NSABP Neoadjuvant Chemotherapy and Axillary Staging Thomas B. Julian, MD, FACS Professor of Surgery - Drexel University College of Medicine Senior Surgical Director-Medical Affairs - NSABP Director-Breast Surgical Oncology - WPAHS Pittsburgh, PA

NC for Operable Breast Cancer Results from First Generation RCTs No difference in outcome between NC and adjuvant chemotherapy NC increases the rate of lumpectomy NC decreases the rate of axillary positivity Achievement of pCR correlates with improved long-term outcome

Neoadjuvant Chemotherapy Potential Advantages Increase in rate of breast-conserving surgery Ability to correlate tumor response to outcome Potential to correlate biomarker expression and changes in biomarkers with tumor response and outcome

NC for Operable Breast Cancer Continuing Clinical Rationale Evaluation of more effective regimens in order to further reduce the extent of loco-regional therapy: In the breast In the axilla (SNB) Use of primary tumor response as a guide of further loco-regional and systemic therapy

Neoadjuvant Anthracycline/Taxane Trials Pathologic Complete Response (pCR) Sequential A/E Taxane AC – TXT 26% 4CVAP – 4TXT: 31% 4ATXL – 4CMF: 23% 3E – 3TXL: 18% 4AC – 4TXT: 22% 12TXLw – 4FAC: 29% 4TXL -- 4FAC: 14% 4(A+C): 13-14% 8 (CVAP) 15% 6(A+C): 24% Combo A/E + Taxane 4(E+TXL): 10% 4(A+TXT): 12% 6(A+TXT): 21% Bear H: San Antonio, 2001, Gianni L: ASCO, 2002, Untch M: ASCO, 2002 von Minckwitz G, et al. ASCO, 2002 Evans T: ASCO 2004, Green MC: ASCO 2002

NSABP B-18 Neoadjuvant vs Adjuvant AC Operable Breast Cancer Clinical Response: 79% cCR: 36% cPR: 43% pCR: 13% Increase in lumpectomy rate: 68% vs 60% Downstaging of (+) axillary nodes: 58% vs 40% No difference in DFS and S Significant correlation between pCR and outcome Stratification • Age • Clinical Tumor Size • Clinical Nodal Status Operation AC x 4 Operation AC x 4

NSABP B-18 Neoadjuvant vs. Adjuvant AC Operable Breast Cancer Disease-Free Survival Stratification 20 40 60 80 100 2 4 6 8 Year P=0.00005 pINV cPR cNR pCR • Age • Clinical Tumor Size • Clinical Nodal Status Operation AC x 4 AC x 4 Operation Wolmark N: JNCI Monogr, 2001 7

B-18: 16-Year Update DFS OS Rastogi P et al: J Clin Oncol 2008

B-18: Overall Survival by Age N Ev HR P Post 388 167 Pre 381 139 .81 0.06 <50yrs N Ev HR P Post 363 148 Pre 361 171 1.23 0.07 ≥50yrs Qualitative Treatment by Age Interaction p=0.01 Wolmark et al: NCI State of the Science Conference 2007 9

Operable Breast Cancer NSABP B-27 Schema Operable Breast Cancer (2411 pts) Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Docetaxel x 4 Surgery Surgery Docetaxel x 4 10

B-27 Response in the Breast Clinical Response Pathologic Response cCR cPR cNR P < 0.001 No Tumor Non-Invasive 100 40% 80 65% 30 P < 0.001 60 85% 91% % 20 18.7% 40 45% 9.8% 10 25.6% 26% 20 13.7% 14% 6.9% 9% 3.9% AC (1502 pts) AC Docetaxel (687 pts) AC (1,492 pts) AC Docetaxel (718 pts) Bear H, et al: JCO 2003

B-27: 8-Year Update DFS RFS Rfs PW Rastogi P et al: J Clin Oncol 2008

B-27: 8-Year Update Overall Survival Rfs PW Wolmark et al: NCI State of the Science Conference 2007

NSABP B-27 pCR as a Surrogate for Clinical Endpoints No-pCR % Disease-Free Hypothesis: Mixed with good prognosis patients who did not benefit from chemotherapy ?? Why is the curve for no-pCR not steeper? Years after Surgery

