Post Neoadjuvant therapy: issues in

interpretation

Disclosure:

 

Overview D

 Prognostic features in assessment of post treatment specimens:

 Tumor size

 Cellularity

 Grade

 Receptors

 LN

 Neoadjuvant chemotherapy: receiving chemotherapy before surgery

 Adjuvant: Chemotherapy after surgery

Who are the candidates

Offered to LABC patients to reduce the size

Improves the surgical options

NACT achieve the same survival results as adjuvant

Advantages of NACT

  In vivo assessment of tumor response to different systemic interventions

  Pathologically detected residual disease predicts prognosis

  Increased eligibility for breast conservation

Tumor bed visible

the periphery residual tumor nodules may or may not be visible

Measure: TB, residual nodules and distance to margins

post-ttt

How to approach a specimen post NACT

Tumor bed is not visible:

Radiology report (residual calcs, response, location)

Clip inserted at the time of the biopsy

Send specimen to imaging

post-ttt

If the specimen is small, tumor bed not clearly

image the specimen, could submit sections guided by location of clip

If the tumor bed is large > 5 cm (variability in guidelines)

Start with 1-2 blocks/1cm, if no residual tumour is found submit in toto

How many sections are enough?

What is pCR 1.No residual invasive tumor in the breast and lymph node

2.No residual invasive or in situ carcinoma in the breast and lymph node

3.No residual invasive carcinoma in the breast

4.No residual invasive carcinoma in the lymph node

pCR

Powerful predictor of long-term outcome(OS and DFS)pCR

pCR: as absence of residual invasive disease in the breast and ipsilateral lymph nodes after NACT

(ypT0/isypN0)

pCR related to several factors

Higher tumor grade

Proliferative fraction

Hormone receptor status (TN and HER2 +ve)

Sorlie et al, Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23.

ve usually achieve pCR while luminal A tumours are least likely,

Luminal B intermediate respond) (Rouzier et al 2005)

Triple Negative

Core bx ER PR

HER2 Tumor bed LN

HER2 positive

Core bx � ER� PR�

HER2� Tumor bed � LN �

Luminal B HER2 positive

Core bx ER PR

HER2 Post ttt LN

Luminal B

Core bx ER PR

HER2 Post ttt LN

Reporting post Neoadjuvant Chemotherapy

  Residual invasive carcinoma (size - cellularity)

  Tumor bed

  Grade

  Margins

  Receptors

  LN

How can we identify the tumor bed ?

pCR or near pCR

If carcinoma is not palpable

Tumor bed   Loosely vascularized fibrotic area

with absence of normal glands

  Fibromyxoid stroma

  Mucin pools (if no epithelial cells present should not be considered residual tumour)

 hemosiderin deposition and absence of normal mammary glandular elements

Residual tumor   Residual tumor: most

show decrease in cellularity.

  Single cells, cords or

stroma, multiple residual foci or a mass that has shrunk in size circumferentially

  Cytologic features: Hyper eosinophilic cytoplasm, nuclear enlargement and vesicular chromatin

Pre-ttt Post-ttt

Post-ttt Post-ttt

Post-ttt Post-ttt

Tumor size

If response is minimal, tumour is

If response is marked, multiple small foci dispersed over a large tumour bed

The size of the largest continuous focus and the number of residual foci should be reported

Tumor cellularity   Carcinomas are often less

cellular post NACT

  Loss of cellularity is not always

which can lead to clinical overestimation

  Cellularity is determined with accuracy only if pretreatment specimen is available for comparison

  Loss of cellularity is associated with better prognosis and clinical outcome

(Ogston et al, 2003)

  Chen A at MD Anderson found that a residual tumor > 2.0 cm is associated with higher LRR

  Multifocal disease is associated with higher LRR

  5 year LRR-free survival for multifocal residual, solitary residual and no residual was 82%, 93% and 95%.

