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Adjuvant Therapy for breast cancer

Tailored to each individual patient

  • Tumour features / receptor status
  • What surgery they have had
  • Co-morbidities / age / Pt Preferences
  • Nodal metastases is usually an indication for systemic therapy
  • Different methods of sequencing chemo and radiotherapy do not appear to have major effect on survival/recurrence as long as both are commenced within 7mths (Cochrane 2006)
  • Some data suggest that RT should be given after chemo

Radiotherapy

  • Causes DNA damage which is repaired more slowly in tumour cells and therefore accumulates to cause cell death

Contraindications

  • Previous radiotherapy
  • Pregnancy
  • Severe heart or lung disease
  • Non-compliant patient
  • Needs to be able to lie flat – dementia, orthopnoea etc.
  • Active / Steroid-dependant connective tissue / collagen vascular disease
    • e.g. Scleroderma, SLE

Side Effects

  • Early
    • Erythema/sunburn
    • Oedema (local or arm oedema)
    • Soft tissue necrosis
    • Decreased arm mobility
  • Late
    • Skin – telangiectasia, pigmentation, fibrosis
    • Shoulder stiffness
    • Arm oedema
    • Organs in close proximity
    • Pneumonitis, oesophagitis, radionecrosis of ribs/bones, brachial plexopathy, radiation related heart disease, vasculitis, induced cancers
  • Systemic
    • Fatigue

Adjuvant After BCS

  • Whole breast Radiotherapy
    • Given to all patients after BCS
    • Even if cPR after neoadjuvent therapy
  • Regional nodal radiotherapy
    • Can be consider in N2+ or high risk N1
    • Includes treatment to supraclavicular, infraclavicular and internal mammary nodes
  • Goal:
    • To eradicate residual microscopic disease at site of primary tumour
    • Treat other foci of invasive or in-situ Ca elsewhere in the residual breast tissue
  • Confers survival & recurrence equivalent to Mastectomy
    • Decreases local recurrence from 30% → 5% at 5yrs
    • 35% to 8% for Locally Advanced Breast Ca
    • Increases survival by 5% at 15yrs

Adjuvant After Mastectomy

  • Post mastectomy radiotherapy (PMRT)
    • Given if high chance of local recurrence
      • After neoadjuvent therapy in:
        • Stage III on presentation
        • Incomplete pathological response
    • RT given to chest wall and to regional nodes
  • Regional nodal radiotherapy
    • After ALND
      • Indicated in patients with positive LN N1+
    • After SLNB
      • To avoid ALND in patients with 1-2 positive LN (AMAROS trial)

Method:

  • 3 field technique, minimized complications (affects skin, muscle, ribs, lung)
  • Conventional versus hypofractionated schedules
    • Conventional
      • 50Gy = 5 x 2Gy (20mins) daily sessions for ≈ 5/52 = Standard Rx
    • Hypofractionated schedules
      • Equivalent tumor control and fewer toxicities, and is now preferred for many patients.
      • 40Gy in 15 fractions - 3weeks
  • Can include boost to chest wall if high risk

Other uses

  • Axillary Irradiation
    • Indications
      • Surgical / pathological evidence of residual disease post-ALND
    • Has not had axillary dissection (e.g. in elderly / if refused / after sampling) & LN Mets present
    • ≥ 4 LN mets (extracapsular spread in itself NOT an indication)
    • ? also survival benefit for T3/T4 tumours with +ve LN
  • Decreases local recurrence from 18 → 3%
  • Complications:
    • Increases arm swelling
      • 20-40% surgery + RT
      • 5-15% surgery alone

Radiation to Other Nodes

  • Supraclavicular Nodes
    • Indications:
      • Apical LN +ve
      • ≥ 4 +ve LN
      • ± Breast Ca located in upper part of breast
      • ? May be considered if 1-3LN +ve
  • Internal Mammary Nodes
    • Controversial because isolated internal mammary recurrence is rare; No RCTs
    • ? may have a role in medial tumours with +ve axilla

Palliative Radiation Therapy

  • Chest wall or axilla for local control
    • If surgery not feasible
  • Any site for local control if non-operative candidate
    • Bony mets
      • Short course 8 Gy in 1 fraction
        • 70% chance of improved symptoms (i.e. decreased pain)
    • Isolated metastases

Adjuvant Chemotherapy

NPI and Tumours that will respond

  • Nottingham Prognostic Index (NPI) helps decide

  • Three elements make up final score (1+2+(0.2x3))

