UPDATES IN

NEOADJUVANT Breast
Surgery/Radiology/Pathol
THERAPY IN BREAST ogy Meeting

CANCER
CANCER AUSTRALIA
STATEMENT
All patients with early breast cancer be tested for hormone and
HER2 receptor status.
Neoadjuvant chemotherapy and endocrine therapy has a number of
benefits compared to surgery as a first treatment.
 Down-stage tumour to achieve operability or BCS.
 Early evaluation of response of cancer to therapy enabling ineffective treatment
to be discontinued and alternate treatments considered.
 Systemic therapy before or after surgery is equally effective in terms of OS and
disease progression.
UK GUIDELINES
Decision for neo-adjuvant therapy to made at MDT.
RCTs show that BCS after neoadjuvant therapy is associated with
increased risk of local recurrence.
BCS following neoadjuvant therapy can be considered based on:
 Size of tumour
 Focality of tumour
 Position of tumour
 ER/HER2 status

Majority of inflammatory cancers will be treated with neoadjuvant

chemotherapy, definitive mastectomy followed by postoperative
radiotherapy
USA NCCN GUIDELINES
NAC is equivalent to adjuvant chemotherapy in terms of DFS and OS.
NAC provides a platform to efficiently evaluate the safety and efficacy of novel
agents while monitoring physical and biological response of the tumour.
Purpose of NAC:
 Increase resectability of locally advanced breast cancer and inflammatory breast cancer and administer
systemic therapy to individuals at highest risk of systemic occult disease.
 Increase feasibility of BCS among women with Stage ii-iii invasive cancer who would otherwise require
mastectomy due to breast to tumour ratio.
 Increase cosmesis of BCS among BCS candidates who may otherwise achieve inferior cosmetic results.
 Decrease morbidity and extent of axillary surgery in women with significant axillary nodal disease.
 Downstage axilla in node positive patients who may benefit from SNB.
 Recommend pre NAC SNB if critical to decision making
 SNB for previously node positive patients now clinically node negative
 An option for anyone for whom adjuvant systemic therapy is indicated.

Contraindications
 Pure DCIS
 T1a (i.e. le 1-5mm)
DUTCH GUIDELINES
NAC
 Indicated for breast cancer with locoregional metastatic disease (Stage III)
 Can be considered for stage II disease where there is already an indication for systemic therapy.

Preconditions
 General
 MDT discussion – document TNM
 Clinical evaluation by surgeon, radio therapist and oncologist
 Breast diagnostics
 Histological biopsy – Tumour grade, hormone receptors, HER2 amplification
 Accurate documentation of tumor size and extent of metastatic disease ideally by MRI (MMG and US minimum)
 Photograph T4 tumors to record skin metastasis
 Place a radio-opaque marker regardless of mastectomy or BCS
 Regional diagnostics
 Record axillary node status clinically and via US
 If cN1-3: cytological confirmation
 If cN0: SNBx preferred prior to NAC
 Screening for distal mets
 Stage all stage III and II with N+
DUTCH GUIDELINES
NAC
 Chemotherapy drugs dependent on tumor characteristics, age an performance per adjuvant
guidelines
 Consists of 6 to a maximum of 8 courses
 Response evaluation should not take place earlier than 3-4 courses except if progression is evident
 Treatment plan with stable disease is to continue chemotherapy as a pathological response may
still occur
 On anthracycline-taxane sequential treatment, evidence of progression indicates an earlier switch
to Taxane
 Locoregional therapy if progression despite taxane containing combination.
 Trastuzumab must be considered in all HER2 over expression cancers

Neoadjuvant Hormone therapy

 Alternative to chemotherapy in the elderly and comorbid in hormone receptor positive tumors
 AI is preferable to Tamoxifen for post menopausal women
 Locoregional therapy to start no later than 3-6 months
Breast Surgery
 Omitting surgery advised against even with clinical complete response
 cT4 if operable after systemic treatment

Contraindications to BCS
 Suspected microcalcification in multiple quadrants
 After NAC and if BCT chosen, patients with two or more of following have increased risk of locoregional recurrence:
 cN2-3
 Multifocal residual tumour
 Residual tumor >2cm
 LVI on biopsy or postoperative specimen

