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Adjuvant Therapy For Breast Cancer. 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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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

Breast Cancer | Worldwide Incidence

  • 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 | Who needs Adjuvant Therapy?

  • 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 | The patient in front of you

  • Patient Age
  • Performance Status

Breast Cancer | Staging: AJCC TNM Staging

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


Breast Cancer | Intrinsic Molecular Subtypes

  • Both prognostic and predicative information

Synder R. Update of breast cancer FRACP Pt1. (2013)


Breast Cancer | Gene Expression Signatures

  • 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)

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


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 ClinOncol. 1996; 14:3105-3111


Breast Cancer | Histology

  • Histological Classification
    • Ductal (75%)
    • Lobular (10%)
    • Tubular (1-4%)
    • Mucinous
    • Medullary
    • Papillary
    • Micropapillary

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

Breast Cancer | Therefore….

  • 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 | Historical Chemotherapy Timeline

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


Breast Cancer | Historical Chemotherapy Timeline

  • CMF (Cyclophosphamide, Methotrexate, 5-FU)
  • AC (Doxorubicin, Cyclophosphamide)
  • FEC (5-FU, Epirubicin, Cyclophosphamide)
  • AC-docetaxel, AC-paclitaxel
  • Dose Dense AC
  • FEC-T

Breast Cancer | What is Gold Standard?

Peto, R San Antonia Breast Cancer Symposium on behalf of the Early Breast Cancer Trialists’ Collaborative Group


Breast Cancer | Rationale for Adjuvant Therapy

  • 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 | 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

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

Breast Cancer | Oestrogen and Progesterone Receptors

  • Hormone Receptors
    • Oestrogen/ Progesterone
      • Regulate gene expression through interaction with hormone response elements.

Breast Cancer | Oestrogen and Progesterone Receptors

  • 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 | Hormone Receptor +ve disease

  • 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 | Endocrine Therapy: Pre-menopausal

  • 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 | Aromatase Inhibitors

  • Suppress plasma oestrogen levels by inhibiting or inactivating aromatase

Breast Cancer | Postmenopausal HR+ve

    • Anastrozole
    • Letrozole
    • Exemestane (steroidal inhibitor)
  • Comparable in efficacy
  • Similar SE profile
    • Arthralgias, myalgias, reduction in bone density

Breast Cancer | HER-2

  • Member of the epidermal growth factor receptor tyrosine kinase family
    • EGFR-1, HER2, HER3, HER4

Breast Cancer | HER2 Overamplification

  • 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 | Trastuzumab

  • 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 | New Therapies

  • 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 | Other HER2 receptor based therapy

  • 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 | Neo-Sphere trial

  • Improvement in pCR with use of dual HER2 blocking therapy and CTx
  • Increased efficacy in the patients with ER/PR –ve disease