What is precision medicine in cancer treatment?

Precision medicine in oncology means matching treatment to the specific molecular characteristics of a patient's tumour — rather than treating all breast cancers, lung cancers, or colon cancers identically based solely on tissue of origin. A tumour's genomic profile (its driver mutations, copy number alterations, fusion genes, and epigenetic features) determines which oncogenic pathways are active and, crucially, which pathways are targetable with approved or investigational drugs. For example: two patients with non-small cell lung cancer (NSCLC) may both receive a diagnosis of 'adenocarcinoma,' but one whose tumour has an EGFR exon 19 deletion will respond dramatically to osimertinib (a third-generation EGFR inhibitor with 80%+ response rate and 18-month median PFS), while another whose tumour has a KRAS G12C mutation will respond to sotorasib, and a third with high PD-L1 expression (≥50%) but no targetable driver mutation will respond best to pembrolizumab immunotherapy. The same diagnosis — radically different biology — requires completely different treatment. Precision medicine is the framework for discovering and acting on those differences.

What is tumour genomic profiling and should every cancer patient have it?

Tumour genomic profiling (also called comprehensive genomic profiling or CGP) uses next-generation sequencing (NGS) to read the DNA (and sometimes RNA) of tumour tissue or circulating tumour DNA (ctDNA) in blood. It identifies: somatic mutations in oncogenes and tumour suppressor genes, copy number variations (amplifications and deletions), structural variants including gene fusions (e.g. EML4-ALK in NSCLC), microsatellite instability status (MSI-H/dMMR), tumour mutational burden (TMB), germline variants in cancer predisposition genes. The clinical question of whether every cancer patient should have CGP depends on cancer type and stage. For advanced/metastatic solid tumours — NSCLC, colorectal, breast (HER2/ER/PR), ovarian, melanoma, gastric, and others with well-established targetable alterations — comprehensive genomic profiling is now the standard of care in major NCCN and ESMO guidelines. For early-stage localised cancers where surgery with curative intent is the primary treatment, the clinical utility of upfront CGP is more limited unless hereditary risk assessment (BRCA1/2, Lynch syndrome) is relevant. Foundation Medicine (FoundationOne CDx), Guardant Health (Guardant360), and Tempus are the leading clinical CGP platforms with FDA-cleared indications.

What are the most important cancer driver mutations and their targeted therapies?

The most clinically actionable oncogene-therapy pairs currently in use: EGFR mutations (exon 19 del, L858R) in NSCLC — osimertinib (Tagrisso), afatinib, erlotinib; HER2 amplification in breast/gastric — trastuzumab, pertuzumab, trastuzumab deruxtecan (T-DXd), lapatinib; BRCA1/2 pathogenic variants in breast/ovarian — olaparib, niraparib, rucaparib (PARP inhibitors); BRAF V600E in melanoma/NSCLC/colorectal — vemurafenib, dabrafenib + trametinib (BRAF+MEK inhibition); ALK/ROS1 fusions in NSCLC — alectinib, lorlatinib, brigatinib; KRAS G12C in NSCLC/CRC — sotorasib (Lumakras), adagrasib (Krazati); BCR-ABL1 fusion in CML/ALL — imatinib, dasatinib, ponatinib; PIK3CA mutations in ER+ breast cancer — alpelisib + fulvestrant; FLT3 ITD mutations in AML — midostaurin, gilteritinib; MSI-H/dMMR in any solid tumour — pembrolizumab (tissue-agnostic approval); high TMB (≥10 mut/Mb) in any solid tumour — pembrolizumab. The FDA's tissue-agnostic approvals for MSI-H and NTRK fusions (larotrectinib, entrectinib) represent a paradigm shift: treatment defined by molecular alteration rather than cancer type.

How does immunotherapy work and who responds to it?