    • Tumour size, lymph nodes stage, histological grade

  • Small, poorly differentiated, triple negative tumours most likely to respond to chemo

  • Node +ve disease gets highest benefit

  • If pt ER +ve then less benefit from chemo (esp. older pts)

  • ER -ve pts tumours tend to be more chemo sensitive, even in elderly pts

Indications for Adjuvant Chemotherapy

  • NCCN 2024 guidlines summary
    • Hormone receptor positive
      • T1-T3, N0-N1
        • Suggest Oncotype DX
        • Low risk - endocrine therapy alone
        • High risk - Chemotherapy + endocrine therapy
      • N2-N3
        • Endocrine therapy + chemotherapy
      • In premenopausal women consider ovarian suppression
    • HER2 positive
      • Adjuvant chemotherapy + Trastuzumab + endocrine therapy
    • Triple negative
      • Chemotherapy

NCCN 2024 guidlines

  • Hormone receptor positive
    • HER2 negative (luminal A/B)
      • Premenopausal T1-T3
        • N0-N1
          • Suggest Oncotype DX
            • Low risk - endocrine therapy only
            • High risk - Chemotherapy + endocrine therapy +/- ovarian suppression
        • N2/3 - Chemotherapy + endocrine therapy +/- ovarian suppression
      • Postmenopausal
        • <0.5cm, N0 - endocrine therapy only

        • 0.5cm or N1 - Oncotype DX

          • Low risk - endocrine therapy only
          • High risk - endocrine therapy + chemotherapy
        • N2/N3 - endocrine therapy + chemotherapy
  • HER2 positive
    • HER2 positive, hormone receptor positive
      • Node positive
        • Adjuvant chemotherapy + Trastuzumab + endocrine therapy
      • Node negative
        • <1cm - endocrine therapy alone vs all three

        • 1cm - All three

    • HER2 positive, hormone receptor negative
  • Triple negative
    • Chemotherapy (unless <0.5cm)

Chemotherapy Regime

  • AC
  • Addition of Taxane (Paclitaxel- weekly)
    • NZGG suggests considering in all that you would give chemotherapy
      • NB: Increased rate of febrile neutropenia
  • Highest benefit in
    • Node +ve, ER-ve, HER2 +ve patients
    • AC for 12 weeks then paclitaxel for 12 weeks (6/12 total)

Side Effects

  • Anthracycline
    • Myocardial damage and CHF
    • Higher doses can cause Acute Myeloid Leukaemia/Myelodysplasia
  • Taxane (Paclitaxel)
    • Neuropathy
  • Alkylating agents (Cyclophosphamide, Methotrexate, Cisplatin)
    • Nausea & vomiting
    • Alopecia
    • Myelosuppression
  • Anti-metabolites (5-FU)
    • Hand-foot syndrome
  • Chemo → only 50% menstruating at the end of Rx
    • Only ≈ 20% maintain fertility

Endocrine Therapy

Indication

  • Offered to all patients with ER/PR positive tumours >0.5mm in size

Treatment choice

  • Pre-menopausal
    • Tamoxifen
    • Aromatase inhibitors contraindicated
    • If giving ovarian suppression therapy (typically offered in high risk patients receiving chemotherapy) then an AIs is a better option
  • Post-menopausal

Receptors

  • Oestrogen receptor activation leads to induction of numerous genes – incl. Progesterone receptor
    • Therefore PR positivity = Indicator of presence of functional ER
    • Hence ER –ve but PR +ve display intermediate responsiveness to hormonal Rx
  • Receptor measures done with IHC

    • 10% stain = positive

    • 60% ER or PR +ve
    • Older more likely to be +ve
    • Male almost always +ve

Tamoxifen

  • Method of action ⇒ Selective Oestrogen Receptor Modulator (SERM)
    • Competitive antagonist of ER receptor in breast
    • Agonist on Endometrium, Bone and Lipids

Indications:

  • Mainly used in pre-menopausal women
  • ER/PR +ve pts (± may benefit pts of unknown ER status) if Ca > 1cm
  • OR > 0.5cm with unfavourable features – e.g. Poorly diff, LVI, Grade 3)
    • NB: If pt is HER2 +ve & ER +ve → Tamoxifen may be ineffective, Aromatase inhibitor probably better

Dose

  • 20mg Daily for 5-10 years

Duration

  • Minimum of 5 years
  • Can be extended to 10 years - balance of risk of recurrence and side effects

