Utility of Sentine Biopsy For B Utility of Sentine Biopsy For B p y
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Utility of Sentine Biopsy For B Utility of Sentine Biopsy For B p y
Utility of Sentine el Lymph Node Biopsy p y For Breast Cancer Facts and Controversies C Henry Mark Kuere er, MD, PhD, FACS Department of S Surgical Oncology University y of Texas MD Anderson Cancer Center National Comprehen p nsive Cancer Network Treatment Guidelines • Use of sentinel node e biopsy in breast cancer –Clinically negative e axilla –Team Team must have ‘documented documented experience’ –SLN SLN positive iti or no one identified id tifi d needs d axillary node disse ection St Gallen Interrnational Expert St. Consensu us Meeting • A negative sentinel lymph node is now accepted as allowin ng avoidance of axillary dissection • Micrometastatic Mi t t ti dise di ease, particularly ti l l isolated cells, are a subject of research J Clin Oncol, Oncol, 2003 Lymphatic Map Mapping ping Technique L Lymphosc Lymphosci h cintigraphy i i h Blue--dye Injection Blue Gamma a-Probe Surgical g Lymph y phatic phatic Mapping pp g S i lL Sentinel Lyymph hN Node d Sentinel Lymph Node Biopsy Optimal O ti l Technique T h i Multi Institutional registry Multi-Institutional - 99 surgeons enrolled 806 pa atients - Attempted SN biopsy followe ed by ALND in all patients - Single-agent (blue dye or ra adiocolloid alone, N=244), or dual-agent (N=562) Results: SN ID-rate ID rate # SN False neg. Single-age ent 86% 1.5 11.8% Dual-agent P 90% ns 2.1 .001 5.8% <.05 .05 McMasters et al, al, JCO JCO,, 2000. Nodal Micro ometastases Definitions and d AJCC Staging Occult nodal disease Clinically node neg gative Microscopically no ode positive Micrometastases Tumor deposit < 2 mm Evidence of diseas se using techniques more sensitive than con nventional methods Serial sections IHC PCR Detection of Micrometastases in Breast Cancer Patients with Negative e Routine H&E Staining Study Friedman et al Bettelheim et al Wells e s et a al Trojani et al Hainsworth et al Bussolati et al Chen et al De Mascarel et al Nasser et al Occult O l Micromets(%) 43/456 (9%) 83/921 (9%) 7/45 / 5 (15%) ( 5%) 21/150 (14%) 41/343 (12%) 12/50 (24%) ( ) 23/80 (29%) 50/218 (23%) ( ) 50/159 (31%) Detection D i T Technique h i Serial Sections IHC X X X X X X X X X X X X X Prognostic Signifiicance of “Occult” Axillary Metastases Study Trojani T j i Sedmak Ludwig g Patients 162 45 921 Chen 80 De Mascarel 218 Hainsworth 343 Histologic Hi t l i Examination IIncidence id off D Decrease iin Di DiseaseOccult Mets (%) Free Survival (%) IImmuno Immuno Multiple p Section ns/ Immuno Immuno Immuno Immuno 14 11 9 22 11 16 29 23 12 16 10 15 2003 AJCC Breasst Cancer Staging: IHC Positive and Is solated Cells = pN0 • • • • • pN0(i-) No metastasis histologically, neg IHC pN0(i+) N0(i+) ITCs, ITC no clust l ter > 0 0.2 2 mm pN0(mol-) negative (R RT-PCR) pN0(mol+) positive (RT T-PCR) pN1mi micrometastasis (> ( 0.2 mm, none > 2.0 mm) Singletary et al, JCO, 2002. 