Cancer immunotherapy works by removing the brakes tumour cells use to evade immune destruction. T cells normally destroy abnormal cells — tumours escape by expressing PD-L1 (programmed death ligand 1) on their surface, which binds the PD-1 receptor on T cells and suppresses the immune attack. Checkpoint inhibitors — pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab, durvalumab — block this PD-1/PD-L1 interaction, restoring T cell cytotoxic activity against the tumour. CTLA-4 inhibitors (ipilimumab) work upstream to release T cell activation at a different checkpoint. The key determinants of immunotherapy response are: (1) PD-L1 expression (IHC 22C3 assay) — the higher the tumour proportion score (TPS), the more likely response to PD-1/PD-L1 inhibition, though high PD-L1 is not required for response; (2) Microsatellite instability-high (MSI-H) / mismatch repair deficient (dMMR) — these tumours have very high mutational burden due to defective DNA mismatch repair, generating many neoantigens that T cells can recognise; response rates to pembrolizumab in MSI-H CRC approach 40% objective response rate in heavily pre-treated patients; (3) Tumour mutational burden (TMB-H, ≥10 mutations/megabase) — similarly predicts neoantigen load and checkpoint inhibitor response across tumour types; (4) KRAS mutant NSCLC with co-occurring STK11/KEAP1 mutations generally does not respond well to immunotherapy despite high PD-L1, illustrating that single biomarkers are insufficient in some contexts.

What is liquid biopsy and how is it used in cancer care?

Liquid biopsy refers to the analysis of tumour-derived material in a blood sample — primarily circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), and exosomes. ctDNA is fragmented DNA shed by tumour cells into the bloodstream; it carries the same somatic mutations as the tumour tissue and can be detected by ultra-sensitive NGS platforms (Guardant360, FoundationOne Liquid CDx). Clinical applications: (1) Initial tumour profiling when tissue biopsy is not feasible or insufficient — liquid biopsy identifies driver mutations from plasma with sensitivity of 60–80% for advanced solid tumours, lower for early-stage. (2) Treatment monitoring and early resistance detection — rising ctDNA during treatment signals disease progression weeks to months before radiographic progression; the emergence of new mutations in ctDNA (e.g. EGFR T790M in osimertinib-treated NSCLC) identifies acquired resistance mechanisms and guides therapy switching. (3) Minimal residual disease (MRD) after curative surgery or radiation — serial ctDNA measurement after resection detects molecular recurrence months before clinical relapse; the GALAXY trial in stage II/III colon cancer showed ctDNA-positive patients post-surgery had 17× higher recurrence risk, enabling pre-emptive intensification of adjuvant therapy. (4) Multi-cancer early detection (MCED) — pan-cancer ctDNA tests (Galleri by Grail, CancerSEEK) aim to detect early-stage cancers in high-risk asymptomatic individuals before symptoms, though sensitivity for stage I disease remains 15–40% and the evidence for survival benefit from MCED-directed care is awaited from the NHS-Galleri and PATHFINDER trials.

What are CAR-T cells and which cancers can they treat?

CAR-T (chimeric antigen receptor T cell) therapy involves engineering a patient's own T cells to express a synthetic receptor that recognises a specific tumour antigen, then infusing them back in vastly expanded numbers. The CAR receptor combines an extracellular antigen-binding domain (usually a single-chain antibody fragment) with intracellular T cell activating domains (CD3ζ chain + co-stimulatory domains from CD28 or 4-1BB). FDA-approved CAR-T therapies: tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) for B cell ALL and large B cell lymphoma (targeting CD19), lisocabtagene maraleucel (Breyanzi) for DLBCL, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti) for relapsed/refractory multiple myeloma (targeting BCMA). Complete response rates of 40–80% in heavily pre-treated haematological malignancies — remarkably high by oncology standards. Key limitations: (1) Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) — serious and sometimes life-threatening toxicities requiring ICU-level management; (2) Manufacturing time (3–6 weeks) and cost ($400,000–600,000 per infusion); (3) Antigen escape — tumours downregulate the target antigen to evade the engineered T cells; (4) Poor activity in solid tumours so far — the immunosuppressive tumour microenvironment, physical barriers, and antigen heterogeneity remain unsolved challenges for CAR-T in lung, colon, breast, and other carcinomas.

