42077
Breast cancer - the
role of the oncologist
- Breast cancer
- Incidence
- In 2007 just over 25,000 cases in the age group
45-69yrs - (200-400 cases per 100,000 women)
- Death rates now below
50 per 100,000 women
- In 2007 just over 25,000 cases in the age group
45-69yrs - (200-400 cases per 100,000 women)
- High risk group = 45-70yrs
- Presentation
- Breast lump/thickening, +/-
axillary lymph node lump
- Nipple retraction, nipple discharge
- Skin changes: redness,
oedema or dimpling
- Breast lump/thickening, +/-
axillary lymph node lump
- Incidence
- Diagnosis
- Triple assessment
- Clinical; history and examination
- Imaging; mammogram, ultrasound,
- Pathology; core biopsy
and fine needle aspirate
- Analysis of the biopsies
- Microscopy
- Cell morphology
- Tissue morphology (ductal or lobular)
- 80% are invasive ductal
- 20% are invasive lobular
- 80% are invasive ductal
- Cell morphology
- Tumour properties
- Oestrogen receptor (ER) status
- Nuclear stain for ER
- Graded by H-score (0-300): % of cells stained
multiplied by... 0 (negative); 1 (weak staining),
2 (moderate staining), 3 (strong staining)
- Graded by H-score (0-300): % of cells stained
multiplied by... 0 (negative); 1 (weak staining),
2 (moderate staining), 3 (strong staining)
- Nuclear stain for ER
- HER2 (ErbB2)
- epidermal GF
receptor
- By immunohistochemistry
- Membrane stain
- Graded as... (Based on intensity
of stain and number of cells)
- 0 = negative
- 1 = negative
- 2 = borderline
- Requires FISH
- Using fluorescent DNA probes to detect
the amplification of the HER2 gene
- Using fluorescent DNA probes to detect
the amplification of the HER2 gene
- Requires FISH
- 3 = positive
- 0 = negative
- Graded as... (Based on intensity
of stain and number of cells)
- Membrane stain
- By immunohistochemistry
- Oestrogen receptor (ER) status
- Prognosis Information
- Grade - based on
microscopic/clinical presentation
- Tumour size
- Nodal status
- Spread to lymph nodes
- Spread to lymph nodes
- ER, PR (progesterone
receptor), HER2 status
- Lymphovascular invasion
- Invasion of the tissue blood/lymphatic
vessels - typically precedes node involvement
- Invasion of the tissue blood/lymphatic
vessels - typically precedes node involvement
- Age
- Nottingham prognostic
index (NPI) - empirical
method of calculating an
individual's outcome
- NPI = (0.2 x tumour size, cm) + tumour
grade (1-3) + lymph node stage (1-3)
- Good = <3
- 5/10/15yr survival rates = 96/86/80%
- 5/10/15yr survival rates = 96/86/80%
- Intermediate = 4.51-5
- 5/10/15yr survival rates = 70/47/37%
- 5/10/15yr survival rates = 70/47/37%
- Poor = >6
- 2/5/10yr survival rates = 67/32/21%
- 2/5/10yr survival rates = 67/32/21%
- Good = <3
- NPI = (0.2 x tumour size, cm) + tumour
grade (1-3) + lymph node stage (1-3)
- TNM staging
- Tumour
- T1 (<2cm); T2 (2-5cm); T3 (>5cm) and
T4 (locally advanced - skin/chest wall
involvement)
- T1 (<2cm); T2 (2-5cm); T3 (>5cm) and
T4 (locally advanced - skin/chest wall
involvement)
- Node
- N0 (no odes); N1 (mobile ipsilateral
nodes); N2 (fixed ipsilateral nodes)
and N3 (internal mammary nodes)
- N0 (no odes); N1 (mobile ipsilateral
nodes); N2 (fixed ipsilateral nodes)
and N3 (internal mammary nodes)
- Metastases
- M0 (no metastases) or
M1 (distant metastases)
- M0 (no metastases) or
M1 (distant metastases)
- Tumour
- Grade - based on
microscopic/clinical presentation
- Microscopy
- Analysis of the biopsies
- Clinical; history and examination
- Triple assessment
- Treatment
- Extent of disease
- Localised
- Operable?
