Breast cancer

Question 1

Notes on hereditary breast cancer

Answer 1

• Most common mutations BRCA1 and BRCA 2
  
  • Clinical factors A/W germline BRCA mutations
    
    • Invasive breast ca <30
    • Triple negative breast ca < 60 years
    • male invasive breast a any age
    • Ovarian or primary peritoneal cancer
    • Ashkenazi Jews

BRCA 1 and BRCA 2

• Tumour suppressor genes
• Repair dsDNA breaks using homologous recombination - mutations → homologous recombination deficiency → over-reliance on homologous end-joining (error-prone repair)
• BRCA 1 → triple negative breast ca
• BRCA 2 → hormon receptor positive ca (and males)

Notes on BRCA mutations and PARP inhibitors

• Base excision repair regulated by protein PARP. Inhibiting PARP → tumour becomes overloaded with errors → unstable → death
• BRCA mutations predict PARP inhibitors benefit → olaparib prolongs survival in patients with advanced breast ca and a germline BRCA mutation

Other hereditary breast cancer syndromes

Li Fraumeni (TP53)

Coden syndrome (PTEN), Peutz-Jegher (STK11), hereditary diffuse gastric cancer syndrome (CDH1)

Question 2

General principles regarding treatment intent in breast ca

Answer 2

• Stage I & II → localised to breast, no lymph nodes. Curative intent
• Stage IV (metastatic) → palliative
• Exceptions:
  
  • Long term control can be seen with HER 2 targeted therapies in HER 2 positive cancer
  • Note long term disease control on immunotherapy very uncommon (unlike melanoma)

Question 3

Summary of hormone receptor positive and HER-2 positive breast ca - proportion, disease recurrence, treatments:

Answer 3

• ER/PR expression identified via immunohistochemistry
• HER-2 requires in-situ hybridisation
• Note late recurrences seen in hormon receptor positive breast ca
• Note luminal = HR positive, HER 2 negative

Question 4

Summary of chemotherapy for early breast ca

Answer 4

• Most node positive → adjuvant chemo → anthracycline plus taxane e.g. doxurubicin and paclitaxel
  
  • Dose dense regimens (shortened interval between cycles) → moderately reduce risk of recurrence and death
• Adjuvant trastuzumab for 52 weeks (monoclonal antibody that binds HER2) if HER 2 positive
  
  • IV infusion
• Neo-adjuvant therapy:
  
  • No RCTs
  • May help identify high risk populations that may benefit from escalation or change of treatment in the adjuvant setting
• Endocrine therapy mainstay adjuvant therapy for HR +ve, HER 2 negative early breast ca (see diagram)
  
  • Pre-menopausal women need ovarian function suppression if on AI (otherwise paradoxical increase in estrogen) → GnRH analogues
  • OFS + tamoxofen in pre-menopausal → superior DFS, exemestane (AI) plus DFS → greater DFS. Absolute benefit OFS greater in higher risk disease (patients who received adjuvant chemotherapy, and the very young <35 years)
  • E.g. aromatase inhibitors → anastrozole, letrozole, exemestene

Question 5

Principles for treatment of metastatic breast cancer

Answer 5

• Phenotypic changes common, may be influenced by treatment exposure → all with new dx metastatic disease → consider for re-biopsy
• Single agent treatment preferred in the absence of rapid clinical progression, life-threatening visceral metastases, or need for rapid symptom and/or disease control
• Novel agents recently approved:
  
  • Cyclin dependent kinase 4/6 inhibitors
  • Alpha specific PI3 kinase inhibitors
  • Antibody drug conjugates
  • Checkpoint bloackade

Question 6

Notes on cyclin dependent kinase 4/6 inhibitors

Answer 6

• E.g. palbociclib, ribociclib, abemaciclib
• PFS benefit as 1st/2nd therapy with endocrine agents in HR positive, HER 2 negative advanced breast ca
• Toxicities
  
