Problemática del Ganglio Centinela y Medición de la Respuesta Patológica

Problemática del Ganglio Centinela y Medición de la Respuesta Patológica Sesión IV - Neoadyuvancia: un Ejemplo de Integración Federico Rojo, Fundación Jiménez Díaz

Pathological complete response predicts survival in breast cancer patients N=11955 patients from 12 trials Cortazar, P et al. Lancet 2014

Pathological complete response predicts survival in breast cancer patients N=11955 patients from 12 trials Cortazar, P et al. Lancet 2014

Terapia neoadyuvante en cáncer de mama precoz: problemáticas en patología Valoración, definición y estandarización en la medida de la respuesta patológica Importancia del carcinoma in situ en la respuesta Respuesta a neoadyuvancia y subtipos Fenotipo postneoadyuvancia Estudio tras neoadyuvancia de la axila (y ganglio centinela)

Q1: Response evaluation criteria Core biopsy Surgical specimen

Q1: Response evaluation criteria Miller-Payne evaluation of neoadjuvant systemic therapy DFS

Q1: Response evaluation criteria Residual Breast Cancer Burden to predict survival after neoadjuvant chemotherapy Symmans, WF et al. J Clin Oncol 2007

Q1: Response evaluation criteria Histological response evaluation classifications *Evaluation of lymph nodes

Q2: Persistent DCIS impacts on survival after neoadjuvant systemic therapy? von Minckwitz, G et al. J Clin Oncol 2012 Cortazar, P et al. Lancet 2014 Mazouni, C et al. J Clin Oncol 2007

Q3: Intrinsic subtypes impact on DFS after neoadjuvant systemic therapy? Luminal A Luminal B1 Luminal B2 HER2 TN von Minckwitz, G et al. J Clin Oncol 2012 N=6377 from 7 AC trials Cortazar, P et al. Lancet 2014

Q4: Intrinsic subtype is modified after neoadjuvant systemic therapy? Parinyanitikul Parinyanitikul, N et al. ASCO Breast Cancer Symposium 2013

Q5: Axillary lymph node status must be evaluated in neoadjuvant response?

Q5: Axillary lymph node status must be evaluated in neoadjuvant response? Any nodal disease after neoadjuvant chemotherapy is relevant Carey L et al. JNCI 2005 Zhang, GC et al. Cur Oncol 2013

Q5: Axillary lymph node status must be evaluated in neoadjuvant response? Any nodal disease after neoadjuvant chemotherapy is relevant 3 sabores

Q5: Axillary lymph node status must be evaluated in neoadjuvant response? Any nodal disease after neoadjuvant chemotherapy is relevant 3 sabores NSABP B18 Fisher, C et al. Cancer 2002

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes Pretreatment Neoadjuvant chemotherapy Posttreatment

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes Author Year FNA N ycn- only IR (%) FNR (%) IHC Breslin et al. 2000 No 51 No 94 6 Yes Patel et al. 2004 No 116 Yes 95 3 No Mamounas et al. (NSABP B27) 2005 No 428 No 85 11 No Lee et al. 2007 Yes 219 No 78 6 Yes Newman et al. 2007 Yes 54 No 98 8 No Shen et al. 2007 Yes 61 No 92 25 No Classe et al. 2009 No 65 No 82 15 Yes Brown et al. 2010 Yes 86 No 89 22 No Ozmen et al. 2010 Yes 77 Yes 92 14 Yes Canavese et al. 2011 No 64 No 94 5 Yes Thomas et al. 2011 Yes 30 Yes 87 17 Yes Alvarado et al. 2012 Yes 121 No 92 21 No Rebollo-Aguirre et al. 2012 Yes 37 No 84 7 OSNA Boughey et al. (ACOSOG21071) 2013 Yes 689 No 93 15 No Kuehn et al. (SENTINA) 2013 No 592 Yes 80 14 No Park et al. 2013 Yes 178 No 95 22 No Takei et al. 2013 No 103 No 91 11 No Yagata et al. 2013 Yes 95 No 85 16 Yes Boileau et al. (SN FAC) 2015 Yes 153 No 88 8 (13) Yes Lee et al. 2015 Yes 55 Yes 86 17 Yes

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes RECOMMENDATION 3.4: PREOPERATIVE/ NEOADJUVANT SYSTEMIC THERAPY Clinicians may offer SNB for women who have operable breast cancer and the following circumstance: preoperative/ neoadjuvant systemic therapy (NACT). Evidence quality: intermediate. Strength of recommendation: moderate. For patients with metastatic nodes before NACT, the FNR with SNB after treatment may range from 10% to 30%, which, in the view of the Update Committee, is unacceptable.

