GenSurg.nz

Early-stage breast cancer

Section: Breast Curriculum: Curriculum, page 13

Definition

  • Early stage breast cancer is operable breast cancer which typically initially undergoes upfront definitive surgery
    • Typically T-T2 and N0-N1
    • The NCCN 2024 guidelines include T3 in this group

Surgery - breast cancer

General Points

  • Prophylactic Abx at induction
  • DVT prophylaxis
  • Mastectomy versus BCS + RT
    • Overall survival and disease specific survival is equivalent
    • Local recurrence rate equivalent

Breast Conserving Surgery (WLE + Radiotx)

Indications

  • Indicated in a patient with resectable breast cancer and who will achieve good cosmetic outcome

Contraindications

  • Oncolgical contraindications
    • No appropriate reconstructive option
    • Inflammatory Breast cancer
    • Diffuse malignant microcalcifications on mammography
  • Radiotherapy contraindications
    • Pregnancy
    • Prev Radiotherapy
    • Connective tissue disorder
  • Patient preference for mastectomy
  • Carful consideration in patients with strong family of breast Ca / BRCA 1 or BRCA 2 carriers

Technique

  • Margin
    • Invasive - “No ink on tumour”
    • DCIS - 2mm
  • Orientate specimen ± X-ray

Mastectomy

Indications

  • See Contraindications to WLE + Radiotx

+/- Reconstruction

  • Delayed reconstruction if poor prognosis / high risk of radiotherapy
  • Don’t delay adjuvant therapy by ↑ risk of wound complications
  • Risk factors for recurrence: Axillary involvement, LVI, Grade 3, > 4cm

Neoadjuvant Therapy in Breast Cancer

Indications

As per the 2024 NCCN guidlines

  • Early breast cancer
    • T2+ or N1+ and HER2+/Triple negative
    • Large primary tumor relative to breast size in a patient who desires breast conservation
    • cN+ disease likely to become cN0 with preoperative systemic therapy
      • Avoid ALND if SNB clear
  • Locally Advanced breast cancer
    • Patients with inoperable breast cancer
      • Bulky or matted cN2 axillary nodes
      • cN3 nodes
      • cT4 tumors (note T3 included in early)
      • Inflammatory breast cancer
  • Temporary Contraindications to Surgery
    • Breast cancer during pregnancy
    • In patients that surgery needs to be delayed

Neoadjuvant Chemotherapy

Benefits

  • Downstage
    • Facilitates breast conservation
    • Can render inoperable tumors operable
  • Prognostic information
    • Allows for complete pathological response
    • In patients with residual disease second line chemotherapy can be used
  • Time
    • Allows time for genetic testing
    • Allows time to plan breast reconstruction in patients electing mastectomy
    • Allows time for delayed decision-making for definitive surgery

Pre-treatment evaluation

  • Tumor
    • Clip
  • Axilla
    • Clip positive node

Post-treatment evaluation

  • Re-examine
  • Re-stage
  • Surgery + SLNB vs TAD vs ALND - see management of axilla

Neoadjuvant Options

Hormone recetor postive, HER2 negative

  • Less likely to respond to chemotherapy
    • Can shrink cancers but less likely to have cPR especially in luminal A
  • Chemotherapy vs endocrine therapy
    • Less side effects in endocrine therapy
    • Time to response slower in endocrine therapy
    • Complete pathological response less likely with endocrine therapy
  • Regime selection
    • Pre menopausal → Chemotherapy
    • Post menopausal
      • Chemotherapy indicated in medically fit patients
      • In patients who are medically unfit for chemotherapy then endocrine therapy is an option
  • Chemotherapy
  • Endocrine therapy

HER2 Positive

Triple negative

Management of the Axilla

Axilla – General Points

  • 95% of breast lymph drained by axilla
  • 50% symptomatic patients and 10-20% screened cancers are node positive
  • Axillary LN status one of the most important prognostic actors in Breast Ca
  • Average of 20 nodes

Axilla – Pre-op Evaluation

  • Palpable node
    • Proceed to USS guided FNA, then core biopsy if negative
    • If decline biopsy → ALND
  • Abnormal node on imaging
    • Pre-op USS is effective way to screen axillary LNs
      • Sensitivity 50%
    • If NAD → SLNB
    • If Abnormal node → FNA/Core →
      • If +ve FNA →
        • Either
          • Neoadjuvent treatment
          • ALND if undergoing primary surgery
            • if luminal A/B → ?overtreatment, role of neoadjv?
      • If -ve FNA → SNB

Sentinel Lymph Node Biopsy

Indications

  • All patients with clinically negative nodes
  • DCIS if mastectomy performed
    • Or consider if suspicious features