  • Palbociclib, ribociclib → neutropaenia
  • Ribociclib → severe LFT derangements, QTx prolongation
  • Abemaciclib → broader spectrum of activity, persistent diarrhoea, less neutropaenia

Question 7

Notes on alpha-specific PI3-kinase inhibitors in advanced metastatic breast ca

Answer 7

• E.g. alpelisib
• PFS benefit in endocrine resistant HR positive, HER 2 negative advanced breast ca in combo with fulvestrant (anti-estrogen)
  
  • Benefit observed only in those with PIK3CA mutations
• Toxicities
  
  • Rash, hyperglycaemia, nausea, vomiting, diarrhoea

Question 8

Examples of antibody-drug conjugate in advanced breast cancer

Answer 8

• Trastuzumab-emtansine: trastuzumab covalently linked to cytotoxic agent DM1. On binding to HER2 on cell surface → DM1 internalised & acts as cytotoxic agent
• Toxicities
  
  • Thrombocytopaenia, Liver toxicity
• PFS and OS benefit. Most commonly used as 2nd line therapy for advanced HER2 positive breast ca (not superior to standard trastuzumab based regimens in 1st line setting)

Question 9

Notes on PD-L1 blockade in advanced breast ca

Answer 9

• PFS and OS benefit for atezolizumab + Nab paclitaxel as first line therapy for advanced triple negative breast ca
  
  • Benefit greatest in PDL1 positive tumours

Question 10

Risk factors for breast cancer

Answer 10

• Previous breast cancer, previous ovarian ca
• Early menarche, late menopause
• Family history
• Obesity
• Previous mantle irradiation
• Nulliparity, age of first pregnancy > 30 years
• Alcohol consumption

Question 11

Side effects of tamoxifen

Answer 11

• Risk of thromboembolism
• Risk of endometrial ca
• Hot flushes
• Cataracts

Question 12

Side effects of aromatase inhibitors

Answer 12

• Loss of bone mineral density → increased risk of fractures
• Muskuloskeletal-arthraglia syndrome → symmetrical pain and joint stiffness reversible on cessation of treatment

Question 13

Long case considerations for breast ca:

Answer 13

• Potential side effects of treatment:
  
  • Weight gain
  • Osteoporosis → vitamin D, exercise
  • Cognitive dysfunction
  • Sexual problems → vaginal atrophy, dyspareunia (consider topical estrogens)
  • Depression, loss of self confidence
  • Vasomotor symptoms
    
    • Can use antidepressants
    • Avoid CYP2D6 inhibitors (paroxetine, fluoxetine) for patients on tamoxifen (metabolised to active agent endoxifen by this enzyme)
  • Early menopause
  • ?Ongoing need for contraception (should not use OCPs)
  • Lymphoedema (if axillary dissection has been performed)
  • Skin damage from radiation

Question 14

Notes on chemoprevention with tamoxifen

Answer 14

• Pre-malignant ER positive tumours (high risk of invasive cancer) → low dose tamoxifen for 3 years effective chemoprevention strategy and well tolerated
• Endometrial ca and VTE risk did not differ from placebo, menopausal symptoms minor
• Raloxifene as effective as tamoxifen in reducing risk of invasive breast cancer with reduced with thromboembolic effects and cataracts

Question 15

Poor prognostic indicators in breast cancer

Answer 15

• Pathologic staging
• ER/PR negative → more likely to recur
• High growth rate (measured as proportion of cells in S-phase) → early relapse rate (also improved response to chemotherapy)
• HER 2 over-expression or mutated p53 gene poor prognosis

Question 16

Absolute contraindications to breast conservation surgery

Answer 16

1. Persistently positive resection margins after reasonable re-excision attempts
2. Two or more primary tumours in separate breast quadrants
3. Diffuse malignant appearing mammographic microcalcifications
4. History of prior radiotherapy to the breast or chest wall (also precludes further radiotherapy)
5. Pregnancy (may be possible to perform in 3rd trimester)