood-cell alterations can complicate interpretation

Age-related genetic changes in blood-forming cells can occasionally be detected in cell-free DNA. These changes may not originate from the tumour and require careful interpretation.

 

 

Tissue Biopsy vs Liquid Biopsy: Main Differences

 

Sample

Tissue NGS uses tumour material from surgery or biopsy.

Liquid biopsy usually uses circulating DNA from blood.

 

Diagnostic value

Tissue can establish or confirm the pathological diagnosis.

Liquid biopsy normally provides molecular information but does not replace a diagnostic tissue examination.

 

Invasiveness

Tissue collection may require an invasive procedure.

Liquid biopsy usually requires a standard blood draw.

 

Risk of a false-negative result

Tissue testing may fail when the sample contains insufficient tumour or degraded material.

Liquid biopsy may miss alterations when the tumour releases insufficient DNA into the bloodstream.

 

Representation of the cancer

Tissue provides detailed information from one sampled tumour location.

Liquid biopsy may capture DNA from multiple disease sites, but only when sufficient tumour DNA is present in the blood.

 

Repeat testing

Repeated tissue biopsies may be difficult or risky.

Blood-based testing is easier to repeat when clinically justified.

 

 

Which Test Is Better?

 

Neither method is universally better. The correct choice depends on the medical question.

 

Tissue-based NGS is often preferred when:

 

- The diagnosis has not been firmly established

- Adequate recent tumour tissue is available

- Histology or immunohistochemistry is required

- RNA-based fusion testing is important

- The tumour is expected to release little DNA into the blood

- A previous liquid biopsy was negative or non-informative

 

Liquid biopsy may be preferred when:

 

- Tissue biopsy is unsafe or technically difficult

- Available tissue is insufficient

- A rapid molecular assessment is needed

- The cancer has progressed after targeted treatment

- A repeat invasive biopsy would place an unnecessary burden on the patient

- The medical team wants to investigate alterations from multiple metastatic sites

 

 

When Both Tests May Be Needed

Tissue and liquid biopsy can provide complementary information.

 

A combined strategy may be considered when:

 

- Rapid blood testing is performed while tissue testing is being arranged

- Liquid biopsy identifies a potentially actionable alteration that requires clinical confirmation

- Liquid biopsy is negative, but a targetable alteration is still strongly suspected

- Tissue and blood results are discordant

- Archived tissue is old and the disease has changed after several treatments

- The oncologist wants to investigate treatment resistance

- One sample does not meet the laboratory’s quality requirements

 

The order of testing should be decided according to the patient’s condition, urgency, available tissue and treatment options.

 

 

Does NGS Determine Whether Immunotherapy Will Work?

 

NGS may report biomarkers associated with possible immunotherapy benefit, including:

 

- Microsatellite instability

- Mismatch-repair-related alterations

- Tumour mutational burden

- Selected tumour-specific molecular findings

 

However, NGS is not the only method used to evaluate immunotherapy eligibility.

 

PD-L1 is usually assessed through immunohistochemistry performed on tumour tissue. Microsatellite instability or mismatch-repair deficiency may be evaluated using immunohistochemistry, PCR or validated NGS methods.

 

No single biomarker predicts treatment response with complete certainty. Results must be interpreted together with the cancer type, stage, previous treatment and overall clinical picture.

 

 

Tumour Testing Is Not the Same as Inherited Genetic Testing

 

Tumour NGS mainly identifies changes present in cancer cells. These are called somatic alterations.

 

Some findings may suggest an inherited cancer predisposition, involving genes such as:

 

- BRCA1

- BRCA2

- PALB2

- TP53

- MLH1

- MSH2

- MSH6

- PMS2

- APC

 

A tumour result alone does not always confirm that an alteration is inherited.

 

When an inherited condition is suspected, the finding may need confirmation through a dedicated germline test using blood or saliva, together with appropriate genetic counselling.

 

This distinction is important because an inherited result may have implications for both the patient and biological relatives.

 

 

Questions to Ask Before Ordering NGS

 

Patients should ask:

 

- Why is NGS being recommended in my case?

- Will the result influence an immediate treatment decision?

- Should tissue, blood or both be tested?

- Is my existing tissue recent and adequate?

- Does the test include DNA and RNA analysis?

- Which genes and biomarker types are covered?

- Does the panel evaluate MSI or tumour mutational burden?

- Is PD-L1 being tested separately?

- How will variants of uncertain significance be handled?

- Will the case be discussed by a molecular tumour board?

- Could the test identify a possible inherited alteration?

- What happens if the liquid biopsy result is negative?