Advantages

  • Axillary dissection does not improve survival but provides local control and staging
    • Adequate staging can be gained with SLNB
    • Adequate local control can often be gained avoiding ALND with radiotherapy
  • Decreased lymphoedema, pain, numbness, movement restriction
  • Intra-op assessment can be done by frozen section → False negative rate of up to 20%!
    • Touch prep cytology has sens of 90%
  • Equivalent staging to level II clearance, with less morbidity
    • Predicts status of remaining axillary LNs in > 95% of pts
    • False negative rate 5-10 %

Five randomized clinical trials have been performed to evaluate the efficacy and safety of SLNB in early breast cancer patients

  • The NSABP B32 trial (Krag et al., 2007)
    • Compared ALND with SLND and only continue to ALND if positive node
    • Showed that if a negative node you dont need a ALND
  • Milan trial (Veronesi et al., 2006b)
  • SNAC trial - Sentinel Node Biopsy versus Axillary Clearance (Gill, 2009)
  • GIVOM trial (Zavagno et al., 2008)
  • ALMANAC Trial - Axillary Lymphatic Mapping Against Nodal Axillary Clearance trial (Goyal et al., 2006)

SNB Technique

  • Technetium99 colloid

    • t1/2 6hrs; injected on am of surgery, or on pm prior to am list
    • SLN by radioisotope defined as containing ≥ 10 x background count

  • ± 2-4 mL Patent Blue V dye after induction

    • cf Methylene blue: faster & can lead to breast tissue necrosis
    • Anaphylaxis 1:2000
    • Intradermal / subareolar injections → Track to axilla in 15mins
    • Peritumoral injection → Track to axilla ± internal mammary nodes

  • Combination of patent blue and radioactive colloid results in significantly higher success rates and lower false negative rates

    • Compared to patent blue alone

  • Ideally get 1-3 LNs

    • 1 x LN → Sensitivity 87%,
    • 2 x LN → Sensitivity 97% (Sens 91% and False negative 4-10%)
    • No advantage if > 3 LNs

  • In 4% (in SNAC trial) SLN not found → Axillary dissection required

  • False -ve ≈ 5%

    • 8% in SNAC trial up to May 05
      • ≈ 13% for tumours >3cm
    • Axillary recurrence rate in SNB –ve 2.7%

  • 50% with +ve SNB have no other +ve nodes

Pathologic Analysis of Nodal Mets

  • Subgroup based on size of largest contiguous tumour deposit in sentinel node (on H&E)
    • Isolated Tumour Cells
      • < 0.2mm tumour deposit in SLN
      • pN0(i+)
      • Prognostically = LN -ve pts
      • Isolated Tumour cells give 5% risk of another node being +ve
    • Micrometastases
      • 0.2-2mm tumour deposit in SLN
      • pN1mi
      • Slightly worse prognosis vs. LN -ve pts
      • Do not predict recurrence
      • ACOSOG-20010 & European IBCSG 23-01 trials
        • No survival benefit or recurrence benefit if axillary dissection done for Micrometastasis
        • Micromets unlikely to have additional nodes involved
        • 97.3% 5y survival and only 1.5% local recurrence
    • Macrometastases

      • 2mm tumour deposit in SLN

      • Worse prognosis the greater the nodal involvement
    • Extranodal Extension
      • Invasive tumour cells or clusters outside of LN capsule
      • Generally tumour present both subcapsular and adjacent extranodal fat
      • More significant if extensive
      • NB: ITCs in perinodal axillary channels are not classified as extranodal extension
    • Occult Metastatic Disease
      • Nodal disease not seen on H&E stain but picked up if doing IHC
      • No significance in terms of surgical management and patient outcomes, still classed as pN0
      • IHC not routinely performed
    • Missed node
      • Risk of a +ve (non-sentinel) node being missed is dependent on
        • Size of micrometastases
        • Extra-capsular spread
        • ≈ 8-20% overall