NSABP B-27 Gene Expression and Survival Outcome 1.0 Low-risk (n=163) 0.8 High-risk (n=163) 0.6 Probability of Survival 0.4 0.2 0.0 20 40 60 80 100 Time (months) Paik et al: Unpublished data

Low-Risk Patients Have Good Outcome Regardless of pCR 1.0 pCR low-risk (16) 0.8 No-pCR low-risk (147) 0.6 Probability of Survival 0.4 0.2 0.0 20 40 60 80 100 Time (months) Paik et al: Unpublished data

Combination of Prognostic Genes and pCR Defines Residual Risk after Chemotherapy High-Risk & pCR (34) 1.0 Probability of Survival 0.8 0.6 High-risk & no-pCR (125) 0.4 Candidates for post-neoadjuvant chemo trials for targeted therapy 0.2 0.0 20 40 60 80 100 Time (months) Paik et al: Unpublished data

Ki-67 Staining Can be Used to Identify High-Risk Group Among no-pCR Patients Paik S: Unpublished data

NSABP B-45: Concept Under Development Residual Invasive Cancer in Breast or Axillary Nodes Following a Minimum of Six Cycles of NC Triple-Negative, Clinical Stage II or Stage III STRATIFICATION Pathological nodal staging (ypNo or ypN1; ypN2; ypN3) Postoperative radiation (yes; no) Randomization Arm 1 * No adjuvant chemotherapy Arm 2 * Eribulin mesylate 1.4 mg/m2 IV Days 1 and 8 Every 21 days X 4 cycles 19

Combined Analysis of B-18/B-27 Independent Predictors of LRF Lumpectomy + XRT (1890 Pts, 190 Events) Mastectomy (1070 Pts, 128 Events) Age (>50 years vs. <50 years) Clinical Tumor Size (>5 cm vs. <5 cm) Clinical Nodal Status (+) vs. (-) Breast/Nodal Path Status Node(-)/No pCR vs. Node(-)/pCR Node(+) vs. Node(-) /pCR Mamounas et al: ASCO Breast 2010, Abstr. 90

10-Year Cum. Incidence of LRF Lumpectomy Patients, >50 years Clin. Node (-) Clin. Node (+) n=58 n=348 n=212 n=90 n=31

10-Year Cum. Incidence of LRF Lumpectomy Patients, <50 years Clin. Node (-) Clin. Node (+) n=84 n=223 n=376 n=135 n=57

10-Year Cum. Incidence of LRF Mastectomy Patients, < 5 cm Clin. Node (-) Clin. Node (+) n=37 n=183 n=46 n=178 n=21

10-Year Cum. Incidence of LRF Mastectomy Patients, > 5 cm Clin. Node (-) Clin. Node (+) n=179 n=95 n=33 n=16 n=11

Development of a Nomogram to Predict LRF Following Neoadjuvant Chemotherapy Results of multivariate analyses in which age and tumor size were used as continuous variables were similar to those in which age and tumor size were used as discrete variables The independent predictors of LRF were then incorporated into two separate nomograms: Lumpectomy + breast XRT Mastectomy

Nomogram for Prediction of 10-Year Rate of LRF After NC Lumpectomy + XRT 10-Year Probability of LRF Age at Entry (Years)

Nomogram for Prediction of 10-Year Rate of LRF After NC Mastectomy 10-Year Probability of LRF Clinical Tumor Size at Entry (cm)

Summary I In patients with operable breast cancer, the 10-year cum. incidence of LRF after neoadjuvant chemotherapy was 10-12% Despite worse patient characteristics in B-27, LRF with AC in B-27 was lower than in B-18 and there was an effect of docetaxel (about 25% reduction) Overall, the ratio of local vs. regional failure is about 3:1 but this ratio is influenced by type of surgery and other independent predictors of LRF

Summary II Independent predictors of LRF in lumpectomy + breast XRT patients include: age, clinical nodal status (before NC) and pathologic breast/nodal response Independent predictors of LRF in mastectomy patients include: clinical tumor size (before NC), clinical nodal status (before NC) and pathologic breast/nodal response The effect of age (in lumpectomy patients), clinical tumor size (in mastectomy patients) and clinical nodal status on LRF appears to diminish with increasing pathologic response in the breast and axillary nodes

