Br-Ca

• HER2 therapy resistance

  
  

  The majority of women with HER2+ breast cancer will respond to trastuzumab and/or other HER2-targeted therapies

  • Fewer than half of patients with HER2+ mBr-Ca initially respond to trastuzumab, however the majority of these will experience tumour progression
  • Many patients with early-stage HER2+ breast cancer treated with trastuzumab also experience recurrence
• Trastuzumab resistance


  • A constitutively active truncated form of HER2 receptor that has kinase activity but lacks the extracellular domain and the binding site of trastuzumab is originated from metalloprotease-dependent cleavage of the full-length HER2 receptor
  • Trastuzumab does not bind to p95HER2 and therefore has no effect against it
  • The remaining intracellular domain of p95HER2 has operational kinase domains and can be targeted by the TK inhibitor lapatinib
  • Epitope masking by MUC4 or CD44/polymeric hyaluronan complex
  • Trastuzumab binding stabilises and activates PTEN and consequently down-regulates the PI3K/Akt signalling pathway
  • When PTEN function is lost, PI3K remains constitutively active regardless of binding of trastuzumab to HER2
  • Genomic aberrations in the PI3K pathway produce constitutive activation which will signal downstream to the nucleus regardless of trastuzumab binding to HER2
  • Increased Akt kinase activity and PDPK1 overexpression have also been implicated with trastuzumab resistance
• HER family


  • EGFR, HER3 and HER4 can all heterodimerise with HER2
  • Following ligand binding, homo- and hetero-dimeric interactions between the HER family in various combinations induce auto-phosphorylation on the intracellular tyrosine kinase domain
  • HER3 lacks kinase tyrosine activity and relies on HER family for trans-phosphorylation
• EGFR

  • Activation of EGFR occurs through the binding of ligands: EGF, TGF-α, HB-EGF, amphiregulin, epiregulin, betacellulin, epigen
  • Induces EGFR homo/hetero-dimerisation with HER2,3,4
  • Activation of downstream signalling pathways: PI3K/AKT, Ras/MERK/ERK, PLCγ/PKC, and JAK/STAT
• EGFR in breast cancer

  • Dysregulation of the EGFR signalling cascade due to overexpression or constitutively activating mutations is well established in cancer
  • EGFR Overexpression is observed in 15% of Br-Ca caused by the EGFR gene amplification and is associated with poor clinical outcome
  • EGFR overexpression can also be triggered by missense mutations, with a higher incidence in hereditary breast cancer
  • EGFR is frequently overexpressed (in at least 50%) of TNBCs and associated with poor prognosis
• HER3


  • HER3 is the only receptor in the family that is catalytically inactive and requires dimerisation with other members in order to be activated
  • HER3 ligands are: NRG1 and NRG2
  • Activation of downstream signalling pathways: PI3K/AKT, Ras/MERK/ERK
• HER3 in breast cancer

  • HER3 is the favoured receptor for dimerisation with HER2 and growing evidence supports HER3 as being a required partner in HER2+ breast cancer
  • HER3 overexpression, due to mutations, has been reported in approximately 20–30% of invasive breast carcinomas particularly in ER+ tumours
  • Co-expression of HER3 and HER2 is frequently observed
  • HER3 is associated with shorter disease-free survival of breast cancer patients
• HER4

  • Ligand-stimulated HER4 can form homodimers or heterodimerise with other HERs which results in trans-autophosphorylation and subsequent activation of downstream signalling cascades
  • HER4 ligands: Neuregulins (NRG1–4), HB-EGF, epiregulin, β-cellulin
• 1. Met

  • The c-Met tyrosine kinase receptor and its ligand, hepatocyte growth factor, are overexpressed in some HER2+ tumours
  • Its co-expression with HER2 is associated with trastuzumab resistance through sustained Akt activation
• HPV vaccine protects against HPV 16 and 18, and 6 and 11
• Pollution levels in the UK tend to be 10X low compared to other countries around the world
• Sensitivity

  TP / (TP + FN)
• Define Sensitivity 


  Percentage of patients with disease who test positive
• Define Specificity


  Percentage of patients without disease who test negative
• Specificity


  TN/ (TN + FP)
• PPV

  • Percentage of patients with positive test who actually have disease
  • TP / (TP + FP)
• NPV

  • Percentage of patients with negative test who do not have disease
  • TN / (TN + FN)
• Measuring Exposure

  Nature: Tobacco Form

  Dose: Quant/Qual., Cigarette p/d, dose per unit of time

  Time: Begin to End, Distribution over time
• Data Sources

  Questionnaire, Survey, Census, Registries, Records, Bio./Env. Measurements
• Measuring Outcome

  Patient Report, Clinical Records, Routine Data
• Measuring Occurrence

  Define, Case, Popul., Time Period.

  Popul. should exclude those w/o risk, Popul. size from which cases originate act as denominator
• Routine Data


  Inc. Rate, est. w/o direct measure of p-t at risk
• P-T at Risk

  Used for Rare Disease, and when Popul. is stable throughout period

  Est. by popul. at mid-point of x length of period
• Incidence

  Unaffected by Rx./Survival. Influenced by Changing Definitions, Improvements in Diagnosis. and Screening. Rises dramatically with age due to build-up of RF. In UK, aged 50-74 account for more than half of new cases
• Concordance

  Probability of pair of individuals both having the disease, given one of the pair does have the disease.
• All-Cause Mortality

  No. of Deaths in population/ Total P-T at risk
• Annual Mortality


  No. of Deaths from disease in Popul. over t/ Mid-Yr Popul
• MoD Prevalence

  No. of Cases in popul. over t/ Popul. at Same Point
• MoD Inc. Risk

  No. of New Cases in Popul. over t/ Popul. initially at Risk
• Rate over T

  No. of New Cases over t/ P-Yrs at Risk
• Leading Causes of Death WW

  1.Lu-

  2.Colo-

  3.Stomach

  4.Liver
• Lu-Ca Epidemiology

  2 Most Common Incidence

  Most Common Cancer Rel. Death
• Lu-Ca Survival

  Female> Male

  1v1.13
• Lu-Ca Diagnosis Route

  GP Diagnosis (49%) greatest 1-yr survival than ED Route (35%) at 9% survival
• Lu-Ca Causes

  Smoking (Environmental alone 15% of ppl), Family History, 25-37% w/ parent, 82% w/ sibling, Radon 9%, Occu 13%, Air Pollution
• Lu-Ca Signs and Symptoms

  Clubbing (-SCLC), Hoarse Voice with Bouine Cough, Facial and Neck Swelling, Loss of Appetite, Unexpected Weight Loss, Chest Pain and Rec. Chest Infections, Pain (Metastasis),, fatigue, monophonic wheeze, >3wks Persistent dyspnoea + cough
• Lu-Ca Types

  NSCLC: Adenocarcinoma, LC Neurfenda, Squamous Carcinoma

  SCLC (Most aggressive, relapsing)

  Pulmonary Blastoma,

  Adenosquamous carcinoma
• Curative Treatment Lu-Ca

  Radical RT, CT, Surgery

  SABR: 3-7 fractions at 55-65 Gu over few doses, Peripheral Cancer.

  CHART: 55 Gu for 14 days, 3x per day, centrally placed large cancers
• Peripheral Cancer

  No Fly Zone

  Pericardial effusion, massive haemoptysis, airway necrosis, Pneumonia
• Lu-Ca CT

  Induction: Pre-op to downsize tumour-curative

  Neo-Adj: Pre-ope to reduce recurrence risk

  Adj: Post-ope to reduce relapse/met