Adjuvant Therapy For Breast Cancer. Breast Cancer | Epidemiology- Australia Australian Institute of...
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Adjuvant Therapy For Breast Cancer. Breast Cancer | Epidemiology- Australia Australian Institute of Health and Welfare 2014. ACIM (Australian Cancer Incidence
Breast Cancer | Epidemiology- Australia Australian Institute of
Health and Welfare 2014. ACIM (Australian Cancer Incidence and
Mortality) Books. Canberra. AIHW Overall is the third leading cause
of cancer Most common cause of cancer in women
Slide 3
Incidence rates higher in economically developed regions Inc.
Australia, Western Europe, Nth. America Increased Incidence in
1980-1990 increased screening Decline in incidence in since 2000
HRT related Worldwide increase in incidence Developing Countries
Breast Cancer | Worldwide Incidence
Slide 4
FactorRelative Risk Gender (female vs. male)100 Age ( 50)6.7
Endocrine Factors -Age of menarche (35) -Nulliparity -Age at
menopause (>55) 1.4-1.9 1.7 1.4 1.3 Benign Breast Disease - ADH,
LCIS4.0 -5.0 Family History -First degree relative -BRCA1/ BRCA2
mutation -P53 (Li- Fraumeni) -PTEN (Cowden Syndrome) 2.0 -7.0 10-30
1.5-6.0 2.0-4.0 Ethnicity (Ashkenazi Jewish)1.4 Therapeutic
radiation35 Breast Cancer | Established Risk Factors: FIXED
Slide 5
FactorRelative Risk Exogenous Hormones OCP Oestrogen
replacement (>10 years) Oestrogen and Progesterone 0.9-1.0 1.1
1.4-3.0 Obesity (>30)2.5 Exercise (>3 hours/ week)0.6 Alcohol
Use1.1-2.2 Diet1.0 Mammographic Density2.2-3.5 Breast Cancer |
Established Risk Factor: MODIFIABLE
Slide 6
All breast cancer patients need consideration of adjuvant
therapy There are multiple possible treatment options which can be
used individually or combined Includes not only chemotherapy but
endocrine and targeted therapy Who to treat with which agents.
Prognostic factors Predictive factors Breast Cancer | Who needs
Adjuvant Therapy?
Slide 7
Patient Age Performance Status Breast Cancer | The patient in
front of you GradeECOG Performance Status 0Fully active 1Restricted
in physically strenuous activity but ambulatory and able to carry
out work of light or sedentary nature 2Ambulatory and capable of
all self care. Up > 50% of waking hours 3Capable of only limited
self care, confined to bed or chair for > 50% of working hours
4Completely disabled. Cannot carry on any self care. Totally
confined to bed or chair
Slide 8
Breast Cancer | Staging: AJCC Tumour Staging
Slide 9
Breast Cancer | Staging: AJCC TNM Staging AJCC Cancer Staging
Manual, 7 th Edition (2010) Springer Science and Business Media
LLC
Slide 10
Both prognostic and predicative information Breast Cancer |
Intrinsic Molecular Subtypes Subtype Luminal AER/PR strongly +ve,
low proliferation Best overall prognosis Luminal BER/PR +ve, high
proliferation Basal LikeTriple negative (ER, PR, HER2 ve) More
common in BRCA-1 Worst prognosis HER2 richHER2+, ER/PR-ve Normal
Synder R. Update of breast cancer FRACP Pt1. (2013)
Slide 11
Gene expression profiling Assessment of the risk of both local
and systemic recurrence among breast cancers with a more FAVOURABLE
profile Those with low risk are unlikely to significantly benefit
from CTx Oncotype DX ( 21 genes) Breast Cancer | Gene Expression
Signatures Va de Vijver et al. Supervised risk predictor of breast
cancer based on intrinsic subtypes. NEJM. 2002: 347: 1999-2009 Paik
et al. A multigene assay to predict recurrence of
tamoxifen-treated, node-negative breast cancer. NEJM: 2004: 351:
2817-2826
Slide 12
Breast Cancer | Oncotype
Slide 13
Slide 14
Breast Cancer | TAILORx Trial Oncotype Dx recurrence score (RS)
Low risk ( 25) CTx +endocrine therapy
Slide 15
Breast Cancer | Anatomical LN Involvement Without Systemic
Treatment 1-3 LN: 25-35% recurrence rate 4-9 LN: 25-55% recurrence
rate >10 LN: >70% recurrence rate Quiet et al. Natural
History of node positive breast cancer: the curability of small
cancers with a limited number of positive nodes. J Clin Oncol.
1996; 14:3105-3111
Slide 16
Breast Cancer | Histology Histological Classification Ductal
(75%) Lobular (10%) Tubular (1-4%) Mucinous Medullary Papillary
Micropapillary
Slide 17
Breast Cancer | Stage I and II Local Disease Control Surgery
Breast Conservation Surgery Mastectomy With sentinel lymph node
biopsy in both Radiation Whole Breast Radiotherapy Applied to the
tumour bed, over a course of 5-6 week, or in older patients this
can be shortened to a 2-3 week period Majority of local tumour
recurrences occur at or around the tumour bed or localised lymph
nodes
Slide 18
Things taken into account when planning adjuvant therapy Age
ECOG Tumour size Tumour Histology Lymphatic Invasion Proliferative
Rate Hormone Receptor Status HER2 Status Intrinsic Molecular
Subtypes Gene Expression Signatures Patient Preference Breast
Cancer | Therefore.
Slide 19
Breast Cancer | Chemotherapy
Slide 20
Breast Cancer | Historical Chemotherapy Timeline Verrill M,
Chemotherapy for early-stage breast cancer: a brief history.
British Journal of Cancer (2009)
Slide 21
1.CMF (Cyclophosphamide, Methotrexate, 5- FU) 2.AC
(Doxorubicin, Cyclophosphamide) 3.FEC (5-FU, Epirubicin,
Cyclophosphamide) 4.AC-docetaxel, AC-paclitaxel 5.Dose Dense AC
6.FEC-T Breast Cancer | Historical Chemotherapy Timeline
Slide 22
NothingCMF regimen Anthracycline containing regimen
Anthracycline AND Taxane Containing regimen Breast Cancer | What is
Gold Standard? Peto, R San Antonia Breast Cancer Symposium on
behalf of the Early Breast Cancer Trialists Collaborative
Group
Slide 23
EBCTCG meta-analysis (2011) Anthracycline- containing regimens
Decreased risk of recurrence resulting in an absolute reduction of
8% Reduction of BC mortality to an absolute decreased of 6.5%
Reduction in overall mortality to an absolute of 5.0% CMF Decrease
in the risk of recurrence in an absolute reduction of 10.2%
Reduction in BC mortality to an absolute decreased of 6.2%
Reduction in overall mortality to absolute decrease of 4.7% Breast
Cancer | Rationale for Adjuvant Therapy
Slide 24
Breast Cancer | Adjuvant CTx: General Principles Maintain full
dose density Women > 70 need more individualised decisions There
is no added benefit to dose escalation in adjuvant treatment
Poly-chemotherapy is preferred
Slide 25
Breast Cancer | High Grade Basal Disease Accounts for 10-15% of
all breast cancer More common in young and/or black patients
Commonly presents as higher grade Prognosis is more difficult Does
not correlate as closely with tumour size or nodal involvement
Requires treatment with adjuvant CTx at a smaller tumour size
Slide 26
Hormone Receptors Oestrogen/ Progesterone Regulate gene
expression through interaction with hormone response elements.