Precision Medicine in Cancer: Genomics and Targeted Therapy

Quick Answer

Precision oncology uses tumour genomic profiling to identify driver mutations, copy number alterations, gene fusions, and immunotherapy biomarkers (MSI, TMB, PD-L1), then matches treatment to molecular targets rather than tissue of origin. Key categories: targeted therapies (kinase inhibitors, monoclonal antibodies matched to EGFR, HER2, BRAF, ALK, KRAS, BRCA, and other oncogenic drivers), checkpoint immunotherapy (PD-1/PD-L1 and CTLA-4 inhibitors, selected by PD-L1 expression, MSI-H/dMMR, and TMB-H status), liquid biopsy (ctDNA for treatment monitoring, resistance detection, and MRD), and CAR-T cell therapy (for haematological malignancies). For patients with advanced solid tumours, comprehensive genomic profiling is now standard of care in most major guidelines — it changes treatment selection in approximately 25–35% of cases.

The Genomic Revolution in Oncology: From Histology to Molecular Pathology

For most of the 20th century, cancer classification — and therefore treatment — was based on histology: the tissue of origin and the microscopic appearance of cells. A lung cancer was a lung cancer; treatment was platinum-based chemotherapy for most. The 5-year survival for stage IV NSCLC was approximately 4% in 2000. The same 5-year survival in 2025 exceeds 20% for all comers and approaches 30–40% for patients with targetable driver mutations.

This transformation began with the recognition that cancer is fundamentally a disease of the genome. Every cancer arises from the accumulation of somatic mutations — changes to DNA that were not present in the germline — that disrupt the normal controls on cell proliferation, survival, and migration. Among the thousands of mutations a typical solid tumour acquires, a small number are driver mutations: changes that confer a growth advantage and are causally required for tumour maintenance. The rest are passenger mutations: bystanders that accumulated during clonal evolution without contributing to the malignant phenotype.

The key insight that enabled precision oncology was that driver mutations define oncogenic dependencies — the cancer cells are often literally addicted to the signalling pathway the driver mutation has constitutively activated. Target the driver with a precisely designed inhibitor, and the cancer cells, unable to switch to an alternative survival pathway, die. Normal cells, which lack the driver mutation, are largely spared. This is the mechanistic basis of the therapeutic window in targeted therapy, and it is fundamentally different from chemotherapy's non-selective cytotoxicity.

The paradigm shift: three eras of cancer treatment

Era 1: Chemotherapy

Non-selective cytotoxicity targeting all rapidly dividing cells. Effective against some tumour types; significant collateral damage. Treatment selection by histology and stage only.

Era 2: Targeted Therapy

Small molecule inhibitors and monoclonal antibodies targeting specific driver oncoproteins. Dramatic response rates in biomarker-selected populations. Acquired resistance in most patients within 1–2 years.

Era 3: Immunotherapy + Combinations

Checkpoint inhibitors unleash T cell immunity. Durable responses in biomarker-selected patients; some cures in previously fatal diseases. Synergies between targeted therapy, immunotherapy, and antibody-drug conjugates emerging.

Tumour Genomic Profiling: Technologies and What They Find

Comprehensive Genomic Profiling (CGP)

CGP panels like FoundationOne CDx (Foundation Medicine) and Tempus xT sequence 300–500 cancer-relevant genes from tumour DNA, identifying all four variant classes (point mutations, indels, copy number alterations, structural rearrangements/fusions). They also report MSI status, TMB, and, in the case of FoundationOne CDx, PD-L1 protein expression. CGP is now FDA-approved as a companion diagnostic for multiple solid tumour types and is listed as standard of care in NCCN guidelines for advanced NSCLC, CRC, breast, ovarian, melanoma, prostate, urothelial, and gastric cancers.

Turnaround: 7–14 days from tissue receipt · Requires FFPE tumour tissue (biopsy or surgical specimen) · Insurance coverage: variable, improving with FDA clearances

Whole Exome and Whole Genome Sequencing

WES sequences all ~20,000 protein-coding genes; WGS sequences the entire ~3 billion base-pair genome including non-coding regulatory regions. Both provide the most comprehensive mutational landscape but are primarily research and specialised clinical tools rather than routine standard-of-care testing. WGS can identify structural variants and non-coding driver mutations invisible to panel tests. Turnaround and cost remain barriers to routine clinical use, though costs have fallen dramatically (whole genome sequencing now ~$500–1,000 reagent cost). The UK's NHS Genomics England programme and the US National Cancer Institute MATCH trial have demonstrated the clinical feasibility of WGS-guided cancer therapy at scale.

