L1 Cancer Clinical biology and treatment of cancer

Overview

This lecture works through the pathway from clinical suspicion to a definitive cancer diagnosis, using breast cancer throughout as the worked example. It covers the four-part diagnostic framework (clinical, radiology, tissue, biomarkers), the TNM staging system and mechanisms of metastatic spread, tumour grading and molecular diagnostics, risk-prediction tools (NHS Predict, Oncotype DX) that combine these features into a treatment decision, the intents behind treatment (neoadjuvant/adjuvant/palliative) and the multidisciplinary/palliative modalities used, and finally how treatment response and benefit are monitored over time.

Establishing a Cancer Diagnosis: The Four-Pillar Framework

Diagnosis is organised under four categories, used as a recurring section framework through the lecture:

• Clinical: history and physical examination
• Radiology: imaging
• Tissue: cytology / histology
• Biomarkers: molecular testing

History and Physical Examination

Suggestive symptoms: pain, lump/bumps, rectal bleeding, fevers/sweats, change in bowel habit, haemoptysis, dyspnoea, neurological symptoms, PV bleeding, weight loss, painless jaundice.

Examination findings: general appearance; lumps (skin, lymph nodes, testicular, breast, prostate, rectum); abnormalities on abdominal or chest examination.

Illustrative case (“John”): history should cover pain (type, distribution), cough, breathlessness, haemoptysis, and symptoms specific to metastatic sites. Chest examination should look for crepitations, stony dullness (suggesting a pleural effusion), wheeze, and reduced expansion.

Findings outside the thorax: lymph nodes (supraclavicular fossa), liver edge, omental caking, ascites, other measurable masses, and neurology, e.g. a sensory level.

A spinal cord lesion produces a sensory level: below the level of the lesion there is loss of pain/temperature/light touch on the contralateral side (lateral spinothalamic tract) and loss of vibration/motor/deep touch/position sense on the ipsilateral side (lateral corticospinal tract).

Screening versus Diagnostic Imaging

Screening mammogram: an X-ray study of the breast used to detect breast changes in women with no signs or symptoms of breast cancer. A meta-analysis of 8 clinical trials showed a 24% reduction in mortality.

Diagnostic mammogram: an X-ray study of the breast used to check for cancer after a lump or other sign/symptom has been found.

National Breast Screening Program eligibility (mammogram every 2 years): women aged 45–69, no symptoms of breast cancer, not currently pregnant or breastfeeding.

Screening operates on an asymptomatic population to enable early diagnosis before symptom onset, whereas diagnostic pathways are only entered after symptoms appear.

Clinical imaging pathway: screening mammogram → recall for diagnostic mammogram ± tomosynthesis + ultrasound (breast and axilla) → biopsy (e.g. ultrasound-guided).

Tissue Diagnosis: Histology versus Cytology

Category	Histology	Cytology
Definition	Study of tissues of animals and plants under the microscope	Study of structure and function of cells
Main focus	Tissues, organs, organ systems	Cells
Scope	Wider	Narrow
Cost	Higher	Lower
Speciality	Reveals tissue architecture	Reveals detailed cellular features

Histological subtypes of invasive breast carcinoma (named, not individually defined): medullary, metaplastic, apocrine, mucinous, cribriform, tubular, neuroendocrine, classic lobular, and pleomorphic lobular carcinoma (Nascimento et al. 2020).

Key distinguishing feature: ductal carcinoma causes fibrosis and forms a lump; lobular carcinoma causes minimal fibrosis and forms no lump.

Tumour Grading

Grading is tumour-type specific: prostate cancer uses the Gleason score, renal cell carcinoma uses Fuhrman grading, breast cancer uses the (Modified) Bloom-Richardson grading system.

General grade categories:

• Grade 1 (score 3–5): cells similar to normal, growing slowly — well-differentiated/low grade
• Grade 2 (score 6–7): cells don’t look normal, growing more quickly — moderately differentiated/intermediate grade
• Grade 3 (score 8–9): cells very abnormal, growing quickly — poorly differentiated/high grade
• GX: grade cannot be assessed — undetermined grade
  (Some systems use more than 3 grades.)