ALND
 Non identified sentinel node in Stage II cT2-3N0
 Clinical positive nodes in case of Stage II cT1-2N1
 Downstaging of Stage III cN2-3 to yN1

Radiation therapy
 Still inoperable disease
 In BCS
 Stage III, cN2-3
 ALND >3 Nodes +ve
 Consider if cT3 and LVI, grade 3, age <40yo
EBCTCG
Meta-analysis of 10 randomised trials (4756 women) between 1983
and 2002 with median 9y follow up (5-14y, last 2013).
 Context:
 Operable cancers, 8 trials surgery regardless of response, 2 trials which do not always perform
surgery after naCT
 Trials selected offer the same naCT and aCT drugs
 62% anthracycline based, 18% anthracycline + taxane, 19% others eg CMF (cyclophosphamide,
methotrexate, furouracil)
 28% with naCT had complete, 41% partial pathological response, 31% stable or progression of
disease
 65% with naCT group had BCS vs 49% with aCT group despite similar number of patients in either
group intended for BCS
EBCTCG
Findings:
 21.4% vs 15.9% local recurrence rate for naCT vs aCT (RR1.37) p=0.0001
 Responders to naCT had lower rates of distant recurrence and breast cancer specific mortality.
However once non-responders combined – no difference vs adjuvant therapy.
 38.2% vs 38.0% naCT vs aCT rate of distant recurrence RR1.02 NS
 34.4% vs 33.7% naCT vs aCT breast cancer mortality RR 1.06 NS
 40.9% vs 41.2% naCT vs aCT any mortality NS
 Tumours that tend to achieve complete pathological response – smaller, ER/PR-, high grade. Not
affected by age, nodal status or planned operation
EBCTCG
 Limitations
 No data on eventual mastectomy vs BCS in the setting of NACT or ACT
 No tumour subtype considerations
 No tumour localisation data, no axillary surgery data
 No radiotherapy data
 New methods in localisation, chemotherapy and radiotherapy not accounted for
 Conclusion:
 NaCT is no better than aCT at reducing breast cancer mortality
 Tumours downsized by naCT may have higher risk of local recurrence vs patients who have aCT likely
due to increased rate of BCS
 RETHINKING NEOADJUVANT
THERAPY
1. Render inoperable tumor operable
 Rarely for curative intent - inoperable large tumour usually accompanied by metastatic disease  systemic therapy only?
 Symptom control – controversial if surgery increases survival duration

2. Allow more conserving surgery

 16-31% conversion from M to BCS
 6-21% increase in absolute risk of loco-regional recurrence

3. Increased OS with locally advanced carcinoma

 No survival benefit vs adjuvant therapy CI 0.90-1.12
 39% complete pathological response, 48% partial response or stable, 12% no response
 Despite best treatment (HER2 amplified – dual blockade via trastuzumab and pertuzumab, 60% patients live with potentially chemoresistant cells for 5-
6 months)

4. Allow assessment of in-vivo response to systemic therapy

 Complete pathological response = true absence of remaining tumor cells.
 Limited by ability to detect all viable cells in primary tumour/systemically
 Based on assumption that behavior of primary tumour equates to behavior of metastatic deposits
 Non operative management of complete responders leads to higher rates of local recurrence.
 Increases in complete pathological response rates does not equal increase to overall survival rates
 Historically some drugs that show better OS show better pathological response eg AI vs T, Trastuzumab
 New drugs eg lapatinib, pertuzumab show better pathological response but no increase to OS
 Biological outcome does not always equate to better clinical outcome.
CONTROVERSIES
Does it make surgery less precise?
 Clinical (palpability), radiological (even on MRI) and histological margins more
difficult to define
 Smaller contiguous structure vs smaller islands scattered throughout margins of
index tumor

Axillary status
 Reliability of SNB after naCT
 SENTINA – 80% detectability, 14.1% FN rate.
 Management of the previously node positive but now clinically neg axilla
CONCLUSION
Systemic therapy before or after surgery is equally effective.
 Similar disease progression and OS.

Increases resectability of locally advanced breast cancer and

inflammatory breast cancer
Increases the feasibility of BCS in smaller tumours – but the risk of
local recurrence is higher.
Consideration of tumour subtypes
 LG vs. HG
 HER2- vs. HER2 enriched