2010 AJCC S Sta aging i Ch Changes • pN0(i+): Cluster < 0.2 2 mm • Classification of ITC C more stringent – Not to exceed 200 cells on one histologic section • Stage I now TWO GROUPS G – IA: – IB: T1 T0 T1 NO N1m mi N1m mi MO M0 M0 Edge et al, 2009 Newer Data: Isola ated Tumor Cells • Netherlands retrospective e analysis: – de Boer et al; NEJM; 2009 9 • Women w/o adjuvant therapy – 856 women node negative e 5y DFS: 86% – 553 women ITCs 5y DFS: 77% – 343 women micromets 5y DFS: 78% • Caveats P<0 001 P<0.001 – Only 2% received chemo, 11% hormonal – Benefit expected to be less with h appropriate systemic therapy Newer Data: Isola ated Tumor Cells • Major Caveats – Only 2 2.2% 2% received chemotherapy and ad tumors > 1 cm >70% of patients ha – 5-year 5 year distant metasstases free rate very similar in node nega ative group versus the ITC/Micromet group p who received adjuvant therapy (2.8% vs. 2..6%) SLN Trials R Recent t Res R ults lt from f US Trials T i l 19 998 2004 998-2004 Practice Patterns: US U National Cancer Database 1998 - 2005 Bilimoria K, et al. J Clin Oncol 2009 U S U. S. Prospective Randomized R Trials • Better understand impact of SLN biopsy in management of earlyy stage breast cancer • Accrual > 11,000 patiients • Firmly establish SLN biopsy as standard of care - NSABP B B--32 (PI: Krag K ) Krag) - ACOSOG Z0010, Z0010 Z0011 Z (PI: Giuliano) NSABP Pro otocol B-32 B 32 Clinically y Ne egative g Axilla RANDOM MIZATION SLN Biopsy* p y and Axillary Dissection * IHC performed on Neg SLNs SLN Biopsy Pathologically Possitive SLN Pathologically Negative** SLN Negative A Axillary Dissection No Axillary Dissection NSABP BB-32 Fals se Negative Rate 9.7 7% (7.6 - 11.9)* *95% 95% CI Julian et al, SABC, 2004 NSABP PB B--32 Sentinel Node by b Biopsy Type Type Technical False Success % Negative Rate % Overall 97.1 1 9.7 FNA/Core 97.0 0 8.0 Incisional 97.6 6 97.3 3 14.3 15.2 P=0.8 83 P=0.02 Excisional B-32 Clinically Negative Axilllary Nodes Randomizatio on GROUP 1 GROUP 2 SN +AD SN Stratification • Age • Clinical Tumor Size • Type of Surgery Intraop cytology & postop HE SN Pos SN Neg (SN+AD) FU 1,975 patients SN p pos + AD SN Neg g (SN only) FU 2,011 patients B-32 Anallysis y Plan 3,989 - SN neg (71% of 5611) 99 9% - follow-up inform mation 99.9% 7.92 years - average tim me on study Primary endpoints OS, DFS, Regional Control Study powered to detec ct 2% difference OS Krag et al ASCO 2010 B-32 DFS NSABP Pro otocol B-32 60 6 40 20 Trt SNR+AD SNR N De eaths 1975 315 2011 336 HR=1.05 p p=0.542 0 %D Disease-F Free 80 100 Disease-Free Disease Free Survival for Sen ntinel Node Negative Patients Data as of December 31, 2009 0 2 Krag et al Lancet Oncol 2010 4 Years After Af Entry 6 8 Krag et al ASCO 2010 B-32 RR Local and Regio g nal Recurrences as First Events Gro oup 1 Group 2 54 (2 2.7%) 49 (2.4%) Axillary 2 (0 0 1%) 0.1%) 8 (0.3%) (0 3%) Extra-axillary y 5 ((0.25% 6 (0.3%) ( ) Local Krag et al Lancet Oncol 2010 Krag et al ASCO 2010 B-32 Morbidity Residual Morbidity at a End of Follow-up • Lower in SN group • Not nonexistent Shoulder abduction deficit Group 1 SN + AD 19% Group 2 SN 13% Arm volume difference >5% % 28% % 17% % Arm numbness 31% 8% Arm tingling 13% 7% Krag et al Lancet Oncol 2010 Ashikaga et al JSO, 2010 All differences p<0.001 Effect of Occult Meta astases on Survival in “Node-Negative” Pa atients: NSABP B-32 • Occult metastases: 15.9% • Independent predicttor of prognosis • Overall survival diffe erence: 1.2% – 94.6% v. 95.8% • Concluded no cliniccal benefit of serial sectioning and or IH HC Weaver et al, NEJM, 2011 NSABP P B-32 Overall Co onclusions No significant differe ences were observed OS, DFS, or Regionall Control SLN vs AD Morbidity decreased When the Wh th SN is i negative, ti SN surgery alone l with no further AD is appropriate, safe, and effective therapy for breast cancer patients ve lymph nodes. with clinically negativ American College of Surgeons Oncology Gro oup SLN Trial T1 and T2 2 Tumors Clinicallyy Neg gative Axilla g BREAST CON NSERVATION Z10 Bone Marrow IHC Z11 SLN Biopsy B Randomization Axillary Observation + Axilla ary Observation Axillary Dissection ACOSOG Z00 010 - Methods • SLNs p processed - standard pathology p gy and H&E staining • SLNs neg by H&E subjected to IHC for cytokeratin (investtigators blinded to results) l ) Z0010 T Treatm ment Variables V i bl Total SLNs Removed Median (Min, Max) Missing ALND Performed, P f d N(%) Yes No Missing Chemotherapy, N(%) Yes No Missing 2 (0,32) 689 Hormonal Rx, N(%) Yes No Missing 2943(67.9) 1389(32.1) 878 925(18.0) 4203(82.0) 82 Radiation Rx, N(%) Yes No Missing 3884(90.8) 394(9.2) 932 Any Adj Rx, N(%) Yes No Missing 4210(98.4) 68(1.6) 932 2297(53) 2035(47) 878 Overall Rate IHC Positive SLNs Z10 5210 Elig gible and E al able Evaluable e Patients SLN H&E Positive N=1215 N 1215 (24%) IHC Negative N=2977 N 2977 (90%) SLN H&E Negative N=3995 (76%) IHC Positive N 349 (10%) N=349 ACOSOG Z0010: Occcult Micrometastases • 5-year overall survival was significantly higher with a negative vs. positive result for: − SLN H&E (≈ 96% vs. 93%; P = .0009) − BM IHC (95% vs. 90%; P = .01) • SLN IHC was NOT significantly associated with overall survival. Overall Survival Multivariable Analysis (Positive vs. Negative) HR ((95% CI)) P Value SLN H&E 1.44 (1.11-1.88) .007 BM IHC 1 88 (1.12-3.17) 1.88 (1 12 3 17) .017 017 SLN IHC 0.98 (0.62-1.54 .93 BM IHC 2 2.22 (1.21-4.10) .011 All Patients SLN H&E– Patients Giuliano et al JAMA 2011 ACOSOG Z10 0 Conclusions • IHC detected SLN me etastases do not appear to impact overall survival • Routine examination of SLN by IHC is not supported in this patie ent population by this study ACOSOG Z0011: A Randomized Trial of Axillary Node Dissection n in Women with Clinical T1-2 N0 M0 M Breast Cancer who have a Posittive Sentinel Node Giuliano AE, McCall L, Beitsch B PD, Whitworth PW, Blumencranz PW, PW Leitch AM M Saha S M, S, Hunt K, K Morrow M, M Ballm man KV Giuliano et al JAMA 2011 Study Population Schema 5/99–12/04 106 (27.4%) patients treated with w ALND h d additio had dditionall positive iti nodes removed beyo ond SLN 72.6% patients p treated with w SLND had all positive p nodes d removed d with ith the th techn nique Patient Characteristics Z11 • • • • Median age: g 55 yyea ars 70% T1 tumors 82% ER ER-positive iti di dissease All pa patients e s had ad nod od de pos positive eb breast eas cancer (overall low burden) – 58% had only one n node positive – Only 21% had ≥ 3 positive p nodes Locoregion nal Recurrences R Recurrence Local (Breast) Regional (Axilla, Supraclavicular) Total Locoregional ALND A (4 420 pts) SLND (436 pts) 15 5 (3.6%) 8 (1.8%) 2 (0.5%) 4 (0.9%) 17 (4.1%) 12 (2.8%) P = 0.11 Median follow-up = 6.3 years Regional R i l re ecurrence seen in i only l 0.7% 0 7% off the entire population p Disease--Free Survival 100 90 80 % Recurre ence-Free and Aliive 70 60 50 40 30 ALND No ALND 20 P-value = 0.14 10 0 0 1 2 3 4 Time (Years) ( 5 6 7 8 43 Overall Survival 100 90 80 70 % Alive 60 50 40 30 ALND No ALND 20 P-value = 0.25 10 0 0 1 2 3 4 Time (Years) ( 5 6 7 8 44 IMPORTAN NT Caveats • WHOLE BREAST T RADIATION • Breast conse erving therapy • Adjuvant System mic Therapy 45 Adjuvant Sys stemic Therapy A ALND SLND Chemotherapy 57.9% 58.0% Hormonal therapy 46.4% 46.6% Either/Both 96.0% 97.0% P = N.S. Recommendations at MD M Anderson for + SLN? • Must be individualizzed • No dissection: –T1/T2 –Less than 3 positiive SLN –If If Whole-breast Whole breast ra adiotherapy –Receiving system mic therapy Caudle, Hunt, Kuerer K et al Ann Surg Oncol, 2011 Recommendationss for Axillary Node Dissection at MD Anderson • Positive SLN –Mastectomy M t t –Partial breast radiiotherapy py –Neoadjuvant chem motherapy Caudle, Hunt, Kue erer et al Ann Surg Oncol, 2011 Compllicated Does the axilla ne eed to be treated when posiitive SLN? Many radiation M di ti o oncologists will treat the a axilla when a positive S SLN is obtained and no d dissection is performed Extende ed Field Radioth herapy? * * * • Which Whi h patients? ti t ? •Recent presented p M MA.20 results •Concern for over treatment/risk T icity? Toxic i ? • Overall Survival for early Stage II breast cancer very high (>9 90%) • What will be the long term effects on h lth healthy: –Lymphatics? y p Sentine el Node Evolving Controvversies Is a Complete Axillary A Lymph Node Dissection Necessary When a Sentine el Lymph Node Contains Metastases ? Is a Complete Axillary Lymph Node Dissectiion Necessary When a Sentinel Lymph Node Contains Me etastases ? ANSW WER: F the For th majorit j itty t off patients ti t NO O Clinicopathologic Factors Predicting Involvement of No onsentinel Axillary Nodes in Women with w Breast Cancer R. Hwang R Hwang, S. S Krishnamurthy, Krishnamurthy K. K Hunt Hunt, N N. Mirza Mirza, F F. Ames Ames, B B. Feig, H. Kuerer, E. Singletary, G. G Babiera, F. Meric, J. Akins, J. Neely and M. Ross Ann Surg Onc, 2003 Multivariate M lti i t Pre P edictive di ti Model M d l 1 26-28 70 1.26-28.70 P Value 0 024 0.024 Coefficient 2 4.1 1 1.42-11.89 0.009 1 LV invasion 3.7 1 1.15-11.70 0.028 1 No. SLN 3 0.19 0.04-0.93 0.04 -2 Characteristic Odds Ratio 60 6.0 Tumor size > 2 cm SLN met > 2 mm 95% CI Nomogram for Predicting the Likelihood of Additional SLN Me etastases in Patients with a Possitive SLN • Pathological size, nuc clear grade, lymphovascular invas sion, multifocality, ERreceptor status, method of detection of SLN metastases; number of o positive SLNs; and number of negative SLNs S • Validated prospective ely in 1545 patients J Clin Onc O 2007 http://www.mskcc.org//mskcc/html/15938.cfm Can Axillary Radiation Be Substituted fo or Completion p Axillary Lyymph Node Disse Di ection ti When a Sen ntinel Lymph N d C Node Contains t i s Metastases M t