SNB after Neoadjuvant Therapy

  • Clinically node negative
    • Negative - no further treatment
    • Shows evidence of cPR - radiotherapy
    • Postive - ALND
  • Clinically node positive prior
    • If remains positive
      • ALND
    • If clinically negative post treatment
      • Target axillary dissection (TAD)
        • ACOSOG Z1071
          • Aim: to determine the false negative rate in SLN after neoadjuvent chemotherapy in patients with node positive disease
          • Inclusion: T1-4, N1-2, M0
          • SLNB alone
            • False negative rate 12.6% (39 patients who had an ALND after negative SLNB)
          • SLNB + clip removed in specimen
            • False negative 6.8%
        • Improved Axillary Evaluation Following Neoadjuvant Therapy for Patients With Node-Positive Breast Cancer Using Selective Evaluation of Clipped Nodes: Implementation of Targeted Axillary Dissection. Caudle AS et al
          • Target axillary LND (TAD) has a false negative rate of 2% compared with SLNB FNR 10.1%
          • Among patients shown to be N+ prior to preoperative systemic therapy, SLNB has a >10% false-negative rate when performed after preoperative systemic therapy, which can be improved by marking and removing the most suspicious biopsied node, using dual tracers, and by obtaining ≥3 sentinel nodes (targeted axillary lymph node dissection). (Caudle AS, et al. J Clin Oncol 2016;34:1072-1078.)
      • If negative - radiotherapy
      • If positive - ALND
        • Residual cancer = Isolated Tumour Cells, Micromets, Macromets
  • Uptodate authors recommend ALND in all patients with pretreatment N2-N3 independent of clinical response

Frozen Section During SNB

  • Melanoma
    • Sensitivity 50%, risk of positive LN = 20%
    • Therefore 10% whom have frozen section will need ALND
  • Breast
    • Sensitivity 75%, Risk of positive LN = 40%
    • Therefore – 30% whom have frozen section will need ALND
    • Frozen section more useful in breast cancer than melanoma
    • NB: False negative rate up to 20%
  • Touch imprint cytology
    • 30-100% sensitivity (poor for lobular)
    • False-negative rates for intra-op assessment are up to 38%
  • Path protocol:
    • 2mm slices, H&E & CAM 5.2 stains: single slice thru each LN

Management after SNB

  • No nodes positive, ITC, or occult mets → No ALND
    • No diff in regional control, overall survival, or disease free survival
  • Positive nodes
    • 1-2 nodes
      • Breast conserving surgery
        • Z11 Eligible → Showed that patients with 1-2 LN did not need ALND
          • Randomised to observation vs ALND
          • Clinically negative nodes, T1 or T2, < 3 positive nodes on SNB
            • Although in practice now criteria is expanding including from SENOMAC trial
          • Undergoing breast conserving therapy followed by whole breast radiation
          • Some patients had boost axilla radiation
          • Similar LR, DFS and OS
      • Mastectomy
        • AMAROS criteria → axillary radiotherapy
          • T1-T2, unifocal, invasive breast cancer without palpable axillary lymphadenopathy
          • After surgery randomised to radiotherapy (mastectomy = boost to axilla OR BSC = whole breast radiotherapy) or ALND
          • Also included patients with mastectomy (and BCS) which showed axillary radiotherapy is a safe alternative to ALND
          • Similar LR, DFS and OS
          • Lower morbidity
    • 3+ nodes
      • ALND

Next questions is can we admit radiotherapy - POSNOC trial

Axillary Lymph Node Dissection

  • Rationale:
    • Stages disease & dictates need for adjuvant treatment
    • Provides local control of axilla - local recurrence < 1% (0.4%)
    • Possible survival implications – unknown if ↑s survival

Indications

  • Tumour larger than 5 cm
  • Locally Advanced or Inflammatory Ca
  • Clinically +ve Axilla
  • +ve SNB (unless meets Z11 criteria)

Procedure

  • Level II dissection is operation of choice
  • Level III if macroscopic evidence of tumour at level II
    • No improved DFS/OS after routine level III AD
    • Up to 25% will have level III involvement if Level I involved
  • Aim to remove 20 nodes for optimal staging

Complications

  • Lymphoedema
    • 15%
    • Physical therapy, arm strengthening, and stretching; compression garments
  • Limitations in postoperative shoulder and arm mobility
  • Prolonged postoperative pain
  • Cording
    • Cording of the axilla and upper arm, is a self-limited, harmless condition
    • Believed to be caused by thrombosis in subcutaneous veins and ligation of veins after axillary dissection
  • Paraesthesia
    • intercostal bracial nerve
      • Upper inner arm
  • Winged scapula - LTN
  • Weakness of the arm with respect to extension, adduction and medial rotation - TDB/Lats

Management of Internal Mammary Nodes

  • Identified on scintigraphy in 2-30%
    • Isolated IMN in < 1% of cases
  • SNB if identified by scintigraphy is considered optional (NCCN 2008)
    • Diagnostic / staging rather than therapeutic role
    • “Non-axillary SLN should be excised if they can be accessed & excised without ↑ed morbidity”
      • No evidence for this statement
  • No survival advantage
  • 40% of medial tumours drain to internal mammary nodes
    • But at least 50% drain to axilla as well
  • Sampling IMNs may upstage 6-7% of pts
    • But associated with high rate of complications
      • 20-30% pneumothorax, haemothorax / effusion, bleeding problems, including potential thoracotomy
    • May only change management in 3%
  • Can irradiate – but again no survival advantage
  • Summary → No proven benefit in removing IMN

