Neo-adjuvant Chemotherapy for Breast Cancer

Neo-adjuvant Chemotherapy for Breast Cancer

Shiuh-Wen Luoh MD PhDPortland VA Medical Center

Oregon Health Sciences University

Neoadjuvant Treatment of Primary BCNeoadjuvant Treatment of Primary BC

Improve Surgical OptionsImprove Surgical Options

Obtain Information on ResponseObtain Information on Response

Obtain Long Term Disease Free ControlObtain Long Term Disease Free Control

JCO Vol 24, pp 1940-, 2006.JCO Vol 24, pp 1940-, 2006.


An increase in the pCR rate as the result of a An increase in the pCR rate as the result of a Superior Treatment has not been proven to Superior Treatment has not been proven to

consistentlyconsistently translate into an Improved Long translate into an Improved Long Term Outcome.Term Outcome.

Caution on Future Trial Design!Caution on Future Trial Design!


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

Annals of Surgery Vol. 243, pp 257- , 2006.Annals of Surgery Vol. 243, pp 257- , 2006.

Predicting Residual Tumor Size is Difficult!Predicting Residual Tumor Size is Difficult!

M D Anderson ExperienceM D Anderson Experience

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, post-chemotherapy tumor size < 20 mm, and treatment in a larger center (>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) versusdoxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1 every21 days followed by docetaxel 100 mg/m2 every 21 days for 4 cycles (AC-DOC).

Cancer 2006; 107:1459–66.

Neo!Adjuvant

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 AdjuvantNeoadjuvant versus Adjuvant - A Meta-analysis- A Meta-analysis

JNCI Vol 97, pp 188-, 2005.JNCI Vol 97, pp 188-, 2005.




Equivalent in Survival and Overall Disease Progression.Equivalent in Survival and Overall Disease Progression.

Statistically Significant Increased Risk of Loco-Regional Statistically Significant Increased Risk of Loco-Regional Relapse if RT without Surgery.Relapse if RT without Surgery.

““Trend Towards Increased Local Recurrence in B18!”Trend Towards Increased Local Recurrence in B18!”

(Multi-centric or Multi-focal Disease)(Multi-centric or Multi-focal Disease)


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 ChemoSentinel Node Mapping post Neo-adjuvant Chemo

-NSABP B-27 ExperienceNSABP B-27 ExperienceID rate: 85%; False (-): 10.7%; Only Node (+): 56%.ID rate: 85%; False (-): 10.7%; Only Node (+): 56%.

JCO Vol. 23, pp 2694- , 2005.JCO Vol. 23, pp 2694- , 2005.


An increase in the pCR rate as the result of a An increase in the pCR rate as the result of a Superior Treatment has not been proven to Superior Treatment has not been proven to

consistentlyconsistently translate into an Improved Long translate into an Improved Long Term Outcome.Term Outcome.

Caution on Future Trial Design!Caution on Future Trial Design!


Nodal Status post Neo-adjuvant Chemo is a Nodal Status post Neo-adjuvant Chemo is a Powerful Prognostic FactorPowerful Prognostic Factor

- NSABP B-27 Experience- NSABP B-27 Experience


Pathologic CR (pCR) post Neo-adjuvant Chemo Pathologic CR (pCR) post Neo-adjuvant Chemo is a Powerful Prognostic Factoris a Powerful Prognostic Factor

- NSABP B-27 Experience- NSABP B-27 Experience


Residual Cancer Burden (RCB)Residual Cancer Burden (RCB)

Measurement of Primary Tumor (size and Measurement of Primary Tumor (size and cellularity) and Nodal Met (Number and Size)cellularity) and Nodal Met (Number and Size)

RCB-0 (pCR) to RCB-3RCB-0 (pCR) to RCB-3

Prognosis: RCB-0 = RCB-1 > RCB-2 > RCB-3Prognosis: RCB-0 = RCB-1 > RCB-2 > RCB-3

ASCO 2006 Abs 536.ASCO 2006 Abs 536.