- Breast conserving surgery + Usentinel lymph node
biopsy (SLNB) / axillary node clearance (ANC)
- Mastectomy + SLNB/ANC
- Offered with plastic surgery
- Offered with plastic surgery
- Typically in combination with adjuvant
therapy - eliminate micrometastases
- Adjuvant therapy
- Clinical trials reveal a combination of adjuvant
therapies to reduce risk of patient mortality by
50-65%
- However absolute patient benefit
depends on patient risk group
- However absolute patient benefit
depends on patient risk group
- Clinical trials reveal a combination of adjuvant
therapies to reduce risk of patient mortality by
50-65%
- Adjuvant therapy
- Breast conserving surgery + Usentinel lymph node
biopsy (SLNB) / axillary node clearance (ANC)
- Non-operable (too big/complicated?)
- Neoadjuvant/primary systemic treatment
- Attempt to shrink the tumour with
adjuvant therapy to allow surgery
- Attempt to shrink the tumour with
adjuvant therapy to allow surgery
- Neoadjuvant/primary systemic treatment
- Operable?
- Metastatic
- Palliative treatment
- Chemo - faster (10
months) and more
effective response,
more toxic
- Endocrine - slower
(2yrs) and less
effective response,
less toxic
- Chemo - faster (10
months) and more
effective response,
more toxic
- Median survival = 2.5yrs
- Common sites:
lungs, liver,
bone, brain,
lymph nodes
- Palliative treatment
- Endocrine resistance
- Develops over time by a mechanism not fully understood
- Not absolute (end of treatment options)
- response still possible with other drugs
- everolimus - mTOR inhibitor (inhibits ER phosphorylation)
- BOLERO 2 trial - combination of exemestane
(aromatase inhibitor) and everolimus increases
patient survival and progression-free survival (PFS)
- BOLERO 2 trial - combination of exemestane
(aromatase inhibitor) and everolimus increases
patient survival and progression-free survival (PFS)
- lapatinib (HER2/EGFR RTK inhibitor) -
in combination (e.g. with capecitabine)
- EGF100151 trial
- EGF100151 trial
- T-DM1 (antibody-drug
conjugation) - Trastuzumab
(herceptin0 is bound to DM1 (a
microtubule inhibitor/cytotoxin)
to deliver DM1 to HER2+ cells
- EMILIA study
- Revealed T-DM1
provides a PFS 3.2
month longer than
lapatinib+capecitabine
combination
- Revealed T-DM1
provides a PFS 3.2
month longer than
lapatinib+capecitabine
combination
- EMILIA study
- Pertuzumab (HER2
dimerisation inhibitor - MAb)
- CLEOPATRA trial
(pertuzumab +
trastuzumab + docetaxel)
- CLEOPATRA trial
(pertuzumab +
trastuzumab + docetaxel)
- Bevacizumab [avastin] (MAb to
VEGFR - anti-angiogenesis)
- E2100 trial (avastin+paclitaxel
(mitosis inhibitor))
- E2100 trial (avastin+paclitaxel
(mitosis inhibitor))
- everolimus - mTOR inhibitor (inhibits ER phosphorylation)
- Johnston, 2010
- Describes the cross talk between the
ERE and GF signalling pathways
- ER can still be activated by
phosphorylation through GF (e.g.
IGFR or HER2)- signalling pathways
- ER can still be activated by
phosphorylation through GF (e.g.
IGFR or HER2)- signalling pathways
- Describes the cross talk between the
ERE and GF signalling pathways
- Not absolute (end of treatment options)
- response still possible with other drugs
- Develops over time by a mechanism not fully understood
- Localised
- Adjuvant therapies
- Chemotherapy
- Reduced risk of death = 20-35%
- Numerous treatment regimens
- CMF (cyclophasphamide, methotrexate, 5-fluorouracil)
- Cyclophosphamide =
alkylating agent (DNA damage)
- Methotrexate = folate metabolism
inhibitor (reduced nucleotide synthesis)
- 5-FU = Thymidylate synthase inhibitor
(reduced nucleotide synthesis)
- Cyclophosphamide =
alkylating agent (DNA damage)
- Anthracycline-containing regimens
- FEC (5-FU, epirubicin, cyclophosphamide)
- Epirubicin = intercolates with DNA
- Epirubicin = intercolates with DNA
- E-CMF (Epirubicin with standard CMF)
- Normally used after surgery and radiotherapy
- FEC (5-FU, epirubicin, cyclophosphamide)
- Taxane-containing regimen
- FEC with docetaxel
- Docetaxel = anti-mitotic drug
- Docetaxel = anti-mitotic drug
- TAC (docetaxel [taxotere], doxyrubicin
[adriamycin], cyclophosphamide)
- Doxyrubicin = inhibits topoisomerase 2
(Inhibition of DNA replication and RNA synthesis)
- Doxyrubicin = inhibits topoisomerase 2
(Inhibition of DNA replication and RNA synthesis)
- FEC with docetaxel
- Other agents...
