Controversies

in Breast

PathologyELENA PROVENZANO

ADDENBROOKES HOSPITAL, CAMBRIDGE

Neoadjuvant

Chemotherapy

Indications:

• Management of locally advanced invasive breast cancers including inflammatory breast cancer

• ‘Down-staging’ of large inoperable cancers to permit surgical

resection

• Routine management of women with high risk disease who

would require adjuvant chemotherapy based on biological

tumour characteristics and clinical-radiological findings

Prognostic factors post NACT –

Size matters

• Complete pathological response

• Pre treatment histological grade

• Post treatment histological grade

• Residual tumour size

• Residual tumour cellularity

• Lymphovascular space invasion

• Number of lymph nodes containing metastatic carcinoma

• Size of metastases

• Evidence of chemotherapy effect in lymph nodes

• TILs (tumour infiltrating lymphocytes)

Size of residual tumour Component of TNM staging

Post treatment TNM stage (6th edition) associated with

outcome

Essential component of RCB scoring system

RCB score shows a strong association with survival

outcomes across all tumour subtypes

TNBC HER2+ER+/HER2-

Measuring Size Post NACT

Thorough macroscopic (gross) assessment of the

specimen critical for accurate classification of pCR and

assessment of size post NACT

A multidisciplinary approach with adequate clinical

information and access to imaging results is essential

Close clinical/ radiological correlation to map the

precise location of the tumour bed is preferable to

exhaustive blind sampling

Placement of a marker clip at the time of diagnosis is

very helpful in the event of an excellent response to

treatment

Measuring Size Post NACT

Minimum information required:

Clear indication neoadjuvant Rx has been given

Location of tumour/s within the breast – diagram best

Pre treatment size on imaging

Post treatment size and whether there has been any response

A. Concentric shrinking

Patterns of tumour response

Measuring size post NACT

Concentric shrinking

pattern – single

residual focus

Measure size of

residual invasive

cancer

Do not include

tumour bed

extending beyond

invasive focus

Measuring size post NACT

B. Scatter pattern

Patterns of tumour response

Measuring size post NACT

Scatter pattern of

response – multiple

islands of tumour cells

spread across tumour

bed

What do you measure?

Total extent of disease

including all foci

Size of largest single

focus

Measuring size post NACT

• Tumour size often more difficult to

assess after neoadjuvant

treatment.

• If there is a single lesion present

on pre-treatment imaging, then

treat residual disease as a single

tumour, especially if tumour cells

are present within a reactive stromal background consistent

with a solitary tumour bed (A).

• The combination of size and

residual tumour cellularity is the best indicator of response.

Provenzano et al., Mod Path 2015.

Measuring size post NACT

• BUT

• (A) is the size measurement

recommended in the RCPath

guidelines

• (A) is the size measurement used

to calculate the RCB

• 7th and 8th edition AJCC TNM –

largest contiguous area of tumour

cells (B) and use (m) modifier to

indicate multifocal disease

• No current published evidence

that shows a relationship between

(B) and survival outcomes

Significance of nodal

disease Nodal status post chemotherapy a strong predictor of

outcome

von Minckwitz G et al. JCO 2012;30:1796-1804

Significance of nodal

disease

Hennessy et al., J Clin Oncol 2005;23:9304-11

403 pts proven node pos

22% axillary pCR, 69% also pCR breast

Axillary conversion the MOST significant predictor of OS

Size of residual breast tumour NOT predictive if residual

nodal disease

No influence of size of metastasis – prognosis still worse if <

0.1 mm

Evidence of nodal response associated with improved DFS

Significance of nodal

disease Cure et al., Breast Ca Res Treatment 2002;76(1):37-45

277 pts, tumours > 3 cm

39% clinically node pos -> ypN0

Number of positive nodes post chemo strongest predictor of survival

Klauber DeMore et al., Ann Surg Oncol 2006;13:685-91

122 pts, 52% node positive pre chemo

Worse DFS/ OS with increased number of nodes and increasing size of metastasis

Size of largest metastasis the strongest predictor of survival on multivariate analysis

ITC’s regarded as node positive

ITC’s post chemotherapy

Presence of isolated tumour cells in lymph nodes

TNM – call ypN0(i) BUT not pCR

WHO/ RCPath – call node positive i.e. NOT pCR

do NOT regard as pCR – nodal equivalent of minimal

residual disease

often background fibrosis indicating previous

macrometastatic disease with regression

measure size of entire deposit including intervening

fibrosis**

ypN post NACTNew definition in 8th edition TNM – introduced beginning 2018

Size of the largest contiguous focus of residual tumour in the node

Any treatment associated fibrosis should NOT be included

A description of number of foci present and total distance over

which they extend may be helpful for clinicians to determine extent

of residual disease

Deposit ≤ 0.2 mm is ypT0(i+); NOT regarded as pCR

This is NOT the measurement of size of metastasis used in the RCB,

which is the largest deposit INCLUDING associated treatment

related fibrosis

No evidence in literature associating nodal status measured in

this way with survival

ypN post chemotherapy

Case study

55 yo female.