Liquid Biopsy (ctDNA / Circulating Tumour DNA)

Blood-based ctDNA profiling (Guardant360, FoundationOne Liquid CDx) detects tumour-derived DNA in plasma using ultra-sensitive NGS with error suppression technology. Sensitivity for detecting driver mutations is 60–80% for advanced-stage tumours (rising to ~90% for high-tumour-burden disease). Key advantages: non-invasive, repeatable, captures tumour heterogeneity from multiple sites (tissue biopsy samples one lesion; ctDNA samples the entire tumour ecosystem). Key limitation: lower sensitivity for early-stage and low-burden disease. Now used routinely for initial profiling when tissue is insufficient and for treatment monitoring.

RNA Sequencing for Fusion Detection

Gene fusions — chromosomal rearrangements creating oncogenic hybrid proteins — are best detected at the RNA level. EML4-ALK, RET fusions, NTRK1/2/3 fusions, ROS1 fusions, and FGFR2 fusions are examples of targetable alterations that may be missed by DNA-only panels if the breakpoints fall in intronic regions not covered by the assay. RNA-based fusion panels (Archer FusionPlex, FoundationOne RNA) are increasingly integrated into comprehensive profiling workflows.

Key biomarkers detected by CGP and their therapeutic implications

Biomarker	Cancer Type	Therapeutic Implication
EGFR exon 19 del / L858R	NSCLC	Osimertinib 1st line (80% ORR, 18-mo PFS)
EGFR T790M (acquired)	NSCLC	Osimertinib 2nd line after 1st gen EGFR-TKI
ALK / ROS1 fusions	NSCLC	Alectinib, lorlatinib (ALK); entrectinib (ROS1)
KRAS G12C	NSCLC, CRC, PDAC	Sotorasib (Lumakras), adagrasib (Krazati)
BRAF V600E	Melanoma, NSCLC, CRC, THCA	Dabrafenib + trametinib (BRAF+MEK)
HER2 amplification / overexpression	Breast, gastric, CRC, NSCLC	Trastuzumab, pertuzumab, T-DXd (trastuzumab deruxtecan)
BRCA1/2 pathogenic variants	Breast, ovarian, prostate, PDAC	Olaparib, niraparib, rucaparib (PARP inhibitors)
MSI-H / dMMR	Any solid tumour	Pembrolizumab (tissue-agnostic FDA approval)
TMB-H (≥10 mut/Mb)	Any solid tumour	Pembrolizumab (tissue-agnostic FDA approval)
NTRK1/2/3 fusions	Any solid tumour (rare)	Larotrectinib (Vitrakvi), entrectinib — 75%+ ORR
PIK3CA mutations	ER+ breast cancer	Alpelisib + fulvestrant
BCR-ABL1 fusion	CML, Ph+ ALL	Imatinib, dasatinib, ponatinib (TKIs)

Targeted Therapies: Mechanism, Evidence, and Resistance

Targeted therapies divide broadly into two modalities: small molecule inhibitors that enter cells and block the enzymatic activity of driver oncoproteins, and monoclonal antibodies that bind extracellular domains of receptor tyrosine kinases or their ligands.

EGFR Inhibitors in NSCLC: The Template for Precision Oncology

The EGFR story is the most instructive in precision oncology. EGFR (epidermal growth factor receptor) is mutated in approximately 15% of Western and 50% of East Asian NSCLC adenocarcinoma patients. First-generation inhibitors (erlotinib, gefitinib, approved 2003–2004) produced dramatic responses in EGFR-mutant patients — 60–70% objective response rates versus ~10% with chemotherapy — but clinicians initially gave them to all NSCLC patients, where the response rate was unremarkable. The discovery that responses clustered entirely in EGFR-mutant patients revealed the principle: the drug only works where the target is present and tumour survival depends on it.

