Cellular / Biochemical / Molecular Targets in
Breast cancer is a heterogenous group of disease with wide ranging
Move toward targeted therapy and personalized medicine is set to
Intrinsic molecular subtypes of breast cancer
Now clear that breast cancer can be usefully classified by gene
- luminal A, luminal B, HER2, basal
ER +ve vs ER -ve tumour profiling is most robust distinction.
- luminal tumours show expression of ER, lmw cytokeratin 8/18
- luminal A = low grade, high ER expression and excellent prognosis
- luminal B = higher grade, higher proliferation and poorer
HER2 stands for Human Epidermal growth factor Receptor 2
- usually ER negative, and characterized by over-expression of HER2
and associated genes.
- tend to be more aggressive, however responsive to targeted
- p53 mutations
- a few (10-15%) are also ER positive and fall into / overlap into
luminal B group
Basal group has higher expression of genes characteristic of normal
- including hmw cytokeratins, HER1 and SM actin.
- generally high-grade, poorly differentiated tumours with a poor
- predominantly negative for ER, PR and HER2; this 'triple negative'
is a surrogate for basal like classification.
- in reality triple-negative is also heterogenous, 70% basal
- Tend to occur in younger women, in BRCA pts, and in those of
A set of 70-gene expression profiles that can classify breast
- more predictive than nodal status
- commercially available (MammaPrint) and undergoing prospective
A 21-gene assay using reverse-transcription PCR on RNA isolated
from paraffin-embedded tumour specs
Validated in a large multi-center trial
- stratifies patients in terms of prognosis
- appears to guide benefit of adding chemo to tamoxifen in high-risk
- potential to guide targeted clinical therapies in at-risk patients
Targeted Molecular Therapies
Also new agents in trials for HER1, VEGF, PART1/2
|Survival benefit, adjuvant therapy and
metastatic disease control.
Anastrolozle (arimidex), Letrozone
|Survival benefit, adjuvant / metastatic
disease. postmenopausal women
|Second-line therapy; metastatic disease in
|Survival benefit, adjuvant and metastatic
|Second-line; metastatic disease; in trials
LHRH blockers - suppresses ovarian fx.
1. Now recognized that there are 2 ERs: alpha and beta
- alpha is the classic ER, detected on usual assays; 75% are +ve
- beta role is uncertain at this time; high ratios may be assoc.
with tamoxifen resistance.
--> activation of nuclear ER receptors is a critical step in the
growth of many breast cancers.
--> ER signaling = estradiol binds to ERs in cell and initiates
transcription, --> cell proliferation, angiogenesis and
Selective ER modulator (SERM), competitively binds to ER, blocking
estradiol from initiating downstream signaling.
Inhibit aromatase, which converts androstenedione to estrodiole
2. PR is an estrogen-responsive gene that results from ER
- 55% of ER+ve tumours are also PR+ve
3. Endocrine therapies target ER pathways in several ways
- selective (tamoxifen) interact directly with the ER, binding to
inhibit estrogen-dependent transcription while maintaining agonist
activity at some sites.
- cf pure antagonists (fulvestrant), binding to ER and degrades the
ER protein without agonist activity.
- aromatase inhibitors and oophorectomy do not interact directly
with ER but reduce amount of estrogen available to bind as a ligand.
4. ER targeting is remarkably successful.
- adjuvant therapy with 5y of tamoxifen reduces recurrence by
- lowers odds of breast cancer death by 30%;
- similar benefit seen with aromatase inhibitors in postmenopausal
- transmembrane TK receptors, including erbB2 (HER2/neu)
2. HER2 over-expression
- HER2/neu is a gene involved in regulation of cell proliferation
- HER2 protein is transmembrane tyrosine kinase receptor that
participates in the growth, differentiation and survival of breast
- is a protoncogene; ie a normal gene with potential to be an
oncogene with molecular alterations (mutaiton, amplification or
over-expression of its product).
- HER2 protein is over-expressed in about 25% of invasive breast
- HER2 amplification is associated with more aggressive phenotype
and predicts for response to trastazumab therapy (recombinant
monoclonal antibody specific to HER2)
- diagnosed by immunihistochemistry and confirmed by FISH when
3. Trastazumab (herceptin)
- a humanized monoclonal antibody that binds to the extracellular
domain of the HER2 protein, inhibiting downstream signalling.
- 5 RCTs from >10000 women randomized showed significant
improvement recurrence, metastasis, disease free (50%) and overall
- clearly limited to HER2 +ve tumours
- mechanisms uncertain and many patients subsequently become less
--> minor cardiotoxicity rate; not a major concern.
- ongoing trials in this space looking at novel inhibitors of HER2
--> Lapatinib current under investigation.
4. PI3K/AKT pathway
- HER family partners, e.g. HER3 necessary for HER2 function; hence
are another target
- focus of acquired resistance to HER2
- Activating mutations of HER3 pathways are common; agents under
5. EGFR and MAPK
- HER2/EGFR heterodimer is a master regulator controlling carcinoma
- targetted with new results in trials.
6. Angiogenesis and Lymphadema targeting
- e.g. VEGF pathways; can be dealt to by a monoclonal antibody
- promising results in early trials.
- highly expressed in inflammatory breast cancer
7. DNA repair pathways
- relevant to BRCA1 and 2
- unable to repair DNA; genomic instability.
- PARP1/2 are enzymes that act as DNA damage sensors
- PARP upregulated in triple negative tumours
- inhibitors of PARP allow theoretically higher efficacy of DNA
damaging cancer drugs e.g. cisplatin
- promising results in early trials.
8. Other directions
- toposiomerases; DNA repair
- microRNAs, protein encoding RNSa that are involved in
proliferation regulation and a good target
- DNA methylation / epigenetics; associated with some cancer
subtypes and explored as a biomarker / target
Endocrine Therapeutic Agents in
1. Breast cancers are highly heterogenous.
- higher concentration of ERs, more likely that anti-estrogen will
- 'any detectable' ER still termed an endocrine-responsive tumour.
2. Tamoxifen remains the cornerstone, but in post-menopausal women,
- increased risk of VTE
- increased uterine cancer.
3. Aromatase inhibitors avoid these problems, more effective and
less toxic in post-menopausal women
- but(!) paradoxically increase estrogen in premenopausal women.
4. The definition of menopause is:
- prior bilateral oophorectomy
- age 60 or older
- age <60 and amennorhoea for 12+ months
- FSH and estradiol levels in the postmenopausal range
1. 20% of breast cancers.
- 60% ER positive.
2. Tamoxifen well proven in multiple trials and quality
- reduces annual recurrence by 40%
- and mortality by 34%
- irrespective of age, menopausal status or node status.
3. Suppression of ovarian function? (LHRH)
- currently unclear if there is additional benefit in this;
- trials need updating in context of modern hormonal and adjuvant
--> guidelines recommend tamoxifen; if contraindicated then
4. Aromatase Inhibitors (AIs) are contraindicated.
1. Several large RCTs support AIs
- current guidelines support use of AI as standard hormonal therapy.
2. If AIs contraindicated
--> 5y of tamoxifen.
Targeted Therapy in Practice
1. Trastazumab guidelines say:
- use in all patients with HER2 +ve disease with tumours >1cm
- regardless of horomone receptors
2. If tumours are <1cm, clinical judgement required as no clear
evidence in this space.