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Neo-adjuvant Chemotherapy for Breast Cancer Shiuh-Wen Luoh MD PhD Portland VA Medical Center Oregon Health Sciences University Slide 2 Neoadjuvant Treatment of Primary BC Improve Surgical Options Obtain Information on Response Obtain Long Term Disease Free Control JCO Vol 24, pp 1940-, 2006. Slide 3 Neoadjuvant Treatment of Primary BC An increase in the pCR rate as the result of a Superior Treatment has not been proven to consistently translate into an Improved Long Term Outcome. Caution on Future Trial Design! JCO Vol 24, pp 1940-, 2006. Slide 4 Recurrence Score in Predicting Response to Chemotherapy Recurrence Score (RS) from Genomic Health -- L Gianni JCO 23:7265-, 2005Pre-OP AP/P -- S Paik JCO 24:3726-,2006Adjuvant CMF -- J Chang ASCO 2006, abs # 538Pre-OP Taxotere Third is the charm for RS? Publication Bias? ASCO 2006, Abs # 538 Slide 5 Slide 6 Slide 7 Annals of Surgery Vol. 243, pp 257-, 2006. Predicting Residual Tumor Size is Difficult! M D Anderson Experience Slide 8 Slide 9 Slide 10 Slide 11 Slide 12 Slide 13 Factors associated with a significantly higher breast-conserving surgery rate: pre-chemotherapy tumor size 10 enrolled patients). doxorubicin 50 mg/m2 plus docetaxel 75 mg/m2 each on day 1 every 14 days for 4 cycles with granulocyte colony-stimulating factor support (ADOC) versus doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every 21 days followed by docetaxel 100 mg/m2 every 21 days for 4 cycles (AC-DOC). Slide 14 Slide 15 Slide 16 Slide 17 Slide 18 Slide 19 Slide 20 Slide 21 Slide 22 Slide 23 Slide 24 Cancer 2006; 107:145966. Neo!Adjuvant Slide 25 Slide 26 A total of 143 neoadjuvant and 170 surgery-first patients were studied. Patients treated with neoadjuvant chemotherapy were significantly more likely to have fewer than 10 lymph nodes retrieved at ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%, P=003). Slide 27 Cancer 2002;95:68195. Slide 28 Neoadjuvant versus Adjuvant- A Meta-analysis JNCI Vol 97, pp 188-, 2005. Slide 29 Neoadjuvant versus Adjuvant- A Meta-analysis JNCI Vol 97, pp 188-, 2005. Slide 30 Neoadjuvant versus Adjuvant- A Meta-analysis Equivalent in Survival and Overall Disease Progression. Statistically Significant Increased Risk of Loco-Regional Relapse if RT without Surgery. Trend Towards Increased Local Recurrence in B18! (Multi-centric or Multi-focal Disease) JNCI Vol 97, pp 188-, 2005. Slide 31 Breast Cancer Vol. 13 No. 3. 2006 Slide 32 Evolving Role of Surgery and Radiationin the Pre-operative Systemic Therapy Setting- Morrow, Giuliano, Harris Expert Opinions Ultrasound and FNA before Neoadjuvant therapy to assess Axillary LN status FNA (+)-- Axillary Clearance after Chemotherapy Pitfalls: 10-20% Error rate even in Best Hands Dr. Morrow Recommends Sentinel Mapping pre-Chemo. Radiation Planning based on pre-treatment tumor features. ASCO 2006 Ticketed Session Slide 33 Evolving Role of Surgery and Radiation in the Pre-operative Systemic Therapy Setting- Morrow, Giuliano, Harris Surgical Options if Residual Tumor Present--- Dr. Morrow Recommends: If Uni-focal tumor found with Negative Margin: Minimal Margin of 2 mm. If Multi-focal tumor found with Negative Margin: Further Surgery to Achieve as Wide Margin as Possible. ASCO 2006 Ticketed Session Slide 34 Slide 35 Slide 36 Sentinel Node Mapping post Neo-adjuvant Chemo -NSABP B-27 Experience ID rate: 85%; False (-): 10.7%; Only Node (+): 56%. JCO Vol. 23, pp 2694-, 2005. Slide 37 Slide 38 Neoadjuvant Treatment of Primary BC An increase in the pCR rate as the result of a Superior Treatment has not been proven to consistently translate into an Improved Long Term Outcome. Caution on Future Trial Design! JCO Vol 24, pp 1940-, 2006. Slide 39 Nodal Status post Neo-adjuvant Chemo is a Powerful Prognostic Factor - NSABP B-27 Experience JCO Vol. 24, pp 2019-, 2006. Slide 40 Pathologic CR (pCR) post Neo-adjuvant Chemo is a Powerful Prognostic Factor - NSABP B-27 Experience JCO Vol. 24, pp 2019-, 2006. Slide 41 Residual Cancer Burden (RCB) Measurement of Primary Tumor (size and cellularity) and Nodal Met (Number and Size) RCB-0 (pCR) to RCB-3 Prognosis: RCB-0 = RCB-1 > RCB-2 > RCB-3 ASCO 2006 Abs 536. Slide 42 In vivo Sensitivity Directed Neoadjuvant Therapy -The Aberdeen Trial Locally Advanced or Large Primary (> 3 cM). 