- Are matched medicines available for my cancer type?

- Are any relevant clinical trials accessible?

- What are the test cost and expected reporting time?

 

 

How Recmed Coordinates NGS Evaluation in Turkey

 

Recmed Medical Travel can coordinate the process for international patients by:

 

1. Collecting pathology reports, imaging and treatment history

2. Confirming where pathology blocks or slides are stored

3. Organizing review by a medical oncologist and molecular specialist

4. Determining whether tissue, blood or combined testing should be considered

5. Coordinating the transfer of appropriate samples

6. Arranging pathology review and additional biomarker testing when indicated

7. Organizing a specialist consultation to interpret the report

8. Requesting a written treatment proposal based on the complete clinical picture

9. Coordinating travel, appointments, accommodation options, transfers and interpretation when treatment in Turkey is planned

 

The NGS report should not be interpreted in isolation. A molecular alteration becomes clinically meaningful only when it is evaluated together with the diagnosis, previous treatment, current disease status, supporting evidence and availability of an appropriate medicine or clinical trial.

 

 

Frequently Asked Questions

 

Can liquid biopsy completely replace tissue biopsy?

Usually not. Liquid biopsy is valuable when tissue is unavailable or unsafe to obtain, but it does not normally replace tissue for confirming the pathological diagnosis. A negative blood result may also require tissue testing.

 

Is a positive liquid-biopsy result reliable?

A result from a validated test may identify a clinically relevant alteration. However, the finding must still be interpreted by the treating oncologist in the context of the cancer type and the test’s approved or validated use.

 

Does a negative liquid biopsy mean that there are no targetable mutations?

No. The tumour may not be releasing enough DNA into the bloodstream. If the result is negative or non-informative, tissue testing may still identify an important alteration.

 

Can old pathology blocks be used?

Sometimes. Their suitability depends on age, storage, tumour content, previous laboratory processing and DNA or RNA quality. The testing laboratory should evaluate the sample.

 

Should the primary tumour or a metastatic lesion be tested?

The most appropriate sample depends on tissue availability, quality, timing and the clinical question. A newer metastatic sample may better reflect the current disease in some cases, but obtaining it must be medically justified and safe.

 

Does finding a mutation guarantee access to targeted therapy?

No. The alteration must be clinically relevant, and the matched medicine must be appropriate for the cancer type and patient. Availability, approval, previous treatment and medical suitability must also be considered.

 

Can NGS show which chemotherapy will work?

NGS is mainly used to identify molecular biomarkers, possible targeted therapies, immunotherapy-related markers, resistance mechanisms and clinical-trial opportunities. It generally cannot predict the effectiveness of every chemotherapy drug.

 

How long does NGS take?

Reporting time varies according to the test, sample quality, laboratory and whether additional analysis is required. Patients should receive a case-specific estimate rather than a fixed promise.

 

 

Request an NGS and Precision-Oncology Case Review

 

For an initial assessment, patients can send:

 

- Pathology report

- Known cancer type and stage

- Date and location of the most recent biopsy

- Information about available paraffin blocks or slides

- Latest CT, MRI or PET-CT

- Previous treatment protocols

- Current medication

- Previous molecular or genetic results

- Main question for the oncology team

 

Recmed will review the completeness of the documentation, coordinate an appropriate specialist assessment and explain whether tissue NGS, liquid biopsy or a combined approach may be considered.

 

Medical disclaimer: This article provides general information and does not replace diagnosis, examination, genetic counselling or advice from a licensed physician. NGS and biomarker testing should be ordered and interpreted by qualified medical professionals. Treatment decisions must be made by the responsible oncology team. In an emergency or during rapid clinical deterioration, patients should seek immediate local medical care.

 

 

Medical and Regulatory Sources

 

- National Cancer Institute – Biomarker Testing for Cancer Treatment
https://www.cancer.gov/about-cancer/treatment/types/biomarker-testing-cancer-treatment

 

- National Cancer Institute – Tests and Procedures Used to Diagnose Cancer
https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis

 

- European Society for Medical Oncology – Recommendations on the Use of Circulating Tumour DNA Assays
https://pubmed.ncbi.nlm.nih.gov/35809752/

 

- European Society for Medical Oncology – Recommendations for the Use of NGS for Patients with Advanced Cancer in 2024
https://pubmed.ncbi.nlm.nih.gov/38834388/

 

- U.S. Food and Drug Administration – Authorized Companion Diagnostic Devices
https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-fda-authorized-companion-diagnostic-devices-in-vitro-and-imaging-tools

 

- National Cancer Institute – Targeted Therapy for Cancer
https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies