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Adjuvant Therapy For Breast Cancer

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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

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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

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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

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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

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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?

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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

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Breast Cancer | Staging: AJCC Tumour Staging

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Breast Cancer | Staging: AJCC TNM Staging AJCC Cancer Staging Manual, 7 th Edition (2010) Springer Science and Business Media LLC

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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)

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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

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Breast Cancer | Oncotype

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Breast Cancer | TAILORx Trial Oncotype Dx recurrence score (RS) Low risk ( 25) CTx +endocrine therapy

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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

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Breast Cancer | Histology Histological Classification Ductal (75%) Lobular (10%) Tubular (1-4%) Mucinous Medullary Papillary Micropapillary

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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

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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.

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Breast Cancer | Chemotherapy

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Breast Cancer | Historical Chemotherapy Timeline Verrill M, Chemotherapy for early-stage breast cancer: a brief history. British Journal of Cancer (2009)

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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

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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

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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

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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

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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

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Hormone Receptors Oestrogen/ Progesterone Regulate gene expression through interaction with hormone response elements. Breast Cancer | Oestrogen and Progesterone Receptors

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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

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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

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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

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Breast Cancer | Endocrine Therapy: Tamoxifen

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Breast Cancer | Aromatase Inhibitors Suppress plasma oestrogen levels by inhibiting or inactivating aromatase

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Anastrozole Letrozole Exemestane (steroidal inhibitor) Comparable in efficacy Similar SE profile Arthralgias, myalgias, reduction in bone density Breast Cancer | Postmenopausal HR+ve

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Breast Cancer | Tamoxifen or AI

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Breast Cancer | Tamoxifen then AI

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Breast Cancer | Big 1-98 trial DFSOS Letrozole alone78.6%87.5% Letrozole2/ Tamoxifen 377.8%87.7% Tamoxifen2 / Letrozole 377.3%85.9%

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Breast Cancer | Adjuvant Endocrine Therapy

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Member of the epidermal growth factor receptor tyrosine kinase family EGFR-1, HER2, HER3, HER4 Breast Cancer | HER-2

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Breast Cancer | HER2 Overamplification

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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

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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

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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

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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

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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

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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

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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

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