Acquired resistance to first-generation EGFR inhibitors developed in virtually all patients within 8–14 months, most commonly through the secondary T790M "gatekeeper" mutation that sterically prevents drug binding. Third-generation osimertinib (AstraZeneca, approved 2015 for T790M, 2018 for first-line) was specifically designed to overcome T790M while remaining active against sensitising mutations. The FLAURA trial (2018, NEJM) established osimertinib as the first-line standard: median PFS 18.9 months vs 10.2 months for first-generation inhibitors, and 38.6 months overall survival vs 31.8 months. For EGFR exon 20 insertion mutations (2–3% of NSCLC, not sensitised to classic EGFR-TKIs), amivantamab and mobocertinib have been approved.

The EGFR story illustrates both the power of precision oncology and its central limitation: acquired resistance is nearly universal. EGFR resistance mechanisms now include C797S mutation, MET amplification, HER2 amplification, BRAF mutations, and small cell transformation — each requiring a different therapeutic counter-move.

KRAS: From "Undruggable" to Clinical Reality

KRAS (Kirsten RAS) is the most commonly mutated oncogene in human cancer — present in approximately 90% of pancreatic ductal adenocarcinoma, 40% of colorectal cancer, and 25–30% of NSCLC. For 40 years after its discovery in 1982, KRAS was considered undruggable: its globular GTPase domain provided no obvious binding pocket for small molecules, and its picomolar affinity for GTP made competitive inhibition impossible.

The breakthrough came from the identification of a cryptic allosteric binding pocket — the switch II pocket — present only in the GDP-bound (inactive) form of the KRAS G12C mutant, exploited by sotorasib (Lumakras, AMG 510) and adagrasib (Krazati, MRTX849). These covalent inhibitors trap KRAS G12C in its inactive GDP-bound state by forming a permanent bond with the mutant cysteine at position 12. FDA approval of sotorasib in 2021 — for KRAS G12C-mutant NSCLC — was a landmark moment. Response rate approximately 37%, median PFS 6.3 months (CodeBreaK 100 trial). KRAS G12C inhibitors are now being tested in combination with SHP2 inhibitors, MEK inhibitors, PD-1 inhibitors, and EGFR antibodies to address resistance mechanisms (primarily reactivation of RAS-MAPK signalling through upstream RTK feedback).

Non-G12C KRAS mutations (G12D, G12V, G13D) are present in even higher numbers but remain more difficult to target — KRAS G12D inhibitors (MRTX1133, HRS-4642) entered clinical trials in 2023–2024.

PARP Inhibitors and BRCA: Synthetic Lethality

BRCA1 and BRCA2 are tumour suppressor genes encoding proteins essential for homologous recombination (HR) — the high-fidelity repair pathway for double-strand DNA breaks. Cells with pathogenic BRCA1/2 variants have defective HR and rely more heavily on alternative repair pathways including PARP1-dependent single-strand break repair. PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib) exploit this dependency through synthetic lethality: they are relatively non-toxic in HR-proficient cells but catastrophically lethal in BRCA-deficient cells, where the combined loss of HR and PARP-mediated repair causes genomic catastrophe and cell death.

PARP inhibitor approvals span: BRCA-mutant ovarian cancer (first-line maintenance and beyond), BRCA-mutant HER2-negative metastatic breast cancer (OlympiAD, EMBRACA trials), BRCA-mutant metastatic castration-resistant prostate cancer (PROfound trial), and BRCA-mutant metastatic pancreatic cancer maintained after platinum (POLO trial). The concept of "BRCAness" — HR deficiency caused by non-BRCA mechanisms (RAD51, PALB2, ATM, FANCA mutations; BRCA1 promoter methylation) — has expanded the potentially eligible population beyond germline BRCA1/2 carriers. HR deficiency testing (HRD score, FOUNDATIONONE CDx) identifies this broader population.

Antibody-Drug Conjugates (ADCs): Targeted Chemotherapy Delivery

ADCs combine the tumour-targeting specificity of monoclonal antibodies with the cytotoxic potency of chemotherapy payloads, linked by a cleavable linker designed to release the payload inside tumour cells. Trastuzumab deruxtecan (T-DXd, Enhertu) — anti-HER2 antibody linked to a topoisomerase I inhibitor — has transformed the treatment landscape for HER2+ and HER2-low (IHC 1+ or 2+/ISH-negative) breast cancer. The DESTINY-Breast04 trial (2022, NEJM) demonstrated 9.9 months median PFS vs 5.1 months chemotherapy in HER2-low metastatic breast cancer — a category that was previously "HER2-negative" and therefore not considered HER2-targetable at all. T-DXd is now approved across breast, gastric, NSCLC, and colorectal cancers with HER2 overexpression, making HER2 a pan-tumour target rather than a breast/gastric-specific one.