t ? Current Study:: EORTC 10981 • SLN-Positive • Tumor < 3 cm * • 3485 Patients • Randomized Trial •ALND vs. Axillaryy Radiotherapyy Sentinel No ode Biopsy p y Before or After Neoad djuvant Chemoth herapy ? SLN Biopsy Before Neoadjuvant Therapy • Commits patients to o an extra axillary operation • SLN Negative: Two operations • SLN Positive: Comm mits patients to axillaryy lymph y p node dissection with a positive SLN before e therapy Conversion of Axiillary Metastases: FNA Positive to Pa athologic Negative POSITIVE 191 patients FAC X 4 Pathologic NEGATIVE 43 patients 23% % Median # LNs R Removed = 16 Kuerer et al, Ann Surg, Surg, 1999 Conversion of Axiillary Metastases: FNA Positive to Pa athologic Negative POSITIVE 109 patients HER2+ Trastuzu umab + A orr T Pathologic NEGATIVE 81 patients 74% % Median # LNs Remo oved = 19 CANCER,, 2010 CANCER Impact of Nodal Diseas se Eradication on DFS Independent Prrognostic Factor Cumulattive Proportion Surviving Disea ase-free 1.0 Nodal Disease Eradicated 0.9 08 0.8 0.7 0.6 Residual Nodal Disease 0.5 0.4 0.3 0.2 P=0 0.00003 00003 0.1 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 Months Annals of Surgery, 1999 SNB Affter NC Multi--Center Stud Multi dies: NSABP BB-27 (n=4 428) • Identification Ratte: 85% • With blue bl dye: d 7 78% • With isotope p + blue b dye: y 88 88--89% • False Negative Rate: R 11% • With blue dye: 14% 1 • With isotope + blue b dye: 8.4% 8 4% Mamounas EP: J Clin Oncol, 2005 SNB Affter NC Meta--Analysis of Single Meta S Single-Institution and MultiMulti-Ce enter Studies • • • • Xi ett all M D Anderson Xing A d 21 studies 1273 patients Identification Rates: 72 72--100% 1 –Pooled estima ate: 90% • False Negative Rates: 0-33% 3 –Pooled estima ate: 12% Conclusion: SNB is a reliable tool for planning treattment after NC SNB After NC: Sing gle Institution Series Positive Axillary y Nodes Before NC Author Stage Shen, 2006 T1 T1--T4, N1N1-N3 Lee, 2006 T1-T4, N1 T1(Palpable (P l bl and d FNA (+) or > 1cm thick with loss of fat hilum on US and SUV > 2.5 Newman, 2007 Resectable T1--3, N1 T1 (FNA (+) under US) All # Pts (No ode +)) Success Rate ( %) FN Rate (%) Accurate 69 9(40) 93 25 No 219 9 (124) 78 6 Yes 40 0 (28) 98 11 Yes 328 8 (172) 84 11.6 ACOSOG G Z1071 SLN surgery aftter neoadjuvant chemotherapy py fo or node p positive breast cancer c PI - Judy C. Boughey B MD Z1071 schema s T1--4 N1T1 N1-2 invasivve breast cancer (Pretreatment axillary ultrasou und with FNA or core biopsy documenting axilllary metastases) REGIST TER* ↓ Patients receive chemotherapy (stratify patients byy age, age stage and number of cycles and tyype of chemotherapy) ↓ REGIST TER* ↓ SLN and d ALND Alternativ Alt tives to t SLN Biopsy B BEFORE Neoad djuvant j Chemottherapy? Initial Nodal Ultrasou und and FNA Biopsy Avoiding Surgiccal SLN Biopsy Krishn namurthy et al, Cancer 2002 Pros and Cons in Timing of SLN Biopsy with Neoa adjuvant Therapy • Presence of axillaryy metastases can be identified with eitherr SLN biopsy or FNA before neoadjuvant therapy • Chemotherapy Ch th can eradicate di t llymph h node metastases in 30 to 40% – Axillary dissection may m be avoided if SLN biopsy p yp performed affter p pre-op p