(Chen A M et al , 2004)

Reporting post Neoadjuvant Chemotherapy

Residual invasive carcinoma (size - cellularity)

Tumor bed

Grade

Margins

Receptors

LN

Histologic grade correlation with Outcomes

Elston & Ellis (1991) Histopathology 19:403

Score Tubule formation Nuclear pleomorphism

Mitotic counts *

1 >75 % similar to normal 0-9

2 10-75% Larger than normal, nucleoli

10-19

3 <10% Marked, large and bizarre

>20

* Mitotic counts depend on field diameter

Nottingham grade   Usually the same

  NACT causes increased pleomorphism of residual cells

  Mitotic activity is reduced in addition to reduction in tumor cellularity which can

mitotic count Pre-ttt Post-ttt

The pretreatment assessment of histological grade remains an independent prognostic factor for DFS and OS

Post NACT grade important ? retains its prognostic value with lower tumour grades associated with better survival

(Pierga et al 2003)

Hormone receptors and HER2

In untreated tumors, minimal discordance between core needle and excisional biopsy has been reported

ER (discordance 1.8%)

PR (discordance 15%)

HER2 (discordance 1.2%)

(Ardenos M et al, 2009)

Hormone receptors can change after treatment

A change in HR status has been reported in 8 - 33% of patients.

For ER, half the discordance was from negative to positive

For PgR, changes from a positive to a negative result was commonly seen

(Van de Ven S etal, 2011)

Tumor heterogeneity

Limited amount present either before or after treatment

Selection: if multiple tumors or heterogenous expression some foci respond to therapy more than others

Technical factors has to be considered as well

HER2

Changes in HER2 after untargeted therapy are uncommon

Some studies reported decrease in expression of HER2 on IHC but in situ hibridization is not changed due to stable HER2 gene

Reporting after Neoadjuvant chemotherapy

Residual invasive carcinoma (size - cellularity)

Tumor bed

Grade

Margins

Receptors

LN

Lymph nodes

Number of involved lymph nodes

Size of the deposits

EXtranodal extension

Lymph nodes showing treatment effects

  Lymphoid depletion

  Fibrous scarring with little or no residual tumour

  LN metasases with CR are often

aggregates of macrophages

  Should not be considered

LN

LMWK �

Micrometastases/ITC

Post NACT micrometastases/ITC are mostly considered macro metastases that partially responded to therapy

(Newman LA et al, 2003)

Post NACT lymph node status is the most important prognostic factor.

LN response after chemotherapy is a better prognostic factor than response of the primary tumor to primary chemotherapy

(Rouzier R et al JCO, 2002).

Fig 2.

Rouzier R et al. JCO 2002;20:1304-1310

©2002 by American Society of Clinical Oncology

Distant disease-free survival according to the axillary nodal status after primary chemotherapy. —, No residual nodal disease; ---, residual nodal disease.�

Number of involved nodes: The increased number of LN with residual positive lymph nodes is associated with worse DFS

Size of the deposit: The larger the size of the metastatic deposit the worse the DFS

Systems for evaluating response to treatment

  American Joint Committee on Cancer system: adds the

  Relies mainly on tumor size post treatment and lymph node status in the post treatment specimen

  Tumor size : based on the size of largest continuos

added.

  The categories are the same as those used for the pre-ttt

  Disadvantage: cellularity is not included in the overall assessment

  The Miller-Payne System: divided into 5 grades based on pre and post treatment cellularity and was correlated with OS and DFS

  Disadvantage: Doesn’t include response in the lymph node

  (Ogston K et al, 2003)

  Residual cancer burden:

  Residual invasive carcinoma cellularity

  Number of lymph nodes with metastases

  Size of the largest metastatic deposit

  Combined to provide a continuos parameter of response (RCB index) divided into four categories

Reporting after neo-adjuvant chemotherapy

Tumor bed

Size of the largest continuous focus or number of foci over the tumor bed

Grade

Margins

LN (number and size of met)