Modified Bloom-Richardson scoring (breast cancer), three features each scored 1–3:

• Tubule formation (% of tumour formed by normal-appearing tubules): >75% = 1; 10–75% = 2; <10% = 3
• Nuclear pleomorphism: small/uniform, no nucleoli = 1; enlarged, mostly uniform, nucleoli present = 2; large, bizarre, dark nuclei, prominent nucleoli = 3
• Mitotic figures (count per 10 high-power fields at 40x, worst area): 0–9 = 1; 10–19 = 2; ≥20 = 3

Modes of Cancer Spread

Four mechanisms of metastatic spread:

• Haematogenous — a tumour cell breaks through a blood vessel wall and travels in the bloodstream to seed a secondary tumour
• Lymphatic — spread via the lymphatic network (vessels/nodes)
• Contiguous — local direct extension of the tumour into adjacent structures
• Transcoelomic — spread across body cavities (e.g. peritoneal/pleural seeding)

Transcript flag (slide 12): the transcoelomic-spread diagram's small step labels were illegible even at high zoom; only the general mechanism (spread across a body cavity) was recorded, not the individual steps.

Breast Anatomy and Lymphatic Drainage

Understanding breast anatomy is important for staging breast cancer. 95% of the breast drains to the axillary lymph nodes (node groups B–F); 5% drains to the internal mammary lymph nodes (node group A).

TNM Staging System

The TNM (AJCC/UICC) system was created by the American Joint Committee on Cancer and the International Union Against Cancer, and is used to describe most cancer types.

Staging prefixes:

• c: clinical stage (e.g. from imaging or biopsy)
• p: pathological stage (after pathological examination)
• y: stage after neoadjuvant therapy
• r: re-staging after a disease-free interval
• a: stage determined at autopsy

TNM components:

• T: Tx = cannot be assessed; T0 = no evidence of primary tumour; Tis = carcinoma in situ; T1–T4 = increasing size/extent (T1 = small, minimal invasion; T4 = large, extensive invasion)
• N: Nx = cannot be assessed; N0 = no node involvement; N1–N3 = increasing regional node metastases
• M: M0 = no distant spread; M1 = distant metastases

T staging (breast, by size on examination/imaging): T1a >1–5mm; T1b >5–10mm; T1c >10–20mm; T2 >20–50mm; T3 >50mm; T4a = direct extension to chest wall (not including pectoralis muscle). Assessed via examination, ultrasound, MRI, and mammogram.

N staging: if sentinel lymph node biopsy (SLNB) is positive, axillary lymph node dissection (ALND) follows. ALND carries roughly a 10% risk of lymphoedema, so the goal is to avoid this morbidity where possible. Internal mammary nodes cannot be surgically resected but can be irradiated, and are picked up on CT/MRI.

Sentinel lymph node biopsy technique: dye/tracer injected into the tumour drains via afferent lymphatics to the first (“sentinel”) node; lymphatic valves allow flow in one direction only.

Axillary/nodal anatomy levels: supraclavicular; high axillary/apical (level III); mid-axillary (level II); axillary vein/low axillary (level I); relative to pectoralis minor muscle; internal mammary nodes; Halsted’s ligament.

Pathological N categories: pN0(i+); pN1mi (>0.2–2mm, or >200 cells); pN1a (1–3 nodes, at least one deposit >2.0mm); pN2a (4–9 nodes, at least one deposit >2.0mm); pN3a (≥10 nodes, at least one deposit >2.0mm). A deposit ≤0.2mm or a cluster of <200 cells does not qualify as a positive node.

M staging: assessed by CT + bone scan, or FDG-PET CT.

TNM clinical and pathological prognostic staging grids (AJCC): the clinical prognostic stage is assigned to all patients regardless of therapy given; the pathological prognostic stage is assigned to patients who had surgery as initial treatment (with pT1, pT2, pN0, M0, ER+, HER2- cancers assigned Pathologic Prognostic Stage IA if the Oncotype DX recurrence score is <11). Both grids cross-reference anatomic T/N/M/grade categories against receptor-subtype combinations (ER/PR/HER2 status) to output an overall anatomic stage and a receptor-adjusted prognostic stage — ranging IA to IIIB on the clinical grid, and extending to IIIC/IV on the pathological grid (which includes additional higher T/N rows).

