Neo-adjuvant Chemotherapy
for Breast Cancer
Shiuh-Wen Luoh MD PhD
Portland VA Medical Center
Oregon Health Sciences University
Neoadjuvant Treatment of Primary BC
Improve Surgical Options
Obtain Information on Response
Obtain Long Term Disease Free Control
JCO Vol 24, pp 1940-, 2006.
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.
Recurrence Score in Predicting Response to Chemotherapy
Recurrence Score (RS) from Genomic Health
-- L Gianni
JCO 23:7265-, 2005
Pre-OP AP/P
-- S Paik
JCO 24:3726-,2006
Adjuvant CMF
-- J Chang
ASCO 2006, abs # 538
Pre-OP Taxotere
Third is the charm for RS?
Publication Bias?
ASCO 2006, Abs # 538
Predicting Residual Tumor Size is Difficult!
M D Anderson Experience
Annals of Surgery Vol. 243, pp 257- , 2006.
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).
Factors associated with a significantly higher breast-conserving surgery rate:
pre-chemotherapy tumor size < 40 mm, non-lobular histological
characteristics, treatment with AC-DOC, clinical response, postchemotherapy tumor size < 20 mm, and treatment in a larger center (>10
enrolled patients).
Neo!Adjuvant
Cancer 2006; 107:1459–66.
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).
Cancer 2002;95:681–95.
Neoadjuvant versus Adjuvant - A Meta-analysis
JNCI Vol 97, pp 188-, 2005.
Neoadjuvant versus Adjuvant - A Meta-analysis
JNCI Vol 97, pp 188-, 2005.
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.
Breast Cancer Vol. 13 No. 3. 2006
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
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
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.
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.
Nodal Status post Neo-adjuvant Chemo is a
Powerful Prognostic Factor
- NSABP B-27 Experience
JCO Vol. 24, pp 2019- , 2006.
Pathologic CR (pCR) post Neo-adjuvant Chemo
is a Powerful Prognostic Factor
- NSABP B-27 Experience
JCO Vol. 24, pp 2019- , 2006.
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.
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.
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.
In vivo Sensitivity Directed Adjuvant Therapy The M.D. Anderson Experience
JCO Vol 22, pp 2294- , 2004.
In vivo Sensitivity Directed Adjuvant Therapy The M.D. Anderson Experience
JCO Vol 22, pp 2294- , 2004.
In vivo Sensitivity Directed Adjuvant Therapy The M.D. Anderson Experience
“What to do When
There is Residual
Disease?”
JCO Vol 22, pp 2294- , 2004.
Neo-adjuvant Chemotherapy
Negative Receptor Status Predicts Higher pCR
JCO Vol 24, pp 1940-, 2006.
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.
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).
Neo-adjuvant Endocrine Therapy Trials
JCO Vol 24, pp 1940-, 2006.
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.
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
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.
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.
Breast Cancer Vol. 13 No. 3. 2006