Timing

  • Start after chemo/radiotherapy
  • Anti-proliferative effects of Tamoxifen seem to make chemo slightly less effective
  • No data re: radiotherapy sequencing

Efficacy

  • EBCTG 1998 – Treatment 5 years
    • Decrease risk of contralateral breast cancer by 40-50%
  • EBCTG 2000 / Cochrane 2001:
    • Decreased likelihood of recurrence by 15% (45 → 33%) at 15yrs (i.e. 41% RR↓)
      • ↓ RR risk of mets by 15% in ER/PR +ve patients
    • Absolute mortality reduction = 10% (<35yrs→26%) @ 15yrs (i.e. 34% RR↓), irrespective of age, menopausal status or chemotherapy
    • In addition to chemo RR of recurrence = 10%
      • N+ 11% absolute decreased mortality, N -ve 5% absolute decreased mortality
  • Adding chemo to Tamoxifen is esp. beneficial in younger women

Other Benefits

  • Prevents bone demineralization
  • Beneficial effect on cardiovascular morbidity (lowers cholesterol)

Tamoxifen Side Effects

  • Common: Hot flushes, irregular periods, vaginal dryness, fluid retention, weight gain
  • Rare: Headache, dizziness, fatigue, nausea, rash, depression
  • Other: Interacts with warfarin (enhances warfarin); hypercalcemia

Risks:

  • Due to its partial oestrogenic effect
    • DVT (same as COC or HRT: 1→2:1000; RR 3)
    • Endometrial Ca (<1/100 over ten years): RR 2.5; usually stage 1, good prognosis
      • Combined these two risks have a 10 yr mortality risk of 0.2%
      • CF 30% reduction in breast cancer mortality
  • Contraindicated if pregnant or breast feeding (or for 2 months after stopping Tamoxifen)
  • Interacts with SSRIs (Paroxetine)

Aromatase inhibitors

  • Non-steroidal - Arimidex (Anastrozole) 1mg Daily
  • Non-steroidal - Femara (Letrozole) 2.5mg Daily - stronger than Anastrozole
  • Steroidal - Exemestane (Vorozole)

Action

  • Inactivate Aromatase enzyme
    • Aromatase converts adrenal steroids (Androstenedione) to Oestrogens (Estrone) in Fat cells
    • Net effect of AI’s is to suppress extra-gonadal production of oestrogen (in fat, liver, muscle)
  • Contraindicated in pre-menopausal women

Unclear length of optimal therapy; currently up to 5yrs

  • MA17 trial, ABCSG-6a and NSABP-B33 have all shown reduction in recurrence and prolonged survival benefit with 5 years of aromatase inhibitors following 5 yrs tamoxifen (total 10yrs endocrine treatment)
  • Probably on-going benefit for up to 10 years and maybe even longer

Especially good if:

  • ER +ve & PR -ve → Risk of a 2nd Breast Ca decreases by 40%
  • Better than Tamoxifen, therefore, can be started instead of Tamoxifen in this group
  • AIs show a survival benefit over other endocrine therapy in treatment of Advanced (metastatic) Breast Ca
  • AIs + Herceptin in women with HER-2 +ve Advanced Breast CA → improved DFS, cf AIs alone (Austr Nat Br CA Guidelines 2008)

Aromatase Inhibitor Side Effects

  • Reduces bone density (DEXA bone density at baseline)
    • T score ≤ -2.5 → Start exercise & Bisphosphonate
      • Ensure adequate levels of calcium and vit D
  • Arthralgia / progression of underlying arthritis (irreversible)
  • Cardiac events and hypercholesterolemia
  • ? Deranged LFTs

Advantages over Tamoxifen:

  • Less DVT risk
  • Less hot flushes / vaginal sx (but more sexual dysfunction)
  • Vaginal dryness should not be treated with oestrogen creams
    • Can cause significant increases in systemic oestradiol

Ovarian suppression

  • Only need to consider in pre-menopausal women
  • Consider if High risk with ER/PR +ve tumours
    • Definition of high risk usually if would get chemo
      • – E.g. node positive, large size, high risk genomic analysis, < 35 etc
      • < 50yrs: ↓s annual risk of death by 24% (EBCTG 1996)

Two options

  • Functional
  • Ovarian Ablation (Bilateral Oophorectomy)
    • Risks: cardiovascular morbidity and osteoporosis
    • Methods: Surgical (lap or open)