Immunotherapy: Checkpoint Inhibition and the Biomarkers That Predict Response

The clinical impact of checkpoint immunotherapy has been most dramatic where responses are durable — something targeted therapies rarely achieve. In melanoma, where nivolumab + ipilimumab achieves 5-year overall survival of ~52% (CheckMate 067), and in MSI-H colorectal cancer, where pembrolizumab produces complete responses in patients who previously had median survival of 6 months, immunotherapy has produced what can credibly be called cures in a meaningful proportion of metastatic solid tumour patients — something that was not possible in the chemotherapy era.

PD-L1 Expression (IHC)

PD-L1 protein expression on tumour cells, measured by immunohistochemistry using the 22C3 antibody assay (Dako), is the primary companion diagnostic for pembrolizumab in NSCLC and other solid tumours. Tumour proportion score (TPS) of ≥50% predicts first-line monotherapy pembrolizumab benefit (KEYNOTE-024); TPS ≥1% qualifies for pembrolizumab + chemotherapy combinations (KEYNOTE-189, KEYNOTE-407). PD-L1 is necessary for selecting anti-PD-1 monotherapy in NSCLC but is an imperfect biomarker — some PD-L1-negative tumours respond and many high-expressors do not. Different antibody assays (28-8, SP263, SP142, 22C3) are not interchangeable across indications.

MSI-H / dMMR: The Most Predictive Immunotherapy Biomarker

Microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) — identified by PCR-based MSI testing or IHC for MLH1, MSH2, MSH6, PMS2 protein expression — is the strongest single biomarker for checkpoint inhibitor response across tumour types. MSI-H tumours have defective DNA mismatch repair (due to germline Lynch syndrome mutations or somatic BRAF V600E-driven MLH1 promoter methylation in CRC) and accumulate hundreds to thousands of insertion/deletion mutations at microsatellite repeats, generating highly immunogenic neoantigens. Pembrolizumab has FDA tissue-agnostic approval for all solid MSI-H/dMMR tumours — the first drug ever approved based on a molecular marker rather than cancer type (May 2017). In MSI-H CRC, pembrolizumab produced a 43% ORR vs 33% chemotherapy in first line (KEYNOTE-158); in second line, complete responses are seen in approximately 10% of patients.

Tumour Mutational Burden (TMB)

TMB quantifies the total number of somatic mutations per megabase of sequenced genome — a surrogate for neoantigen load and immune recognition potential. FDA approval for pembrolizumab in TMB-high (≥10 mut/Mb) solid tumours (June 2020) was the second tissue-agnostic checkpoint inhibitor indication. TMB-H identifies a different — and partially non-overlapping — population from MSI-H; many TMB-H tumours are MSI-stable (bladder cancer, melanoma, SCLC, and tobacco-associated lung cancer can be TMB-H without MSI-H). The clinical utility of TMB is context-dependent: in NSCLC, TMB-H predicts atezolizumab benefit in NSCLC (IMpower110); in CRC, most TMB-H tumours are also MSI-H and the additional predictive value is limited.

CTLA-4 Inhibition and Combination Immunotherapy

Ipilimumab (anti-CTLA-4) released T cells at an earlier checkpoint in the immune activation cascade — preventing tolerisation rather than rescuing exhausted T cells. Monotherapy produces durable responses in approximately 15–20% of melanoma patients but with high immune-related adverse event (irAE) rates. The combination of nivolumab + ipilimumab (dual checkpoint blockade) demonstrated 52% 5-year overall survival in melanoma (CheckMate 067) and has reshaped first-line treatment in melanoma, MSI-H CRC, and selected NSCLC subsets. The price of dual blockade is a 55–60% rate of grade 3–4 irAEs, managed by early steroid intervention and specialist monitoring.