- Capecitabine = pro-drug of 5-FU
- Gemcitabine = nucleotide analogue
- Vinorelbine = mitosis inhibitor
- Carboplatin = cisplatin
analogue (DNA damage)
- Eribulin = mitosis inhibitor (used
after two previous chemo therapies)
- Capecitabine = pro-drug of 5-FU
- CMF (cyclophasphamide, methotrexate, 5-fluorouracil)
- Side
effects
- Acute
- Immunosupression, nausea,
diarrhoea, vomiting, hair loss,
peripheral neuropathy and
generally feeling shitty
- Immunosupression, nausea,
diarrhoea, vomiting, hair loss,
peripheral neuropathy and
generally feeling shitty
- Medium
- Fatigue, menopausal
symptoms and infertility
- Fatigue, menopausal
symptoms and infertility
- Late
- Leukaemia and heart failure
- Leukaemia and heart failure
- Acute
- Reduced risk of death = 20-35%
- Radiotherapy
- Following all breast-conserving surgery
- Maybe necessary after mastectomy
- Local control of tumour
- Reduces risk of
recurrance ( following
surgery alone)
- Reduces risk of
recurrance ( following
surgery alone)
- Following all breast-conserving surgery
- Endocrine therapy
- Only if ER and/or PR positive
- = 70% of all breast cancers
- Oestrogen signalling
pathway (top =
classical/genomic; mid =
non-genomic/non-ligand
dependant; bottom =
ligand-dependant)
- Ligand binds to cytosolic ER causing activation -> ER
dimerise and bind to DNA at the response elements
ERE's -> recruit Co-activators (CoA) and HATs
- Activated ER can also bind to AP-1 (c-fos:c-jun TF)
- Activated ER can also bind to AP-1 (c-fos:c-jun TF)
- GF signalling results in the phosphorylation of ER by Erk
(MAPK) and Akt -> formation of transcription complex
- Ligand binding can also recruit a cytosolic
protein complex (including PI3K and Src)
that activate Akt and cause transcription
- Ligand binds to cytosolic ER causing activation -> ER
dimerise and bind to DNA at the response elements
ERE's -> recruit Co-activators (CoA) and HATs
- = 70% of all breast cancers
- History of treatment:
1896 - oophorectomy
in breast cancer
patient improved the
outcome (patient
survived 4 years)
- Link between the
ovaries and breast cell
proliferation (hormones)
- Link between the
ovaries and breast cell
proliferation (hormones)
- Premenopausal
- Tamoxifen (for 5yrs)
- Oestrogen analogue that
inhibits ER dimer activation
- Originally designed as a contraceptive
- Classed as a selective
oestrogen receptor
modulator (SERM)
- Clinical trials revealed benefit in patient
survival from breast cancer (1980's)
- Except in bone - where it acts
as an agonist and promotes
bone synthesis (preventing
oesteoporosis - seen with
aromatase inhibitors)
- Also a partial-agonist in
endometrial tissue - risk
of endometrial cancer
- Also a partial-agonist in
endometrial tissue - risk
of endometrial cancer
- Originally designed as a contraceptive
- Oestrogen analogue that
inhibits ER dimer activation
- Ovarian ablation (surgical
removal [oophorectomy] or
hormonal therapy e.g.
