Post Neoadjuvant therapy: issues in interpretation

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

How to approach a specimen post NACT Tumor bed visible the periphery residual tumor nodules may or may not be visible Measure: TB, residual nodules and distance to margins post-ttt

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

How many sections are enough? 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

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 Pre-ttt Post-ttt Post-ttt Post-ttt Cytologic features: Hyper eosinophilic cytoplasm, nuclear enlargement and vesicular chromatin 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 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 Elston & Ellis (1991) Histopathology 19:403

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

LN Lymphoid depletion Fibrous scarring with little or no residual tumour LN metasases with CR are often aggregates of macrophages Should not be considered

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. Distant disease-free survival according to the axillary nodal status after primary chemotherapy., No residual nodal disease; ---, residual nodal disease. Rouzier R et al. JCO 2002;20:1304-1310 2002 by American Society of Clinical Oncology

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 prettt 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)