Immunotherapy immune-related adverse events (irAEs): management principles

Checkpoint inhibitors can cause immune activation in any organ — most commonly colitis (10–20%), pneumonitis (3–5%), hepatitis (2–5%), endocrinopathies including hypothyroidism (10–20%) and hypophysitis (2%), skin toxicity, and rarer cardiotoxicity and neurotoxicity. Early recognition is critical: grade 1 irAEs are often managed with close monitoring; grade 2 typically require corticosteroids; grade 3–4 require high-dose IV methylprednisolone, immunotherapy hold, and often specialist consultation (gastroenterology, endocrinology, pulmonology). Endocrinopathies (thyroid dysfunction, adrenal insufficiency) are generally permanent and require lifelong hormone replacement. IrAE occurrence correlates with treatment response in some tumour types — a phenomenon reflecting global immune activation.

Liquid Biopsy: Real-Time Tumour Genomics from a Blood Draw

Circulating tumour DNA (ctDNA) is cell-free DNA shed by tumour cells into the bloodstream. It constitutes a small fraction (0.01–10%) of total plasma cell-free DNA, detectable by ultra-sensitive next-generation sequencing with molecular barcoding (Guardant360, FoundationOne Liquid CDx) or digital PCR. Its clinical utility spans the cancer treatment continuum:

Initial Profiling

When tissue is insufficient, inaccessible, or heterogeneous. For NSCLC, Guardant360 detects EGFR sensitising mutations with 82–94% sensitivity and >99% specificity vs tissue. If liquid biopsy is negative in a clinical scenario where tissue biopsies are technically challenging, tissue biopsy remains necessary — ctDNA sensitivity drops below 50% in stage I–II disease.

Resistance Detection

Rising ctDNA or emergence of new mutations during treatment signals acquired resistance weeks before radiographic progression. EGFR T790M emergence in plasma can direct switch to osimertinib before clinical deterioration. Serial liquid biopsy every 3–6 months during targeted therapy is increasingly used to anticipate rather than react to resistance.

Minimal Residual Disease (MRD)

ctDNA detection after curative resection identifies patients at high recurrence risk who may benefit from adjuvant therapy intensification. The GALAXY trial in stage II/III CRC showed ctDNA-positive patients post-surgery had 17× higher recurrence risk; ctDNA clearance during adjuvant chemotherapy predicted better outcomes. The FDA approved the Signatera assay for colorectal cancer MRD monitoring in 2022.

Multi-Cancer Early Detection

MCED tests (Grail Galleri) analyse ctDNA methylation patterns to detect cancer signals in asymptomatic individuals, with the ability to identify tissue-of-origin. Sensitivity for stage I cancer is ~15–20%; for stage III–IV, ~65–75%. The NHS-Galleri trial (140,000 participants) and PATHFINDER trial are generating evidence on whether MCED screening reduces cancer-specific mortality — results expected 2026–2028.

Hereditary Cancer Risk and Germline Testing

Precision oncology includes not only the somatic (tumour) genomic landscape but also the germline — inherited mutations in cancer predisposition genes that increase lifetime cancer risk and have treatment implications.

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BRCA1/2: Pathogenic germline variants confer lifetime breast cancer risk of 50–72% (BRCA1) and 40–65% (BRCA2), and ovarian cancer risk of 44% (BRCA1) and 17% (BRCA2). Additionally: prostate cancer risk 2× elevated (BRCA2 8× elevated for aggressive disease), pancreatic cancer risk 3–6× elevated. BRCA1/2 germline status qualifies patients for PARP inhibitor therapy (olaparib, niraparib), risk-reducing surgeries (bilateral mastectomy, salpingo-oophorectomy), and cascade testing of first-degree relatives.

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Lynch Syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM): The most common hereditary colorectal cancer syndrome, with lifetime CRC risk of 25–80% depending on gene. Germline Lynch mutations are the cause of dMMR tumours in these patients and qualify them for pembrolizumab and aspirin chemoprevention protocols. Universal tumour testing for dMMR/MSI-H (IHC) is now recommended for all newly diagnosed CRC — approximately 15% are dMMR, of which ~25% are Lynch syndrome (the rest are somatic MLH1 methylation).