Summary III These independent predictors of LRF after neoadjuvant chemotherapy can be incorporated to separate nomograms for lumpectomy + breast XRT and mastectomy patients to provide guidance on the need for regional XRT after lumpectomy or loco-regional XRT after mastectomy Further development and validation of these nomograms with inclusion of treatment effect is planned

New Directions with Neoadjuvant Chemotherapy NSABP New Directions with Neoadjuvant Chemotherapy Use pCR as a correlate of chemotherapy efficacy to test new drugs and regimens Utilize micro-array technology to identify genomic profiles associated with pCR to specific drugs or combinations Candidates: Sequential anthracycline/taxane combinations New targeted therapies in combination with chemo 31

New Directions with Neoadjuvant Chemotherapy NSABP New Directions with Neoadjuvant Chemotherapy Use pCR as a correlate of chemotherapy efficacy to test new drugs and regimens Utilize micro-array technology to identify genomic profiles associated with pCR to specific drugs or combinations Candidates: Sequential anthracycline/taxane combinations New targeted therapies in combination with chemo 32

Agents Targeting the VEGF Pathway Soluble VEGF receptors (eg, VEGF-Trap) Anti-VEGF antibodies (eg, bevacizumab) VEGF P P Anti-VEGFR antibodies (eg, IMC-1121b) Endothelial cell VEGFR-1 VEGFR-2 Small-molecule VEGFR inhibitors (eg, vatalanib, sunitinib, ZD6474, AZD2171) ANGIOGENESIS Proliferation Survival Migration Manley et al. Expert Opin Investig Drugs. 2002;11:1715. 33

NSABP B-40 R SURGERY +/- X 10 +/- Accrual Completed: 1205 A A A A C C Tissue for Biomarkers Tissue for Biomarkers T T T T A A A A SURGERY C C C C Operable Breast Cancer R T T T T A A A A X X X X +/- C C C C T T T T A A A A G G G G C C C C X 10 B +/- B B B B B B Accrual Completed: 1205

NSABP B-40 Pathologic Complete Response (Breast and Nodes) % pCR (Breast + Nodes) OR = 1.27 Chi-square test: p=0.09

NSABP B-40 Pathologic Complete Response (Breast and Nodes) for HR+ and TN Breast Cancer % pCR (Breast + Nodes) N=349 N=351 OR = 1.59 p=0.033 OR = 1.15 p=0.458 Interaction p value = 0.256

Capecitabine +/- Lapatinib: Time to Progression (Intent-to-Treat) Lapatinib + Capecitabine 0.00016 P-value (log-rank, 1-sided) 69 (43%) 45 (28%) Progressed or died* 19.7 36.9 Median TTP, wk 161 160 No. of pts 0.51 (0.35, 0.74) Hazard ratio (95% CI) % of Patients Progression Free* 100 10 20 30 40 50 60 Time (weeks) 10 20 30 40 50 60 70 80 90 *Censors 4 patients who died due to causes other than breast cancer 70 Geyer et al: N Engl J Med 2006

NSABP B-41: Neoadjuvant Study with Lapatinib vs. Trastuzumab vs. Combo Tissue for Biomarkers Tissue for Biomarkers SURGERY AC  TH Operable Breast Cancer HER-2 neu Positive R Trastuzumab for a total of 1 year AC  TL AC  THL Endpoints: pCR, cardiac events, DFS, OS 38

52 weeks of anti-HER2 therapy NeoALTTO Study Design S U R G E Y A N D O M I Z E lapatinib trastuzumab paclitaxel + 12 wks 6 wks 34 weeks 52 weeks of anti-HER2 therapy lapatinib trastuzumab F EC X 3 Stratification: T ≤ 5 cm vs. T > 5 cm ER or PgR + vs. ER & PgR – N 0-1 vs. N ≥ 2 Conservative surgery or not Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N=450 39

NeoALTTO Efficacy - pCR and tpCR L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response 40

GEPARquinto Trial

Neoadjuvant Therapy Questions in Hormonally Sensitive BC Role of neoadjuvant chemotherapy in certain ER-positive/HER-2 negative breast cancers has been questioned Value of down-staging with neoadjuvant endocrine therapy has been shown Potential for genomic profiling to assign ER-positive patients to neoadjuvant endocrine therapy vs. neoadjuvant chemotherapy Is pCR the most appropriate endpoint for these patients?

