Neoadjuvant Neoadjuvant SystemicTreatment Strategies SystemicTreatment Strategies

for Breast Cancerfor Breast Cancer

Donald W. Northfelt, MD, FACPDonald W. Northfelt, MD, FACPProfessor of MedicineProfessor of Medicine

Mayo Clinic College of MedicineMayo Clinic College of Medicine

Associate Medical Director, Breast ClinicAssociate Medical Director, Breast Clinic

Mayo Clinic ArizonaMayo Clinic Arizona

northfelt.donald@mayo.edunorthfelt.donald@mayo.edu

DISCLOSURESDISCLOSURES

• no conflicts of interestno conflicts of interest

• no off-label uses discussedno off-label uses discussed

Historical Treatment Paradigm for Historical Treatment Paradigm for Breast CancerBreast Cancer

• Radical surgeryRadical surgery

• Radical surgery + post-operative systemic Radical surgery + post-operative systemic therapy (improve long term disease free therapy (improve long term disease free survival)survival)

• Limited surgery +/- radiotherapy + post-Limited surgery +/- radiotherapy + post-operative systemic therapyoperative systemic therapy

• Pre-operative systemic therapy to facilitate Pre-operative systemic therapy to facilitate even more limited even more limited surgerysurgery

• Curative systemic therapyCurative systemic therapy

Rationale for Neoadjuvant Rationale for Neoadjuvant Systemic TherapySystemic Therapy

• to improve surgical optionsto improve surgical options

• to determine the response to NST (and to determine the response to NST (and abandon ineffective therapy?)abandon ineffective therapy?)

• to obtain long-term disease-free survivalto obtain long-term disease-free survival

(conventional post-operative adjuvant (conventional post-operative adjuvant therapy addresses only the third objective)therapy addresses only the third objective)

Kauffman, et al. J Clin Oncol 2006;24:1940-1949.

NSABP B-18 SchemaNSABP B-18 Schema

Operable breast cancer

Randomization

AC x 4

surgery

surgery

AC x 4

Tam x 5 Yrs

NSABP B-27 SchemaNSABP B-27 Schema

Rastogi P, et al.Rastogi P, et al. J Clin Oncol J Clin Oncol 2008;26:778-785.2008;26:778-785.

Rastogi P, et al.Rastogi P, et al. J Clin Oncol J Clin Oncol 2008;26:778-785.2008;26:778-785.

Rastogi P, et al.Rastogi P, et al. J Clin Oncol J Clin Oncol 2008;26:778-785.2008;26:778-785.

Bear HD, et al.Bear HD, et al. J Clin Oncol J Clin Oncol 2003;21: 4165-4174 2003;21: 4165-4174

pCR Rate Per Treatment in NSABP B-27pCR Rate Per Treatment in NSABP B-27

Rastogi P, et al.Rastogi P, et al. J Clin Oncol J Clin Oncol 2008;26:778-785.2008;26:778-785.

Survival Better If pCR AchievedSurvival Better If pCR Achieved

B-18 (neoadjuvant AC)B-18 (neoadjuvant AC) B-27 (all patients)B-27 (all patients)

Rastogi P, et al.Rastogi P, et al. J Clin Oncol J Clin Oncol 2008;26:778-785.2008;26:778-785.

Trend Toward ImprovedTrend Toward ImprovedSurvival with NST - B18Survival with NST - B18

B-18 (neoadjuvant AC)B-18 (neoadjuvant AC)

age < 50:

DFSHR 0.85 P = .09

OSHR 0.81P = .06

HER2 + Breast CancerHER2 + Breast CancerNeoadjuvant Systemic TherapyNeoadjuvant Systemic Therapy

HER2+ Breast Cancer NST

de Azambuja E et al. Lancet Oncology 2014;15:1132-1146

Neo-ALTTOComplete Pathologic Response

Proportions

NeoSphere Study Schema

TH q 3w x 4(n = 107)

Surgery

THP q 3w x 4(n = 107)

HP q 3w x 4(n = 107)

TP q 3w x 4(n = 96)

H q 3w x 13+

FEC q 3w x 3

H q 3w x 13+

FEC q 3w x 3

H q 3w x 17+

FEC q 3w x 3

H q 3w x 13+

T q3w x 4

FEC q 3w x 3

T = Docetaxel, H = Trastuzumab, P = PertuzumabF = 5-fluorouracil, E = Epirubicin, C = Cyclophosphamide

SurgerySurgerySurgery

R

Gianni L et al. Proc SABCS 2010;Abstract S3-2.

Gianni L et al. Lancet Oncology 2012;13:25-32

NeoSphereComplete Pathologic Response

ProportionspCR TH THP HP TP

intent-to-treat

29.0 45.8 16.8 24.0

node –@ surgery

21.5 39.3 11.2 17.7

node +@ surgery

7.5 6.5 5.6 6.3

ER/PR + 20.0 26.0 5.9 17.4

ER/PR - 36.8 63.2 27.3 30.0

Schneeweiss A et al. Ann Oncol 2013;24:22788-2284

TRYPHAENAComplete Pathologic Response

Proportions

““Triple Negative”Triple Negative”Breast CancerBreast Cancer

Neoadjuvant Systemic TherapyNeoadjuvant Systemic Therapy

Sikov, W et al. J Clin Oncol 2014 (online)

CALGB 40603“Triple-Negative” Breast Cancer NST

Sikov, W et al. J Clin Oncol 2014 (online)

CALGB 40603“Triple-Negative” Breast Cancer NST

Sikov, W et al. J Clin Oncol 2014 (online)

CALGB 40603“Triple-Negative” Breast Cancer NST

Neoadjuvant Endocrine Neoadjuvant Endocrine TherapyTherapy

• safety establishedsafety established

• clinical responses frequentclinical responses frequent

• proportion of patients undergoing proportion of patients undergoing breast conservation can be increasedbreast conservation can be increased

• pCR is rare (< 5% of patients)pCR is rare (< 5% of patients)

• efficacy: AIs > tamoxifenefficacy: AIs > tamoxifen

• decline in Ki67 may predict outcomedecline in Ki67 may predict outcome

• optimal duration of therapy uncertainoptimal duration of therapy uncertain

Selection of Patients for Selection of Patients for Neoadjuvant Systemic TherapyNeoadjuvant Systemic Therapy

• pCR = lower recurrence riskpCR = lower recurrence risk

• factors associated with a higher factors associated with a higher likelihood of pCR:likelihood of pCR:

• tumor size (small > large) tumor size (small > large) • histology (ductal > lobular) histology (ductal > lobular) • intrinsic subtype (basal, HER2 > luminal)intrinsic subtype (basal, HER2 > luminal)• hormone receptor status (ERhormone receptor status (ER - - > ER+) > ER+)• grade (high > low)grade (high > low)

Gralow JR et al. Gralow JR et al. J Clin OncolJ Clin Oncol 2008;22:814-819 2008;22:814-819..

CONCLUSIONSCONCLUSIONS

• Neoadjuvant systemic therapy is Neoadjuvant systemic therapy is appropriate (preferred?) for any appropriate (preferred?) for any patient for whom adjuvant systemic patient for whom adjuvant systemic therapy is appropriate.therapy is appropriate.

• Increasingly effective neoadjuvant Increasingly effective neoadjuvant strategies are being developed.strategies are being developed.

• Importance of pathologic complete Importance of pathologic complete response may vary with breast response may vary with breast cancer subtype.cancer subtype.