In vivo Sensitivity Directed Neoadjuvant Therapy In vivo Sensitivity Directed Neoadjuvant Therapy -The Aberdeen Trial-The Aberdeen Trial

Locally Advanced or Large Primary (> 3 cM).Locally Advanced or Large Primary (> 3 cM).

162 Patients Completed 4 Cycles of CVAP162 Patients Completed 4 Cycles of CVAP

52 Responders to get 4 More Cycles of CVAP (Group 1),52 Responders to get 4 More Cycles of CVAP (Group 1),

52 Responders to get 4 Cycles of Taxetere (Group 2),52 Responders to get 4 Cycles of Taxetere (Group 2),

55 Non-Responders to get 4 Cycles of Taxotere (Group 3).55 Non-Responders to get 4 Cycles of Taxotere (Group 3).

pCR: 16% (Gr 1); 34% (Gr 2); 2% (Gr 3).pCR: 16% (Gr 1); 34% (Gr 2); 2% (Gr 3).

Improved BCS and 3 year Survival for Group 2.Improved BCS and 3 year Survival for Group 2.


In vivo Sensitivity Directed Neoadjuvant Therapy In vivo Sensitivity Directed Neoadjuvant Therapy - The Gepartrio Trial- The Gepartrio Trial

TAC x2 to Select for Responders- >50% Size ReductionTAC x2 to Select for Responders- >50% Size Reduction

Responders to Complete TAC x6.Responders to Complete TAC x6.

Non-responders randomized to TAX x4 or NX x4.Non-responders randomized to TAX x4 or NX x4.

pCR in Responders after TAC x6: pCR in Responders after TAC x6: 22.6%;22.6%;

pCR in Non-responders after TAC x6:pCR in Non-responders after TAC x6: 7.3%;7.3%;

pCR in Non-responders after NX x4:pCR in Non-responders after NX x4: 3.1%.3.1%.

More Effective Treatments Needed for Non-respondersMore Effective Treatments Needed for Non-responders

Annals Oncology Vol 16, pp 56- , 2005.Annals Oncology Vol 16, pp 56- , 2005.

In vivo Sensitivity Directed Adjuvant Therapy - In vivo Sensitivity Directed Adjuvant Therapy - The M.D. Anderson ExperienceThe M.D. Anderson Experience

JCO Vol 22, pp 2294- , 2004.JCO Vol 22, pp 2294- , 2004.





““What to do When What to do When There is Residual There is Residual Disease?”Disease?”


Neo-adjuvant Chemotherapy

Negative Receptor Status Predicts Higher pCR

ILC Patients: 122 (12%) vs IDC Patients: 912 (88%).ILC Patients: 122 (12%) vs IDC Patients: 912 (88%).

Invasive Lobular Carcinoma (vs Ductal)Invasive Lobular Carcinoma (vs Ductal)

Older (53 y vs 47 y); More HR (+) (92% vs 62%); Older (53 y vs 47 y); More HR (+) (92% vs 62%); Lower Nuclear Grade and Higher Stage at Diagnosis.Lower Nuclear Grade and Higher Stage at Diagnosis.

Less Likely to have pCR (3% vs 15%).Less Likely to have pCR (3% vs 15%).

Less Breast Conservation Surgery (16% vs 29%).Less Breast Conservation Surgery (16% vs 29%).

Longer Recurrence Free and Overall Survival!!!Longer Recurrence Free and Overall Survival!!!


Invasive Lobular Carcinoma and Response to Invasive Lobular Carcinoma and Response to Neo-adjuvant ChemotherapyNeo-adjuvant Chemotherapy

Single Institution 1990-2002.Single Institution 1990-2002.

Pure ILC (n=118, 14%), Pure IDC (n=742, 86%).Pure ILC (n=118, 14%), Pure IDC (n=742, 86%).

Lobular Histology- Older (53 y vs 49.6 y); Lower Grade;Lobular Histology- Older (53 y vs 49.6 y); Lower Grade;Larger Primary (T3: 38.1% vs 21.4%); More N0;Larger Primary (T3: 38.1% vs 21.4%); More N0;More HR(+) (89% vs 60%). More HR(+) (89% vs 60%).