Distant Recurrence at 10 Years 21-Gene Recurrence Score Predicts Degree of Benefit from Chemotherapy or Hormonal Therapy 43 Greater hormonal therapy benefit Greater chemotherapy benefit Distant Recurrence at 10 Years Main point: Results of exploratory neoadjuvant studies are consistent with findings from adjuvant studies in terms of predicting likelihood of response to chemotherapy and endocrine therapy. Endocrine therapy benefit: the lower the RS, the greater the benefit of endocrine therapy. Chemotherapy benefit: the higher the RS, the greater the benefit of chemotherapy. Paik S, et al. N Engl J Med. 2004;351:2817. Paik S, et al. J Clin Oncol. 2006;24:3726. Gianni L, et al. J Clin Oncol. 2005;23:7265. Chang JC, et al. Breast Cancer Res Treat. 2008;108 (2):233. Dotted lines represent 95% CI Recurrence Score Paik S, et al. N Engl J Med. 2004;351:2817. Paik S, et al. J Clin Oncol. 2006;24:3726. Gianni L, et al. J Clin Oncol. 2005;23(29):7265-7277. Chang JC, et al. Breast Cancer Res Treat. 2008;108 (2):233-240. Akashi-Tanaka S et al. Breast. 2009 Jun:171-174 43 43

Neoadjuvant Trial Proposal for HR+ BC HR+/Her-2 Neg. Breast Cancer Needing Neo Rx to Achieve BCT Core BX for 21-Gene RS < 11 11-25 > 25 Neoadjuvant Hormonal Tx Randomize Neoadjuvant Chemotherapy Neoadjuvant Hormonal Tx Neoadjuvant Chemotherapy SURGERY Endpoints: Clinical Response, BCT, RCB, pCR

Axillary Node Surgery After Neoadjuvant Chemotherapy Assuming clinical nodal exam, MRI and/or axillary US pre-treatment are negative, what axillary node staging recommended? Axillary node dissection? Sentinel node biopsy? Before NCT? After NCT?

What if ?-- MRI Prior to Neoadjuvant Therapy Axillary nodes largest 2.1 x 2.3 x 3.5 cm Positive for cancer on US-guided biopsy

Role for Sentinel Lymph Node Biopsy in Patients Receiving NCT? NCCN and ASCO guidelines: NCT is a contraindication to use of SLN biopsy Many advocate SLN biopsy prior to NCT What are potential advantages and pitfalls to SLN biopsy AFTER NCT?

Axillary Node Down-Staging with NCT More than 40% of initially node-positive women could potentially avoid ALND! 50 40 30 20 10 % Conversion From Node (+) To Node (-) 43 37 30 19 AC NSABP B-18 FEC EORTC AT→CMF ECTO AC→TXT NSABP B-27* *Assuming 30% nodal down-staging with neoadjuvant AC

Arguments Against SLN Biopsy After NCT SLN mapping after NCT may fail and/or may not be accurate (i.e, high false negative rate) (Failure to map is really NOT an issue – if can’t find SLN, then do ALND, which is what SLN opponents recommend in the first place)

False negative rate = 10.7% (15/140) Pathologic Status of Sentinel Nodes and Non-Sentinel Nodes (N=343) - NSABP B-27 Identification Rate: 85% (343/428) Sentinel Node(s) Positive 125 pts Negative 218 pts Non-Sentinel Node(s) Negative 70 pts Positive 55 pts Negative 203 pts Positive 15 pts False negative rate = 10.7% (15/140) No significant difference between clinically node negative (12.4%) vs. node positive (7.0%) Mamounas et al JCO, 2005