Transcript flag (slides 22–23): the full TNM prognostic staging grids are large tables cross-referencing T/N/M/grade against receptor subtype; only the overall structure and stage range were captured, not every individual cell value.

Molecular Diagnostics and Biomarkers

Immunohistochemistry (IHC) assesses receptor status (ER, PR, HER2), shown as paired negative/positive micrographs with brown DAB staining in receptor-positive tissue.

Fluorescence in situ hybridisation (FISH) detects gene amplification (e.g. HER2 gene copy number): FISH− = no amplification signal pattern; FISH+ = amplified signal pattern.

Ki-67 is a marker of cell proliferation with potential predictive/prognostic significance, staining categorised as negative, low, moderate, or high. Concordance between Ki-67 measured on core needle biopsy versus surgical excision samples has not been clearly shown; a review of 22 studies found some concordance, but interpretation is difficult due to differing measurement methodologies worldwide.

Receptors key: ER = estrogen receptor; PR = progesterone receptor; Ki67 = cell proliferation marker; HER2 = human epidermal growth factor receptor 2.

Molecular subtypes of breast cancer (ranked best to worst prognosis):

• Luminal A (~40%): ER+/PR+, HER2−, Ki67 low, low proliferation — best prognosis
• Luminal B (~20%): ER+/PR+, HER2 +/−, Ki67 high, high proliferation
• HER2-enriched (~10–15%): ER−, PR−, HER2+ — more aggressive, worse prognosis than luminal subtypes
• Triple negative (~15–20%): ER−, PR−, HER2− — most aggressive, worst prognosis, no specific targeted treatment available at the time of the slide

Next-generation sequencing (NGS)/liquid biopsy reports can provide: blood tumour mutational burden, ctDNA tumour fraction, microsatellite instability (MSI) status, and specific genomic findings — e.g. EGFR exon 19 deletion, T790M, CDK4 amplification, MDM2 amplification, MET amplification (with copy number), TP53 mutations. Panels commonly test >300 cancer-related genes, including a routine subset for a given tumour type (e.g. ALK, BRAF, EGFR, ERBB2, KRAS, MET, RET, ROS1 for lung).

Oncotype DX is a gene-expression-based molecular subtyping/recurrence-score assay; gene-expression heat-map/dendrogram clustering distinguishes subtypes such as Luminal A, Luminal B, Basal-like, and HER2- [remainder of legend cut off at slide edge in source].

Risk Prediction Tools and Worked Case

NHS Predict (breast.predict.nhs.uk) is prognostic for risk from the current cancer and predictive of benefit from therapy; it models averages from clinical trial data and extrapolates to the individual patient using clinico-pathological characteristics. Inputs: age at diagnosis; post-menopausal status; ER status; HER2/ERBB2 status; Ki-67 status (positive = >10%); invasive tumour size; tumour grade; mode of detection (screening/symptoms/unknown); number of positive nodes; whether nodal involvement is micrometastases only.

Case study (54-year-old woman): right screen-detected early breast cancer, lobular carcinoma (classic type), pT3 (60mm) G2 pN0 (0/4)(sn)(i−) cMx, ER positive (100%), PR positive (100%), HER2 IHC 1+, FISH negative.

Cumulative 10-year overall survival benefit by added treatment: surgery alone = 78%; + endocrine therapy = +4.8% (cumulative 83%); + chemotherapy = +3.9% (cumulative 87%); + bisphosphonates = +1.3% (cumulative 88%).

Oncotype DX Recurrence Score (RS) for this patient: 13. Distant recurrence risk at 9 years with endocrine therapy alone (aromatase inhibitor or tamoxifen): 4% (95% CI 3–5%) [TAILORx]. Group average absolute chemotherapy benefit for RS 11–25 (all ages): <1% (95% CI −1–2%).