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TP53 (Li-Fraumeni Syndrome): Germline TP53 pathogenic variants (Li-Fraumeni syndrome) confer extremely high lifetime cancer risk (~70–90%) across osteosarcoma, rhabdomyosarcoma, adrenocortical carcinoma, brain tumours, and early-onset breast cancer. Management includes intensive cancer surveillance (annual whole-body MRI) and avoidance of ionising radiation where possible. Increasingly detected incidentally on somatic tumour CGP panels that include germline reporting.

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Polygenic Risk Scores (PRS): Beyond single high-penetrance gene variants, GWAS-derived polygenic risk scores aggregate hundreds to thousands of common low-effect variants into a composite risk estimate for breast, prostate, colorectal, and other cancers. PRS for breast cancer (313-variant score, Mavaddat et al. 2019) stratifies risk approximately 3-fold between the top and bottom deciles and is beginning to inform screening intensity decisions in population-based programmes. See our dedicated guide to polygenic risk scores.

Challenges in Precision Oncology: Resistance, Heterogeneity, and Access

Acquired Resistance: The Central Unsolved Problem

Virtually all patients on targeted therapy develop acquired resistance within months to years, as rare resistant clones — present at sub-detection levels at diagnosis — are selected and expand under drug pressure. Resistance mechanisms are diverse: secondary mutations in the target gene (e.g. EGFR T790M, EGFR C797S, KRAS G12C secondary mutations), activation of bypass signalling pathways (MET amplification, HER2 amplification, BRAF amplification), lineage plasticity (small cell transformation in EGFR-mutant NSCLC, neuroendocrine differentiation in prostate cancer), and loss of the tumour suppressor that synergised with the driver (e.g. RB1 loss). Current strategies: combinatorial blockade of the driver plus common resistance bypass nodes, adaptive therapy (cycling drugs based on serial ctDNA monitoring), and triplet combinations incorporating immunotherapy.

Tumour Heterogeneity

A single tumour is not genetically uniform — different regions of the primary tumour and different metastatic sites carry different mutational profiles (spatial heterogeneity), and the tumour continues to evolve under treatment pressure (temporal heterogeneity). A biopsy from one site samples one clonal subpopulation. This means that a mutation identified by tissue biopsy may be absent in 20–50% of tumour mass, and a mutation missed by tissue biopsy may be present in metastases. Liquid biopsy captures a more representative sample of the heterogeneous tumour ecosystem and can detect resistance mutations emerging at any site.

Access and Cost

Comprehensive genomic profiling costs $3,000–5,000 per test; targeted therapies cost $10,000–30,000 per month; CAR-T therapy costs $400,000–600,000 per course. In the US, insurance coverage is improving as FDA companion diagnostic approvals expand, but significant gaps remain — particularly in community oncology settings and in low-income countries where precision oncology capabilities are largely unavailable. The access gap in precision oncology represents one of the most significant health equity challenges in modern medicine.

What Patients Should Ask: A Practical Checklist

Has my tumour had comprehensive genomic profiling? For stage III–IV solid tumours, standard panel IHC testing (e.g. HER2 only) is insufficient. Insist on NGS-based CGP (FoundationOne, Tempus, Guardant) that covers the full actionable mutation landscape including MSI, TMB, and fusion genes.

Do I have any targetable alterations or immunotherapy biomarkers? Ask specifically about EGFR, ALK, ROS1, KRAS G12C, BRAF, HER2, NTRK, RET (for NSCLC); HER2, BRCA1/2, PIK3CA (for breast); BRCA1/2, NTRK, MSI-H (for ovarian/CRC); and MSI-H and TMB-H for all solid tumours.

Should I have germline testing? If you have breast, ovarian, prostate, pancreatic, or colorectal cancer, or a family history suggesting hereditary risk, germline testing for BRCA1/2, Lynch syndrome genes, and other high-penetrance variants may have treatment and family planning implications.

Are there relevant clinical trials? Precision oncology advances fastest through clinical trials. Platforms like NCI-MATCH, MyPathway, TAPUR, and investigational drug programmes specifically enrol patients based on molecular alteration rather than cancer type — a separate search from histology-based standard trials.

What is the plan for monitoring and resistance? Serial liquid biopsy every 3–6 months during targeted therapy is increasingly standard practice to detect resistance mutations early. Ask whether ctDNA monitoring is part of your treatment plan.

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Precision Medicine in Cancer