Comparison of False Negative Rates Between SN Multicenter Studies Study FNR (SN-/N+) Multicenter SB-2 Trial 11% (13/114) Italian Randomized Trial 9% (8/91) Ann Arundel 13% (25/193) University of Louisville 7% (24/333) NSABP B-32 Randomized Trial 10% (75/766) NSABP B-27 (After NC) 11% (15/140) Meta-Analysis (Xing, 2006) 12% (65/540) Meta-Analysis (Kelly, 2009) 8% (~64/758) Krag DN: N Engl J Med 1998 Veronesi U: N Engl J Med 2003 McMasters KM: J Clin Oncol 2000 Mamounas EP: J Clin Oncol 2005 Tafra L: Am J Surg 2001 Xing Y:Br J Surg 2005 Julian JB: SABCS 2004. Kelly, AM: Acad Radiol, 2009

FALSE NEGATIVE RATES (%) M.D. Anderson Comparison of SLN After Chemotherapy to Primary Surgical Patients Clinically node negative: Negative on PE and US GROUP FALSE NEGATIVE RATES (%) Planned SLN + ALND Overall After 2000 Surgery 1st (n = 542) 4.1 2.7 Chemo 1st (n = 84) 5.9 (p = 0.39) 5.5 K. Hunt et al, Ann. Surg, 2009

Axillary Dissections (%) Regional Recurrence Rates (%) M.D. Anderson Comparison of SLN After Chemotherapy to Primary Surgical Patients GROUP Axillary Dissections (%) Regional Recurrence Rates (%) T2 T3 Surgery 1st (n = 3171) 40.6 65.7 0.9 Chemo 1st (n=575) 27.1 (p < 0.001) 45.1 (p<0.045) 1.2 K. Hunt et al, Ann.Surg,, 2009

Arguments Against SLN Biopsy After NCT Loss of important prognostic information derived from pre-chemo nodal pathology (Leads to recommendation to do SLN prior to treatment)

(without pCR in Breast - 1881) B-27 DFS By Nodes (without pCR in Breast - 1881) 1-3 4-9 10+ #N % 0 47 1-3 32 4-9 16 10+ 5

SLN Biopsy After Neoadjuvant Chemotherapy – Do We Lose Prognostic Information? Post-treatment nodal status is at least as powerful as pre-treatment nodes In fact, by possibly removing the only positive nodes with SLNB prior to treatment, we lose even more important information

SLN Before Neoadjuvant Chemotherapy Two Major Disadvantages for patients with positive nodes at diagnosis: Two separate axillary surgical procedures Many women (~ 40%) will undergo unnecessary ALND

Eradication of LN Metastases with Chemotherapy + Trastuzumab 109 consecutive patients with HER-2+ BC and biopsy-proven LN metastases NCT + trastuzumab All had complete ALND at surgery 81 (74%) had all negative nodes Dominici, et al., MDACC, SABCS 2009, Abstract # 1086

Caveat – Potentially High FN Rate for Node-Positive Patients 69 patients with biopsy- proven axillary LN metastases – 25% FNR (N2 & N3 included) 47 patients with clinical N1-N2 disease – 30% FNR J. Shen et al., Cancer, 2007 P. Gimbergues et al., ASO, 2008

ACOSOG Z1071 Schema Accuracy of SLN After NCT in Node Positive Breast Cancer T1-4, N1-2 invasive breast cancer (pretreatment axillary ultrasound with FNA or core biopsy documenting axillary metastases) REGISTER* Patients receive neoadjuvant chemotherapy (stratify patients by age, stage and number of cycles and type of chemotherapy) SLN and ALND *Patients can be registered pre or post chemotherapy

ASBD Consensus Statement on SLN in NCT Patients - 2010 Clinically node negative initially - SLN acceptable before or after NCT Factor in impact of initial node status on treatment Clinically node positive initially – Pathologic confirmation recommended Z1071 results pending ALND “standard of care” at definitive surgery

Summary In pts with operable BC, NC results in equivalent outcomes to those achieved with adjuvant chemotherapy but has several potential advantages Information on outcome based on response to NC can be obtained on an individualized basis Loco-regional therapy can be tailored based on tumor response in the breast and axillary nodes This approach holds great promise as NC regimens with targeted biologics become considerably more effective and as genomic and imaging technology allows for more accurate prediction and identification of pathologic complete responders