SENTINA Trial

Journal discussion regarding inel Node Biopsy after Neoadjuvant Chemotherapy in Breast Cancers

1. Journal club Sentina TRIAL Dr. D. Pradeep MCh Postgraduate TN Govt Multi Super Speciality Hospital Chennai 28 Dec 2018

2. Background Optimum timing of SLNB for breast cancer patients treated with NACT is uncertain SENTINA ( SENTinel NeoAdjuvant ) – evaluate a specific algorithm for timing of SLNB in patients undergoing NACT 12/28/2018

3. Need for Study Nodal stage after Neoadjuvant chemotherapy reflects prognosis more accurately than does initial axillary status Previous cohort studies done in SLNB after NACT are retrospective Metaanalyses show detection rates of 63-100% and false negative rates of 0-39% To provide reliable data for feasibility and accuracy of SLNB in different settings before and after NACT. 12/28/2018

4. Evidence So Far Khan et al – detection rate for second SLNB after NACT was 97% and false negative rate 4.5% Prospective multicenter study – detection rate of SLNB after NACT was 94.6% and 81.5% for cN0 and cN + status. 12/28/2018

5. Objectives Primary outcome Accuracy of SLB after NACT for patients who converted from cN + to cN0 Secondary outcome Comparison of detection rate of SLNB before and after NACT False negative rate and detection rate of second SLNB after removal of SLN 12/28/2018

6. Definition False negative rate = No of patients with negative SLN and one or more positive non sentinel LNs / No of patients with at least one involved LN among people at least one SLN detected Successful SLN detection – Surgical removal of one or more lymph nodes visualized by lymphatic mapping 12/28/2018

7. Trial Methodology 4 arm, Prospective Multicentre cohort study 103 centres in Germany and Austria Patients with breast cancer who are scheduled for 6 cycles of Anthracycline based regimen Arms decided according to clinical axillary nodal status (both by palpation and ultrasound) 12/28/2018

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9. SLNB procedure Use of radiocolloid and preoperative lymphoscintigraphy necessary for all patients Additional blue dye was optional Site of injection individual choice Dose and volume within limits Slicing of nodes at 2.0 to 3.0mm intervals – paraffin embedded & step sectioning of slices at intervals <500um IHC not required 12/28/2018

10. Nodal status assessment Palpation and ultrasound shows no suspicious nodes – cN0 Palpable nodes – but ultrasound Normal sized nodes with regular morphology of hilum and cortex – cN0 Suspicious nodes – Ultrasound (cortex asymmetry or loss of hilum relation hilum:cortex ratio >2:1 or total loss) USG guided FNA or CNB recommended (not mandatory) If reported negative, taken as cN0 and SLNB done 12/28/2018

11. Statistical Workup FNR of 7% in arms B and C based on validation trial Calculated sample size of at least 196 in every arm Expect 13% of entire study population will have positive axillary status in arm B and 14% in arm C resulting in total number of 1508 patients To compare rates across groups – Pearson chi square test Fisher exact test for FNR and detection rate Wilcoxon and Kruskal-wallis test – compare the number of detected SLNs between 2 groups Multivariate regression to find factors that affected detection rate and FNR 12/28/2018

12. Of 2234, 1737 entered in trial 2009 to 2012 103 centres Median 8 per insititute cN0 1022 pts 59% cN + 715 pts 41% SLNB done pN0 662 pts 65% pN + 360 pts 35% NACT cN0 592 pts 83% cN + 123 pts 17% 12/28/2018

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20. Arm B Arm C Successful SLNB 219 patients 474 patients ypN0 155 (70.8%) 248 (52.3%) ypN + 64 (29.2%) 226 (47.7%) False Negative rate 51.6% 14.2% Median no of resected non sentinel LNs 11 13 LN involvement restricted to SLN 45 (70.3%) 131 (58%) 12/28/2018

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22. Strengths Strict standardization of SLNB procedure Predefined chemotherapy regimens 12/28/2018

23. Limitations FNR of arm A cannot be obtained as they were excluded from Axillary dissection Restricted lymph node assessment to palpation and ultrasound SLNB after neoadjuvant chemotherapy technically more challenging 12/28/2018

24. Our Study Comparison Second SLNB detection rate 66% 97% Khan et al Second SLNB False negative rate 51.6% 4.5% Khan et al cN + to cN0 post NACT SLNB detection rate 80.2% 81.5% Classe et al cN + to cN0 post NACT False negative rate 14.2% 15% Classe et al FNR based on no of LNs One node – 24.3% Two nodes – 18.5% One node – 17.7% Two nodes – 10% (NSABP B32) Addition of blue dye to radiocolloid in arm C Detection rates 77.4% to 87.6% improvement 78.1% to 87.6% Mamounas et al Addition of blue dye to radiocolloid in arm C False negative rate 8.6% for combined vs 16% for radiocolloid 10.8% for combined vs 20% for radiocolloid (ACOSOG Z1071) 12/28/2018

25. Concerns Neoadjuvant chemotherapy Impairs lymphatic drainage Tumor regression in axilla could follow a non uniform pattern Second SLNB Additional node involvement cannot be detected once primary drainage has been destroyed 12/28/2018

26. Conclusion SLNB less reliable (inferior detection rates and accuracy) if undertaken after neoadjuvant chemotherapy who are cN + to cN0 Use of combined tracer might improve FNR Accuracy of SLNB is closely related to number of sentinel nodes removed Still Unclear – lower FNR with combined tracer due to mapping technique or additional nodal harvest No difference in detection rate and FNR for patients confirmed by FNA or CNB compared with exclusive clinical assessment in arm C 12/28/2018

27. Ideas Need for addressing the clinical effect of increased FNR after NACT 12/28/2018

28. Similar Trials ACOSOG Z1071 Trial published in 2013 756 pts from 136 institutions Primary aim – FNR after NACT for SLNB cN + to cN0 after NACT SLN identification rate 92.9% False negative rate 12.6% But <10% when 2 or more SLNs removed 12/28/2018

29. Similar Trials SN FNAC (Sentinel Node biopsy aFter Neoadjuvant Chemotherapy in biopsy proven cN +) To find out accuracy of SLNB after NACT setting Identification rate 87.6% False negative rate 13.3% IHC mandatory in this trial, so with IHC positivity, FNR is reduced to 8.4% 12/28/2018

30. Ongoing Trials Second biopsy of Axillary Sentinel node in Local recurrence of breast cancer after mastectomy and first negative sentinel node 2012 to ongoing 12/28/2018

31. Ongoing Trials Towards plannable breast surgery: Diagnostic accuracy of microbubble enhanced Iodine-125 seed localization of the sentinel lymph node. (NTR 3690) 2012 to ongoing 12/28/2018

32. Ongoing Trials MAGSTAR Trial 2015 to ongoing Magnetic vs Standard technique of axillary mapping Magnetic tracer and Magnetometer ( Sentimag ) 12/28/2018

33. Thank You 12/28/2018