Mastectomy Rate: 70% (ILC) vs 52% (IDC).Mastectomy Rate: 70% (ILC) vs 52% (IDC).

pCR: 1% (ILC) vs 9% (IDC).pCR: 1% (ILC) vs 9% (IDC).

DFS at 60 month: 76.5% (ILC) vs 60.8% (IDC).DFS at 60 month: 76.5% (ILC) vs 60.8% (IDC).

OS at 60 month: 91.7% (ILC) vs 79.3% (IDC).OS at 60 month: 91.7% (ILC) vs 79.3% (IDC).


Neo-adjuvant Endocrine Therapy Trials

Neoadjuvant Treatment of Primary BCNeoadjuvant Treatment of Primary BCCandidate Selections as in Adjuvant TherapyCandidate Selections as in Adjuvant Therapy

-Avoid Over-treating.-Avoid Over-treating.Endocrine Tx. for menopausal women unfit for chemo.Endocrine Tx. for menopausal women unfit for chemo.Low pCR (1-8%) with Endocrine Tx.Low pCR (1-8%) with Endocrine Tx.Higher pCR with HR(-) than HR(+).Higher pCR with HR(-) than HR(+).A Trial shows Endocrine and chemo comparable.A Trial shows Endocrine and chemo comparable.Optimal Regimen or Duration not Established.Optimal Regimen or Duration not Established.-- 3-4 Month of Endocrine Tx. or 4 Cycles of Chemo.-- 3-4 Month of Endocrine Tx. or 4 Cycles of Chemo.Sentinel Node Mapping after Tx. Might be Reasonable.Sentinel Node Mapping after Tx. Might be Reasonable.Marker Studies pre- and post- Tx.Marker Studies pre- and post- Tx.


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 Neo-adjuvant Dose Dense AC-Taxol

A60C600 X 4cycles q2W followed byA60C600 X 4cycles q2W followed byTaxol175 (N=34) or Taxotere90-100 (N=8) q2W.Taxol175 (N=34) or Taxotere90-100 (N=8) q2W.

42 Patients (6IIA, 12IIB, 10IIIA, 5IIIB, 9IIIC).42 Patients (6IIA, 12IIB, 10IIIA, 5IIIB, 9IIIC).

Grade III 19, ER(+) 18, HER-2(+) 8, Clinically N(+) 26.Grade III 19, ER(+) 18, HER-2(+) 8, Clinically N(+) 26.

cCR plus cPR > 95%.cCR plus cPR > 95%.

pCR 33%(14/42) -- pCR 52.4% (HR-) versus 17.6% (HR+).pCR 33%(14/42) -- pCR 52.4% (HR-) versus 17.6% (HR+).

Dose Dense AC-Taxol Safe, Efficient and High pCR Rate. Dose Dense AC-Taxol Safe, Efficient and High pCR Rate.

SABC 2005 Abst #5062.SABC 2005 Abst #5062.

Docetaxel/Xeloda versus Adria/Cytoxan Docetaxel/Xeloda versus Adria/Cytoxan

Neo-adjuvant Chemo for Stage II/III BCNeo-adjuvant Chemo for Stage II/III BCMature Result from a Randomized Phase III Trial.Mature Result from a Randomized Phase III Trial.

Positive Axillary Nodes by PET or FNA.Positive Axillary Nodes by PET or FNA.

A60C600 q3W X4 versus D75X(1000bid d1-14) q3W X4.A60C600 q3W X4 versus D75X(1000bid d1-14) q3W X4.

209 Patients (Aug 02-April 05).209 Patients (Aug 02-April 05).

Primary Tumor pCR DX (23%) versus AC (8%) p=0.0059.Primary Tumor pCR DX (23%) versus AC (8%) p=0.0059.

More Hand-Foot Syndrome, Skin ∆ Mucositis with DX .More Hand-Foot Syndrome, Skin ∆ Mucositis with DX .

SABC 2005 Abst #5052.SABC 2005 Abst #5052.

Breast Cancer Vol. 13 No. 3. 2006

Neo-adjuvant Chemotherapy for Breast Cancer

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