Inflammatory breast cancer.

Neoadjuvant chemotherapy on NeotAnGo

trial.

Post treatment mastectomy and axillary

clearance.

Case study

30 mm residual invasive lobular carcinoma

Partial response to neoadjuvant

chemotherapy

7/11 nodes with metastatic carcinoma in

the form of scattered single cells within

background fibrosis

Case Study

How do you report nodal status in this

case?

A. Measure excluding fibrosis = ITCs - Negative

[ypN0(i+)] but not pCR = ypTNM

B. Measure entire deposit including fibrosis -

Positive [ypN2] and not pCR = RCPath/ RCB

Would you recommend regional nodal

irradiation for this patient

Take Home Points

Changes in the way size of tumour and

metastases measured in latest TNM

Size measurement used for TNM not

the same as size measurement used for

RCB or recommended way of

measuring size in RCPath guidelines

HER2 status

Rakha et al., J Clin Path 2014

HER2 status

3+ 2+

Current ISH Guidelines

Definitely

Positive

Uncommon groups with uncertainty as

to clinical significance

Definitely

Negative

HER2 FISH

HER2 FISH – ‘polysomy’

• Multiple green and orange

signals

• True polysomy of chr 17 is very

rare

• Usual scenario is co-

amplification of both CEP17 and

HER2 loci

Sapino et al., Frontiers in Onc 2013

HER2 FISH – CEP 17

monosomy

Only one green signal

due to loss of the

CEP17 site

What does this mean clinically?

BCIRG Meta-analysis

Press et al., JCO 2016;34:3518-28.

Review of pooled data from BCIRG trials

Group 1: 20% 0/1+, 30% 2+, 50% 3+

Group 2: 91% 0/1+, 9% 2+, 0% 3+

Group 3: 77% 0/1+, 11% 2+, 11% 3+

Group 4: 94% 0/1+, 5% 2+, 1% 3+

Group 5: 99% 0/1+, 0.5% 2+, 0.05% 3+

BCIRG Meta-analysis

BCIRG Meta-analysis

Press et al., JCO 2016;34:3518-28.

Review of ISH Guidelines

Clarify interpretation of ISH to reduce variation

Require concomitant review of IHC AND ISH to arrive at diagnosis

Avoid routine use of alternative chr17 probes

Literature sparse

Variable results depending on probe used

Introduction of statistical error due to multiple testing

HER2 Guidelines – Focused

update (unpublished)

Reflex ISH for IHC 2+

Call HER2 negative if low absolute HER2 copy number

Ratio >2, HER2 < 4

Ratio < 2, copy number 4-6 (= current UK guidelines)

Call HER2 positive if ratio > 2, HER2 4-6

Call HER2 positive if Ratio < 2, HER2 ≥6

Heterogeneous group

Recent data shows some but not all patients respond to HER2 targeted therapy

HER2 Guidelines – Focused

update (unpublished)

Updated guidelines still unpublished

Recommendation is to continue to use 2013 guidelines

NHS BSP Pathology Co-Ordinating Committee is

undertaking a UK based review of these cases prior to

adopting the ASCO CAP Update once it is published

My reports – add a comment

‘This tumour has an elevated HER2:CEP17 ratio due to relative loss of the CEP 17 locus without an increase in HER2 copy number. Whilst regarded as HER2 positive

under current guidelines, this subgroup did not show a benefit from HER2 targeted therapies in the BCIRG analysis.’

HER2 Status – Are all HER2

+ve cancers the same? Retrospective analysis of NOAH study looking at PAM50

subtypes

Only 55% of HER2+ tumours HER2-E subtype; 21% luminal,

7% basal-like, 18% normal-like

Prat et al., Clin Cancer Res 2014;20(2):511-21.

• Better pCR rates in

HER2-E vs luminal

HER2+ tumours

(53% v 29%) with

larger improvement

in EFS with

addition of

Trastuzumab

HER2 Status – Are all HER2

+ve cancers the same?Predictors of response in HER2 positive cancers

In the NEOSPHERE trial, higher levels of HER2 protein expression

associated with pCR after dual targeted Rx

Bianchini et al., Breast Ca Res 2017;19:16.

FISH:

higher HER2:CEP17 ratio – OR = 2.11, optimum cut off 4.5

higher HER2 copy number – OR = 1.15, optimum cut off 14

Wu et al., Oncotargets and Therapy 2018;11:801-8

Higher pCR rate with high level amplification (copy number >10)

than low level amplification (6-10) – 55% v 24%

No difference in RFS or OS

Guiu et al., BrJC 2010;103:1335-42.