TAILORx/NSABP B-20 exploratory subgroup analysis of absolute chemotherapy benefit for distant recurrence, by age and RS:

• Age >50: RS 0–25 = no benefit (<1%); RS 26–100 = >15% benefit
• Age ≤50: RS 0–10 = no benefit (<1%); RS 11–15 = ~1.6% benefit; RS 16–20 = ~6.5% benefit; RS 21–100 = >15% benefit

(Decisions around the RS 25 cutoff may factor in other clinical considerations.)

Treatment Intent

Three treatment intents:

• Neoadjuvant (curative intent): systemic therapy given before surgery, for risk reduction, making surgery easier, understanding tumour biology, and identifying high-risk patients; higher toxicity accepted given the curative goal.
• Adjuvant (curative intent): systemic therapy given after surgery, for risk reduction; higher toxicity accepted given the curative goal.
• Palliative (non-curative): systemic therapy to palliate symptoms, aiming for tumour response, prolongation of life, and maintaining quality of life; high toxicity is unacceptable given the palliative intent.

Worked examples: NSCLC stage IIIA; rectal cancer — chemoradiotherapy before surgery; triple-negative or HER2-positive early breast cancer.

Multidisciplinary Team and Palliative Treatment Modalities

The Cancer Multidisciplinary Meeting involves: surgeon, pathologist, radiologist, radiation oncologist, medical oncologist, palliative care, clinical nurse specialists, and organ specialist — across specialties including CNS, skin, lung, breast, lymphoma, upper GI, lower GI, sarcoma and bone, genitourinary, and gynae-oncology.

Treatment modalities used with palliative intent, by category:

• Surgery (loco-regional problems only): toileting mastectomy; spinal cord compression; CNS shunts; prophylactic pinning of bones; malignant bowel obstruction; fistula management; GnRH analogues
• Radiotherapy (loco-regional problems only): pain; bleeding; superior vena cava obstruction (SVCO); spinal cord compression
• Systemic anti-cancer therapy: chemotherapy; antibody-drug conjugates (ADCs); PD-1/PD-L1 inhibitors; endocrine therapy; anti-angiogenic drugs; BiTEs; CAR T cells; vaccine therapy; small molecule inhibitors
• Palliative care: physical, spiritual, whānau; complex pain management; symptom-directed care (e.g. pain, nausea, bowels); dying
• Clinical research: Phase 1, Phase 2, Phase 3, translational research, qualitative research

PET Imaging Tracers

• FDG ([¹⁸F]fluorodeoxyglucose): general oncology imaging; shows focal high tracer uptake at a tumour deposit
• PSMA (prostate-specific membrane antigen): imaging in prostate cancer; also used theranostically (diagnosis and treatment)
• Others named: FES; octreoscan (dotatate) — also used in neuroendocrine tumours; FET

Monitoring Treatment Response and Benefit

Methods of measuring benefit/response:

• Pain scores, e.g. the Visual Analogue Scale (VAS): 0 = no pain; 1–3 = mild; 4–6 = moderate/severe; 7–9 = very severe; 10 = worst pain possible
• Reviewing the medication card for analgesic consumption (available on electronic health records) as a proxy for symptom burden
• Monitoring bloods, e.g. liver function tests (can show rising bilirubin, alkaline phosphatase, GGT, ALT, AST over serial dates)
• Monitoring tumour markers, matched to cancer type:

Cancer type	Marker(s)
Prostate cancer	PSA
Germ cell tumours	AFP, beta-HCG
Hepatocellular carcinoma	AFP
Gastrointestinal malignancy (e.g. colorectal)	CEA
Epithelial ovarian and other peritoneal malignancies	CA125
Upper GI epithelial malignancies	CA19.9
Neuroendocrine tumours (NETs)	5-HIAA, chromogranin A
Breast cancer	CA15.3, CA27.29
Lymphoma and melanoma	LDH

• Cross-sectional imaging, usually CT chest/abdomen/pelvis, for serial monitoring of treatment response

Rising tumour markers (e.g. CA125 in ovarian cancer, or ctDNA) can precede clinical or radiological detection of recurrence — this is lead-time bias, illustrated by CA125 rising above the upper limit of normal before clinical recurrence was diagnosed.