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes The meta-analysis of Fu et al. revealed that the FN rate decreased from 16.0% to 8.7% when IHC was added to negative nodes according to H&E staining (P= 0.001). The meta-analysis of Tan et al. also indicated that IHC could decrease the FN rate after NAC in node negative patients from 12% to 9%. Fu, JF et al. Plos One 2014 Tan, VK et al. J Surg Oncol 2011

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes Sentinel-lymph-node biopsy after neoadjuvant chemotherapy (SN FNAC) prospective phase II trial (N=153) Boileau, JF et al. J Clin Oncol 2015

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes Sentinel-lymph-node biopsy after neoadjuvant chemotherapy (SN FNAC) prospective phase II trial (N=153) Boileau, JF et al. J Clin Oncol 2015

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes Sentinel-lymph-node biopsy after neoadjuvant chemotherapy (SN FNAC) prospective phase II trial (N=153) One of the most important findings of the SN FNAC trial is that after neoadjuvant treatment, SN metastases of any size are significant and should be considered positive. At the time of pathologic evaluation, SNs that were negative on HE staining were submitted to mandatory IHC staining. ypn1mi and ypn0(i) SNs were more likely to be identified primarily by IHC staining. In the absence of neoadjuvant treatment, the rate of positive non- SNs increased with the size of SN metastases. After neoadjuvant treatment, at least for patients with biopsy-proven node-positive disease at presentation, the rate of positive non-sns was high and independent of the size of SN metastases. Boileau, JF et al. J Clin Oncol 2015

Terapia neoadyuvante en cáncer de mama: problemática en el ganglio centinela

Terapia neoadyuvante en cáncer de mama: problemática en el ganglio centinela En axila clínica/ecográficamente negativa de inicio (cn0), puede realizarse la BSGC tanto previa al tratamiento sistémico primario como posterior En cn1/n2 de inicio con negativización clínica y ecográfica tras la neoadyuvancia (cyn0) puede realizarse la BSGC después del tratamiento sistémico y evitar la linfadenectomía cuando el GC sea negativo Su diagnóstico debe ser intraoperatorio Aceptables hasta 3 ganglios (recomendable limitar a 2) Se recomienda estudiar el ganglio en su totalidad. La única técnica que permite el estudio en su totalidad es la técnica molecular one step nucleic acid amplification (OSNA), por lo que se considera el procedimiento de elección Es aceptable el estudio intraoperatorio histopatológico mediante cortes por congelación, impronta o raspado de las superficies del ganglio y confirmación por protocolo de niveles posterior

Terapia neoadyuvante en cáncer de mama: problemática en el ganglio centinela OSNA Muestra no diluida de CK19 Resultado Interpretación 5000 5000 copias ++ Macrometástasis 250 copias < 5000 + Micrometástasis 100 copias < 250 - L ITC sólo si la muestra diluida tiene más de 250 copias copias < 100 - Negativo

Terapia neoadyuvante en cáncer de mama: problemática en el ganglio centinela OSNA Correlation between Histopathology and OSNA Assay, by Nodes (N=567) OSNA CK19 assay Negative (n=561) Histopathology Macrometastasis (n=1) Micrometastasis (n=5) No. of nodes % No. of nodes % No. of nodes % Negative (n=514) 514 91,6 0 0 0 0 Macrometastasis (n=19) 14 2,5 1 100 4 80 Micrometastasis (n=26) 25 4,5 0 0 1 20 Low expression (n=8) 8 1,4 0 0 0 0 Discrepancy (complete series): 9.0% (51 nodes) Bernet, L et al. Diag Mol Pathol 2012

Q6: Sentinel lymph node biopsy after neoadjuvant therapy in previously clinically positive nodes Molecular detection of sentinel-lymph-node biopsy in breast cancer patients treated with preoperative systemic therapy Osako, T et al. Br J Cancer 2013

Terapia neoadyuvante en cáncer de mama: problemáticas en patología Mensajes Realizar una valoración de respuesta del tumor primario y de la axila, siguiendo las clasificaciones referenciadas, aunque no existe un consenso En axilas clínicamente no afectas, puede realizarse biopsia de ganglio centinela postneoadyuvancia En axilas clínicamente afectas previamente a la neoadyuvancia, existen datos contradictorios sobre el valor del ganglio centinela postneoadyuvancia (carga tumoral, método de detección, tasa de falsos negativos) Las técnicas complementarias (IHC, OSNA) podrían reducir la probabilidad de falso negativos en ganglio centinela postneoadyuvancia