162 Patients Completed 4 Cycles of CVAP 52 Responders to get 4 More Cycles of CVAP (Group 1), 52 Responders to get 4 Cycles of Taxetere (Group 2), 55 Non-Responders to get 4 Cycles of Taxotere (Group 3). pCR: 16% (Gr 1); 34% (Gr 2); 2% (Gr 3). Improved BCS and 3 year Survival for Group 2. JCO Vol 20, pp 1456-, 2002. Slide 43 In vivo Sensitivity Directed Neoadjuvant Therapy - The Gepartrio Trial TAC x2 to Select for Responders- >50% Size Reduction Responders to Complete TAC x6. Non-responders randomized to TAX x4 or NX x4. pCR in Responders after TAC x6: 22.6%; pCR in Non-responders after TAC x6:7.3%; pCR in Non-responders after NX x4:3.1%. More Effective Treatments Needed for Non-responders Annals Oncology Vol 16, pp 56-, 2005. Slide 44 In vivo Sensitivity Directed Adjuvant Therapy - The M.D. Anderson Experience JCO Vol 22, pp 2294-, 2004. Slide 45 In vivo Sensitivity Directed Adjuvant Therapy - The M.D. Anderson Experience JCO Vol 22, pp 2294-, 2004. Slide 46 In vivo Sensitivity Directed Adjuvant Therapy - The M.D. Anderson Experience JCO Vol 22, pp 2294-, 2004. What to do When There is Residual Disease? Slide 47 JCO Vol 24, pp 1940-, 2006. Neo-adjuvant Chemotherapy Negative Receptor Status Predicts Higher pCR Slide 48 ILC Patients: 122 (12%) vs IDC Patients: 912 (88%). Invasive Lobular Carcinoma (vs Ductal) Older (53 y vs 47 y); More HR (+) (92% vs 62%); Lower Nuclear Grade and Higher Stage at Diagnosis. Less Likely to have pCR (3% vs 15%). Less Breast Conservation Surgery (16% vs 29%). Longer Recurrence Free and Overall Survival!!! JCO Vol. 23, pp 41-, 2005. Slide 49 Invasive Lobular Carcinoma and Response to Neo-adjuvant Chemotherapy Single Institution 1990-2002. Pure ILC (n=118, 14%), Pure IDC (n=742, 86%). Lobular Histology- Older (53 y vs 49.6 y); Lower Grade; Larger Primary (T3: 38.1% vs 21.4%); More N0; More HR(+) (89% vs 60%). Mastectomy Rate: 70% (ILC) vs 52% (IDC). pCR: 1% (ILC) vs 9% (IDC). DFS at 60 month: 76.5% (ILC) vs 60.8% (IDC). OS at 60 month: 91.7% (ILC) vs 79.3% (IDC). Slide 50 Slide 51 Slide 52 Slide 53 Slide 54 Slide 55 JCO Vol 24, pp 1940-, 2006. Neo-adjuvant Endocrine Therapy Trials Slide 56 Neoadjuvant Treatment of Primary BC Candidate Selections as in Adjuvant Therapy -Avoid Over-treating. Endocrine Tx. for menopausal women unfit for chemo. Low pCR (1-8%) with Endocrine Tx. Higher pCR with HR(-) than HR(+). A Trial shows Endocrine and chemo comparable. Optimal Regimen or Duration not Established. -- 3-4 Month of Endocrine Tx. or 4 Cycles of Chemo. Sentinel Node Mapping after Tx. Might be Reasonable. Marker Studies pre- and post- Tx. JCO Vol 24, pp 1940-, 2006. Slide 57 SWOG 0012 Locally Advanced and Inflammatory Breast Cancer A60C600 q3w x 5 cycles vs. A24qw+ oral C60qd +G x 15w Followed by Taxol 80 qw x 12w. 372 Patients Enrolled, 265 evaluable. All Received MRM. FN: 1.8% and 0.6%. No Grade V Toxicity. More Hand Foot and Stomatitis with Continuous Chemo. pCR plus N0 is 26% versus 13% P=0.02. Highest PCR rate reported for LABC and IBC. SWOG 0221 is companion Adjuvant Trial S0012 and S0221 both closed due to poor accrual. ASCO 2006 LBA #537 Slide 58 Slide 59 Neo-adjuvant Dose Dense AC-Taxol A60C600 X 4cycles q2W followed by Taxol175 (N=34) or Taxotere90-100 (N=8) q2W. 42 Patients (6IIA, 12IIB, 10IIIA, 5IIIB, 9IIIC). Grade III 19, ER(+) 18, HER-2(+) 8, Clinically N(+) 26. cCR plus cPR > 95%. pCR 33%(14/42) -- pCR 52.4% (HR-) versus 17.6% (HR+). Dose Dense AC-Taxol Safe, Efficient and High pCR Rate. SABC 2005 Abst #5062. Slide 60 Docetaxel/Xeloda versus Adria/Cytoxan Neo-adjuvant Chemo for Stage II/III BC Mature Result from a Randomized Phase III Trial. Positive Axillary Nodes by PET or FNA. A60C600 q3W X4 versus D75X(1000bid d1-14) q3W X4. 209 Patients (Aug 02-April 05). Primary Tumor pCR DX (23%) versus AC (8%) p=0.0059. More Hand-Foot Syndrome, Skin Mucositis with DX. SABC 2005 Abst #5052. Slide 61 Breast Cancer Vol. 13 No. 3. 2006