Nodal Metastasis and the Occult Primary

  • 1/300

  • 70% with adenocarcinoma in the axilla will have breast cancer

  • Most seen on mammogram

  • MRI will detect 70% not seen on mammogram

  • Treatment is as per palpable axillary nodes in breast cancer

    • If truly no identifiable breast cancer, you can discuss close observation of the breast
      • Most women would feel more comfortable with mastectomy

  • Pathology/DDx

    • Cat Scratch Fever – Bartonella – need to biopsy to diagnose
    • Brucellosis – unsterilized milk or meat – blood culture or serology
    • Other viral/ bacterial infection of the arm
    • Lymphoma – fever, night sweats, >10% weight loss
    • Melanoma
    • Rheumatoid arthritis

  • Work-up

    • Triple assessment, breast mammogram, USS of LN, FNA of LN
      • If FNA is lymphoid → Flow cytometry of sample ± Core Bx
    • If probable occult breast tumour → MRI
    • If no answer - Excision Biopsy
      • FRESH to lab
        • Piece for micro (3-5mm) not in RPMI
        • Piece for flow cytometry (at least 5mm) in RPMI
        • Piece for cytogenetics (3-5mm) in RPMI
      • Freeze some & process some in formalin for H&E staining
    • Flow cytometry can use immunohistochemistry (gives specific subtype of lymphoma & helps to narrow DDx for malignancies) – use the principle of antibodies binding to cellular antigens (CD20/CD3)
    • Cytogenetics – Chromosomes, FISH
    • CD4 & CD8 immunostains only work on frozen material

  • Management

    • Where primary not found should have an axillary dissection, adjuvant systemic Rx and breast irradiated or kept under observation

Management of Axillary Recurrence

  • Stage to detect metastatic disease
  • Isolated/operable axillary mets
    • Proceed to Level 3 clearance
  • Isolated inoperable mets
    • ? radiotherapy (if not previously had)
  • And/or systemic treatment

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
    • Angiosarcoma
  • Systemic
    • Fatigue

Adjuvant After BCS

  • Whole breast Radiotherapy
    • Given to all patients after BCS
    • Even if cPR after neoadjuvent therapy
  • Tumour bed boost
    • Given in higher risk patients
  • 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)
    • High risk features on presentation
      • Stage III+
      • Incomplete pathological response
    • Positive margins
  • Regional nodal radiotherapy
    • Can be consider in N2+ or high risk N1 (TNBC, LVI, High grade)
    • 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

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 systemic therapy

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 systemic therapy

For the exam

  • The discussion should be made on

    • Patient wishes
    • Tumour characteristics
      • I use UK predict
        • Size
        • Grade
        • Receptor status
        • Ki-67
        • Detected by screening, symptoms or unknown
        • Number of positive nodes
      • This gives me an idea of 5 and 10 year survival and the benefit from chemotherapy and endocrine
    • I use OncoTypeDX if there is equivocal benefit to further guide treatment

  • I would discuss and prescribe endocrine therapy

  • Refer on for chemotherapy

  • NCCN 2024 guidlines summary

    • Hormone receptor positive * Kate Rapson discusses with everyone *
      • T1-T3, N0-N1
        • Suggest Oncotype DX (could use NHS predict)
        • 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 (Modified Allred score)

    • 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
      • Decrease risk of breast cancer
    • Agonist on Endometrium, Bone and Lipids
      • Increases risk of endometrial cancer

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)
    • DEXA for bone density on AI prior to commencing for baseline and every 2 yrs thereafter
    • 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
  • Duration: 1 year

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%)

Follow-up

  • RCTs have shown routine surveillance after primary surgery and adjuvant therapy does not improve survival
  • Clinic
    • Pt can be seen at 6/52 post-op for wound r/v
    • If OK then can have a breast prosthesis (i.e. bra with one side filled to simulate a breast) fitted
    • Post-op: 3 months for 1st visit then 6mths for 2nd visit then annually
  • Imaging
    • Yearly mammograms for 10yrs after surgery to max of 75yrs & regular clinical exam
    • Thereafter screening mammography according to physiological age?
    • Yearly mammogram is required on reconstructed breasts, including implants, immediate and delayed flaps (looking for microcalcifications & deep recurrence)
  • F/up according to NPI (diff for different centres)
    • F/up for 5 years if NPI > 5 (NSH)
    • Otherwise for 2 years

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