Self-test

1. List the four categories used in the framework for establishing a cancer diagnosis.
2. List the TNM staging prefixes (c, p, y, r, a) and state what each indicates.
3. Describe the T-staging thresholds for breast tumour size on examination/imaging, from T1a to T4a.
4. Describe the sentinel lymph node biopsy technique and explain how a positive result changes axillary management.
5. Distinguish the pathological N-staging categories pN1mi, pN1a, pN2a, and pN3a.
6. List the four mechanisms of cancer spread and briefly describe what each one involves.
7. Distinguish histology from cytology.
8. Distinguish ductal from lobular breast carcinoma by their key clinical feature.
9. Describe the three features scored in the Modified Bloom-Richardson grading system and how the total score maps to Grade 1–3.
10. Distinguish the four molecular subtypes of breast cancer by receptor profile and prognosis.
11. Explain why concordance of Ki-67 measurement between core needle biopsy and surgical excision is difficult to interpret.
12. Describe what NHS Predict models and list the patient/tumour inputs it requires.
13. For the case-study patient (pT3, G2, pN0, ER+/PR+, HER2 1+/FISH-negative, Oncotype RS 13), explain what the RS result and the TAILORx data indicate about her likely chemotherapy benefit.
14. Distinguish neoadjuvant, adjuvant, and palliative treatment intent, including the toxicity profile accepted with each.
15. List the roles/specialties that make up a cancer multidisciplinary meeting.
16. List the five categories of treatment modality used with palliative intent, giving one example from each.
17. Distinguish the clinical use of FDG-PET from PSMA-PET.
18. List the methods used to monitor a patient’s benefit from and response to cancer treatment.
19. Explain lead-time bias using the CA125/ovarian cancer example.
20. A patient with known breast cancer has a rising CA15.3 on serial blood tests but no new symptoms. Explain what this could represent and why it needs to be interpreted alongside imaging/clinical findings.
21. Using the case-study patient as an example, explain how TNM stage, tumour grade, and molecular subtype/receptor status are combined to determine a prognostic stage grouping and to inform tools like NHS Predict and Oncotype DX.