Breast Cancer | Oestrogen and Progesterone Receptors
Slide 27
Positive prognostic indicator Late disease recurrence ER/PR ve:
greatest risk < 5 years, then dramatic decline ER/PR +ve: Slower
rise in recurrence and more gradual decline Predictive indicator Of
response to endocrine therapy Higher degrees of positivity indicate
increased response Breast Cancer | Oestrogen and Progesterone
Receptors
Slide 28
Endocrine Therapy Reduces the risk of systemic recurrence
Increased overall survival All women regardless of age, menopausal
status, nodal involvement, tumour size, HER2 status or use of
chemotherapy Therefore almost universal use across the population
of HR +ve patients Breast Cancer | Hormone Receptor +ve
disease
Slide 29
The diagnosis of menopause is made at the time of diagnosis
Tamoxifen for 5 years is the current standard therapy Aromatase
Inhibitors are not active for women with intact ovarian function
Including amenorrhic women secondary to chemotherapy Ovarian
Suppression Ovarian ablation/ Oophorectomy LHRH agonist Breast
Cancer | Endocrine Therapy: Pre-menopausal
Slide 30
Breast Cancer | Endocrine Therapy: Tamoxifen
Slide 31
Breast Cancer | Aromatase Inhibitors Suppress plasma oestrogen
levels by inhibiting or inactivating aromatase
Slide 32
Anastrozole Letrozole Exemestane (steroidal inhibitor)
Comparable in efficacy Similar SE profile Arthralgias, myalgias,
reduction in bone density Breast Cancer | Postmenopausal HR+ve
Slide 33
Breast Cancer | Tamoxifen or AI
Slide 34
Breast Cancer | Tamoxifen then AI
Slide 35
Breast Cancer | Big 1-98 trial DFSOS Letrozole alone78.6%87.5%
Letrozole2/ Tamoxifen 377.8%87.7% Tamoxifen2 / Letrozole
377.3%85.9%
Slide 36
Breast Cancer | Adjuvant Endocrine Therapy
Slide 37
Member of the epidermal growth factor receptor tyrosine kinase
family EGFR-1, HER2, HER3, HER4 Breast Cancer | HER-2
Slide 38
Breast Cancer | HER2 Overamplification
Slide 39
Overexpression of the HER2 protein is a consequence of gene
amplification Occurs in 20% of BC Strong predictive indicator
Increased efficacy of certain CTx agents Increased resistance to
endocrine therapy Modest prognostic indicator Independent of other
prognostic indicators Breast Cancer | HER2 Overamplification
Slide 40
Trastuzumab (Herceptin) Adjuvant: survival advantage IV
delivery ? Role for s/c in future Side effect profile Modify
cardiac muscles response to stress 5% of patients experience
asymptomatic decrease in EF Increased risk with advanced age, HTN,
poor initial EF Breast Cancer | Trastuzumab
Slide 41
TrialEligibility Requirements TreatmentHR for Disease Free
Survival NSABP B-31Node +ve diseaseAC-T vs AC-TH0.48 NCCTG
N9831Node +ve or high risk node ve AC-T vs. AC-TH (concurrent) 0.48
AC-T vs. AC-T-H0.86 BCIRG 006Node +ve or high risk node ve AC-D vs.
AC-DH0.61 FinHERNode +ve or high risk node ve D or V +FEC vs. D or
V+ FEC + H FNCLCC-PACS 04Node +veFEC or ED vs. FEC of ED + H 0.86
Breast Cancer | Seminal Adjuvant Trastuzumab Trials
Slide 42
HER2 is a tyrosine kinase receptor that activates downstream
oncogenic signaling pathways HER2/HER3 Dimers may provide an escape
mechanism for trastuzumab Therefore it has been postulated that a
combination of HER2 receptor targets may have synergistic effects
Breast Cancer | New Therapies
Slide 43
Pertuzumab Shows survival benefit in neo-adjuvant and
metastatic setting NCCN guidelines 2014 indicate that it can be
incorporated into adjuvant treatment alongside CTx and trastuzumab
Adjuvant trials ongoing Breast Cancer | Other HER2 receptor based
therapy
Slide 44
TRASTUZUMABPERTUZUMAB Trastuzumab continually suppresses HER2
activity Inhibits HER formation of dimer pairs Flags cells for
destruction by the immune system Suppresses multiple HER signalling
pathways Does not inhibit HER2 dimerizationFlags cell for
destruction by immune system Breast Cancer | Other HER2 receptor
based therapy
Slide 45
Trial ArmComplete Pathological ResponseER/PR-ve A (107)29.0%
(31 0f 107)36.8% B (107)45.8% (49 of 107)63.2% C (107)16.8% (18 of
107)29.1% D (96)24.0% (24 of 96)30.0% Improvement in pCR with use
of dual HER2 blocking therapy and CTx Increased efficacy in the
patients with ER/PR ve disease Breast Cancer | Neo-Sphere
trial