Ovarian Function Suppression

  • GnRH Analogues (LHRH Agonists)
    • Suppress the production of oestrogen (chemical ovarian ablation)
    • Stimulates production of oestrogen/testosterone in a non-pulsatile manner
      • Disruption of feedback system resulting in overall down regulation of testosterone and oestrogen
      • NB: Initial increase in production but after ~ 14-21 days there is a significant reduction in LH release
  • Sex hormones are reduced to castrate levels
  • Options
    • Goserelin (Brand name - Zoladex)
    • Leuprolide or Leuprorelin (Brand name - Prostop, Lutate)
    • Triptorelin
Zoladex (Goserelin)
  • Dose: 3.6mg S/C Monthly

Side Effects

  • Amenorrhoea, nausea, headache
  • Fully reversible
  • Trials

Trastuzumab

  • Recombinant humanised monoclonal antibody specific to the human HER2 receptor
  • Significant improved survival benefit in Metastatic Breast Ca

Mechanism:

  • HER-2 growth factor receptor = Glycoprotein – plays critical role in tumour development
  • Overexpressed in 15-20% of Breast Ca
  • Independent marker of poor survival
    • Tend to be high grade, high rate of nodal metastases, resistant to chemo & endocrine therapy
  • Resulting in ↓ cell proliferation & formation of angiogenesis factors
  • ↑s immune system recognition of the Ca cells → ↑ destruction of tumour cells via Ab-dependant cellular cytotoxicity
  • Prevents formation of ‘p95’ (a cleaved form of HER-2 that ↑s cell signalling)
  • Amplification measured by immunohistochemistry – score 1-3.
    • If HER 2 score = 1 – negative – no Herceptin
    • If HER 2 score = 2 – equivocal – do FISH to directly detect quantity of HER-2 gene copies on chromosome 17 (2 = normal)
      • If +ve on FISH – Herceptin
    • If HER 2 score = 3 – positive – Herceptin
  • In NZ funded for 12-month course for Early and Advanced (Metastatic); must be 3+
    • Give concurrently with chemotherapy

Adverse Effects

  • Cardiomyopathy 1% with Herceptin alone, 2-3% when combined with anthracycline based chemo
  • Do 3 monthly echocardiogram; consider stopping if LVEF ↓s by 10-15%
  • Avoid combo with AC chemo if any pre-existing cardiac dysfunction (use Taxane instead)

Herceptin Indications

  • Neoadjuvant
    • Rx for HER-2 +ve T2+ or N1+
    • Offered with pre-op chemo Adjuvant
  • Rx for HER-2 +ve early breast

    • 1cm +/- LN +ve

    • No trials in node negative Ca < 1cm
  • Considered in 0.6-1.0cm tumours which are poorly differentiated or unfavourable - e.g. LVI, Grade III
  • Role as single agent (cf with chemo) not yet evaluated in RCTs
  • Optimal duration uncertain – currently given for 12/12
    • HERA study, NCCTG N9831& NSABP-B31 Trials:
      • ↓LR / ↑DFS: after 12/12 (to 3yrs): 9-12% difference (86 vs. 77%)
      • ↑OS at 2-4yrs: ≈ 4% difference (33% RR) (91 vs. 87%)
    • 9 weeks
    • FINHer Trial: v small numbers
      • ↑DFS @ 3yrs by 11% (89 vs. 78%)

Palliative

  • Rx – for HER-2 +ve mets
  • Herceptin + Paclitaxel – first line
  • Can be used as single agent Rx if other systemic therapy is inappropriate
  • Continue until evidence of disease progression, in the absence of unacceptable toxicity

Bisphosphonates

  • Zoledronic acid 4mg IV 6 monthly for 3-5 years
  • Or oral clodronate 1600mg daily for 2-3 years

Mechanism of action

  • Inhibits Osteoclastic Bone Resorption
  • Prevent treatment induced osteoporosis, helps with bony pain
  • Inhibits development of bony metastases

Adjuvant Effect (Anti-cancer benefits are small)

  • May directly affect tumour cells via apoptosis and inhibiting tumour cell growth
  • Small disease-free survival advantages seen in post-menopausal women

Indications:

  • Osteoporosis (T-score ≤ -2.5) or history of fragility fracture
  • Post-Menopausal women receiving adjuvant systemic therapy (with mod-to-high risk distant recurrence), regardless of bone-density, to reduce risk of recurrence

Side Effects

  • Hypocalcaemia, renal toxicity, GI upset
  • Rarely: Osteonecrosis of the Jaw (0.7%)

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