Answers

Reveal answers

1. Clinical (history and physical examination), radiology (imaging), tissue (cytology/histology), and biomarkers (molecular testing).
2. c = clinical stage; p = pathological stage (after pathological exam); y = stage after neoadjuvant therapy; r = re-staging after a disease-free interval; a = stage determined at autopsy.
3. T1a >1–5mm; T1b >5–10mm; T1c >10–20mm; T2 >20–50mm; T3 >50mm; T4a = direct extension to the chest wall (not including pectoralis muscle).
4. Dye/tracer is injected into the tumour and drains via afferent lymphatics (which have one-way valves) to the first, “sentinel,” node, which is biopsied. If the SLNB is positive, axillary lymph node dissection (ALND) is performed; ALND carries ~10% risk of lymphoedema, so it is avoided unless the sentinel node is positive.
5. pN1mi = micrometastasis >0.2–2mm or >200 cells; pN1a = 1–3 positive nodes with at least one deposit >2.0mm; pN2a = 4–9 positive nodes with at least one deposit >2.0mm; pN3a = ≥10 positive nodes with at least one deposit >2.0mm (a deposit ≤0.2mm or <200 cells does not count as positive).
6. Haematogenous (tumour cell crosses a vessel wall and travels via the bloodstream to seed elsewhere); lymphatic (spread via lymph vessels/nodes); contiguous (direct local extension into adjacent structures); transcoelomic (spread across a body cavity, e.g. peritoneal/pleural seeding).
7. Histology studies tissues/organs/organ systems (wider scope, higher cost, reveals tissue architecture); cytology studies individual cells (narrower scope, lower cost, reveals detailed cellular features).
8. Ductal carcinoma causes fibrosis and forms a palpable lump; lobular carcinoma causes minimal fibrosis and forms no lump.
9. Tubule formation (% normal-appearing tubules: >75% = 1, 10–75% = 2, <10% = 3); nuclear pleomorphism (small/uniform = 1, enlarged/mostly uniform = 2, large/bizarre = 3); mitotic count per 10 HPF at 40x (0–9 = 1, 10–19 = 2, ≥20 = 3). Summed score 3–5 = Grade 1, 6–7 = Grade 2, 8–9 = Grade 3.
10. Luminal A: ER+/PR+, HER2−, Ki67 low — best prognosis. Luminal B: ER+/PR+, HER2 +/−, Ki67 high. HER2-enriched: ER−/PR−, HER2+ — more aggressive/worse prognosis than luminal. Triple negative: ER−/PR−/HER2− — most aggressive, worst prognosis, no targeted treatment (at time of slide).
11. Because different methodologies are used to measure Ki-67 worldwide, making the degree of concordance between core biopsy and excision samples hard to interpret, even though some concordance does appear across the 22 studies reviewed.
12. NHS Predict estimates prognosis from the current cancer and predicted benefit from therapy by modelling averages from clinical trial data and extrapolating using the patient’s/tumour’s clinico-pathological characteristics. Inputs: age at diagnosis, menopausal status, ER status, HER2 status, Ki-67 status, tumour size, tumour grade, mode of detection, number of positive nodes, and whether nodal disease is micrometastatic only.
13. RS 13 falls in the RS 11–25 group, where the group average absolute chemotherapy benefit is <1% (95% CI −1–2%), and her distant recurrence risk at 9 years on endocrine therapy alone is already low (4%). This indicates minimal expected added benefit from chemotherapy, supporting a treatment plan built around endocrine therapy (as reflected in the survival-benefit table: endocrine therapy adds +4.8%, chemotherapy only a further +3.9% on top).
14. Neoadjuvant = curative-intent systemic therapy before surgery (risk reduction, eases surgery, reveals tumour biology, identifies high-risk patients); adjuvant = curative-intent systemic therapy after surgery (risk reduction); both accept higher toxicity given the curative goal. Palliative = non-curative, aims for symptom response/prolonged life/quality of life; high toxicity is unacceptable.
15. Surgeon, pathologist, radiologist, radiation oncologist, medical oncologist, palliative care, clinical nurse specialists, and organ specialist.
16. Surgery (loco-regional only, e.g. spinal cord compression decompression); radiotherapy (loco-regional only, e.g. for bleeding or pain); systemic anti-cancer therapy (e.g. chemotherapy or PD-1 inhibitors); palliative care (e.g. complex pain management); clinical research (e.g. Phase 1 trials).
17. FDG-PET is a general oncology tracer showing focal areas of high glucose uptake at tumour deposits; PSMA-PET targets prostate-specific membrane antigen and is used specifically in prostate cancer, including a theranostic (diagnostic + therapeutic) role.
18. Pain scores (e.g. VAS), analgesic consumption from medication records, blood monitoring (e.g. LFTs), tumour marker trends, and cross-sectional imaging (usually CT chest/abdomen/pelvis).
19. CA125 levels can rise above the upper limit of normal before a clinical recurrence is detected or symptomatic — i.e., the biomarker signals disease earlier than clinical/radiological methods would, which is lead-time bias; the same principle applies to ctDNA.
20. It could represent early biochemical recurrence preceding clinical or radiological detection (lead-time bias), so a rising marker alone needs to be correlated with imaging and clinical assessment before concluding recurrence has occurred.
21. TNM stage (T/N/M category) combines with tumour grade and receptor-based molecular subtype (ER/PR/HER2) in the AJCC prognostic staging grids to output a receptor-adjusted prognostic stage (e.g. IA–IIIB clinical, extending to IV pathological). This same set of features (grade, ER/PR/HER2, nodal status, tumour size) feeds into NHS Predict to estimate prognosis and treatment benefit, and into Oncotype DX to generate a Recurrence Score — as seen in the case-study patient, where pT3 G2 pN0 ER+/PR+/HER2 1+-FISH-negative status and an RS of 13 together supported a low chemotherapy-benefit, endocrine-therapy-led treatment decision.