zoladex [GnRH analogue])
- Anti-oestrogen (e.g. faslodex)
- Tamoxifen (for 5yrs)
- Postmenopausal
- Tamoxifen (low risk patients - for 5yrs)
- Aromatase inhibitors (steroidal
- exemestane; or non-steroidal
- arimidex) for 5yrs
- Inhibit oestrogen synthesis
- Cause
osteoporosis
- Cause
osteoporosis
- Inhibit oestrogen synthesis
- Anti-oestrogen (e.g. faslodex)
- Tamoxifen (low risk patients - for 5yrs)
- Two trials
- EBCTCG (Lancet, 2005)
- Tamoxifen alone reduces chance of
tumour recurrance by ~12% over 15yrs
- Tamoxifen alone increases
15yr survival rate by 9.2%
- Tamoxifen alone increases
15yr survival rate by 9.2%
- Tamoxifen alone reduces chance of
tumour recurrance by ~12% over 15yrs
- ATAC (arimidex, tamoxifen; alone or
combined) trial (Lancet oncology, 2008)
- Reduced tumour recurrence and increased time
until recurrence seen with arimidex over tamoxifen
- in postmenopausal women (drug of choice)
- Reduced tumour recurrence and increased time
until recurrence seen with arimidex over tamoxifen
- in postmenopausal women (drug of choice)
- EBCTCG (Lancet, 2005)
- Side
effects
- Tamoxifen
- May induce menopause (hot flushes etc.)
- Risk of venous thromboembolism (VTE)
- Risk of endometrial cancer
- May induce menopause (hot flushes etc.)
- Aromatase inhibitors
- May induce menopause
- Joint pains (~20% of cases)
- Osteoporosis
- May induce menopause
- Tamoxifen
- Only if ER and/or PR positive
- Biological
therapy
- HER2 blockade
- Amplified/overexpressed in
20-35% of breast cancers -
associated with poor prognosis
- No natural ligand and
forms heterodimer when
activated (e.g. with EGFR)
- Many downstream
substrates - including Ras
signalling / Akt activation
- Many downstream
substrates - including Ras
signalling / Akt activation
- No natural ligand and
forms heterodimer when
activated (e.g. with EGFR)
- Trastuzmab (Herceptin)
- MAb - binds to the receptor
and prevents dimerisation
- Inhibits HER2 signalling
- MAb signals for cell death by
immune effector cells (e.g. NK cells)
- MAb induces cell internalisation and degradation
- Inhibits HER2 signalling
- 4 trials (in >10,000 women)
- HERA, NSAPB-31, N9831 and BCIRG006
- BCIRG006 (NE J Med, 2011)
- Patient survival was increased to >80% in patients
recieving standard TAC regimen in combination
with herceptin; compared to TAC alone (=75%)
- Patient survival was increased to >80% in patients
recieving standard TAC regimen in combination
with herceptin; compared to TAC alone (=75%)
- Interim trials stopped early because of the
obvious benefits; decreased relapse risk
(-50%) and survival advantage of 2.5%
- BCIRG006 (NE J Med, 2011)
- HERA, NSAPB-31, N9831 and BCIRG006
- MAb - binds to the receptor
and prevents dimerisation
- Amplified/overexpressed in
20-35% of breast cancers -
associated with poor prognosis
- Anti-angiogenesis (clinical
trials only at this point)
- Avastin (bevcizumab)
- Avastin (bevcizumab)
- HER2 blockade
- Chemotherapy
- Future
- Mapping genes and
understanding the
genetic pathway of
breast cancer will allow
for a more tailored
treatment that is more
effective and less toxic
- Personalised treatment regimens
based on tumours genetic profile
- Only 10% of breast cancers linked with an
inherited mutation (e.g. BRCA1, BRCA2 - other
minor risk genes = CHEK2, BRIP, PALB2 and ATM)
- High risk families....
- 4 or more relatives with breast/ovary cancer
- 3 relatives <60yrs with breast/ovary cancer
- 2 relatives <40yrs with breast/ovary cancer
- 1 relative with both OR bilateral breast cancer
- 4 or more relatives with breast/ovary cancer
- High risk families....
- Only 10% of breast cancers linked with an
inherited mutation (e.g. BRCA1, BRCA2 - other
minor risk genes = CHEK2, BRIP, PALB2 and ATM)
- Personalised treatment regimens
based on tumours genetic profile
- Mapping genes and
understanding the
genetic pathway of
breast cancer will allow
for a more tailored
treatment that is more
effective and less toxic
- Extent of disease
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