therapy py DCIS S Should Pa atients with DCIS C S be Offered e ed S SLN Biop psy p y? Sentinel Lymph h Node Biopsy Patients With h ‘Pure’ DCIS • • • • European Institute of o Oncology 223 unselected patients with DCIS Metastases in 3.1% %, most micromets C Completion l ti di dissecti tion no additional dditi l mets • Select patients – pa alpable mass ? Diffuse disease ? Intra et al, Arch Surg 2003 SLN Bi Biopsy ffor ‘‘High ‘Hi h Ri Risk’ k’ DCIS • DCIS with microinvasion (N=31) – 10% Positive SLN • ‘High-Risk’ DCIS (N=7 76) – Palpable or mass on M MMG – Extensive high-grade lesions • 12% Positive SLN • Mastectomy = Lose ch hance for later SLN Klauber--DeMore, Klauber D Ann Surg Onc, Onc, 2000 MD Anderson Cancer C Center S l ti U Selective Use off SL LN Bi Biopsy iin DCIS • 399 patients with INITIAL diagnosis of DCIS • 20% of patients will have invasive carcinoma on final pathology – Predictors: CORE Biop psy diagnosis diagnosis, age < 55 55, HG tumors, > 4 cm on MMG M • 10% positive SLN (H a and E in 93% 93%, n = 141) – Highly selected group of o patients Yen et al, Journal Am merican College of Surgeons, 2005 Reoperative Senttinel Node Biopsy after Mas stectomy • Karam et al – JACS 2008 – Recurrence: 20 patients – 65% could find a SLN • Intra et al – J Surg Oncol 2007 – Four patients – 2 had positive SLN Technical Advancement and Advanced Surgical Techniques Beyond SL LN Biopsy? A ill Axillary R Reve erse Mapping M i Thompson et al, Ann Surg Onc 2007 • Can we identify the critical lymphatic pathways for the arm, spare them and d preventt lymphedema? Feasibility and On ncologic Safety of ARM iin B Breast C Cancer P Patients i • Bedrosian et al M D Anderson • • • • • 30 patients documente ed axillary node mets Blue injected in the arm m/Colloid in the breast 70% had blue lymphattic and or node 18% had mets in blue node CONCLUSION: Not sa afe to preserve blue node/lymphatic Cancer 2010 Current Indication ns and Standards for Sentinel Node Biopsy Clinically NEGATIVE E axilla – T1, T1 T2, T2 T3 tumors t • If a SLN is found to be positive: p – Mastectomy: Comp pletion dissection – Breast Conserving w WBT: Individualize • DCIS: High-risk forr Invasive and receiving mastectom my Current Indication ns and Standards for Sentinel Node Biopsy • Neoadjuvant therap py – Before B f or after ft chem h mo; prefer f nodal d l ultrasound with FNA A biopsy – Risks and benefits should s be discussed in detail with patient Meta-Analysis of No Metaon--SN Metastases on Associated with Micrrometastases in the SN in Brea ast Cancer • 25 studies reporting on n nonnon-SN involvement associated with lowlow-vo olume SN involvement (789 pts H&E (+) SNs, 345 pts IHC (+) SNs) • The weighted mean esstimate for non non--SN metastases after lowlow-volume v SN involvement is around 20 % • The incidence is aroun nd 9 % if the SN involvement is detecte ed by IHC alone Cserni G, et al: Br J Surg, 2004 Summ Summ mary • SLN biopsy accurattely predict the presence or absencce of axillary-node axillary node metastases in breasst cancer • SLN bi biopsy iis suitab it b bl tto evaluate ble l t th the axillary lymph node status in patients with clinically node negative breast ca ce cancer