Medical Oncology Training Program Resident Teaching

Friday January 7th, 2011 @ PMH, 5-223

Locally Advanced and Inflammatory Breast Cancer

Eitan Amir

Medical Oncology

Princess Margaret Hospital

Challenges/Objectives in the Management of Locally Advanced Breast Cancer

• Surgical oncology• Who to send for

preoperative therapy?

• Role of breast conservation

• Role of SLN surgery

• Surgery on relapse

• Medical oncology• What drugs to give for

preoperative therapy?• How can we improve

response rates?• What to give on

relapse?

• Radiation oncology• Combined chemo-rads?• Role of breast

conservation• Radiotherapy for

inoperable/progressive disease despite NAT

• Radiotherapy on relapse

What is LABC?

• LABC – 10 -15% of all new Breast Cancers

• Prognosis is poor– local recurrence– systemic relapse– overall survival– 15 yr OS

• 20% IBC, 40% NIBC

Inoperable• Improve surgical options

• Deliver adequate “adjuvant” chemotherapy

• Provide in vivo anti-tumour assessment

• Assess surrogate biologic endpoints for response & survival

Goal OperableWhat are the indications for neoadjuvant therapy?

What is the current systemic treatment standard?

Challenges in the Management of LABC

Clinical response and pathologic response are currently used as a surrogate of survival and as a tool to compare chemotherapy regimens

40

50

60

70

80

90

100

0 1 2 3 4 5

% S

urv

ivin

g

Years after Surgery

•TRT N Deaths•Non pCR 1899 396•pCR 409 31 HR=0.33p<0.0001

NSABP B-27: Overall Survival - pCR vs. non-pCR patients (Bear JCO 2003)NSABP B-27: Overall Survival - pCR vs. non-pCR patients (Bear JCO 2003)

Operable Breast CancerOperable Breast Cancer

StratificationStratification• • AgeAge• • Clinical Tumor SizeClinical Tumor Size

• • Clinical Nodal StatusClinical Nodal Status

OperationOperation

+ TAM if + TAM if >>50 50 yrsyrs

AC x AC x 44

+ TAM if + TAM if >>50 yrs.50 yrs.

AC x 4AC x 4

OperationOperation

Operable Breast Cancer: NSABP B-18

No difference in DFS and OS

Lumpectomy Rates

60% vs 68%

Preop AC

cCR pCR

36% 13%

00

20%20%

40%40%

60%60%

80%80%

100%100%

22 44 66 88YearYear

P=0.00005P=0.00005pINVpINVcPRcPRcNRcNR

pCRpCR

22 44 66 88

pINVpINVcPRcPRcNRcNR

pCRpCR

P=0.0008P=0.0008

Wolmark N: CDC, 2000Wolmark N: CDC, 2000

• Clinical response predicts overall survival Clinical response predicts overall survival

• Pathologic response predicts overall survivalPathologic response predicts overall survival

Neoadjuvant therapy - Operable Breast CancerNeoadjuvant therapy - Operable Breast Cancer

B-18 DFS by response B-18 OS by response

B-27 Schema (n=2,411)B-27 Schema (n=2,411)

Operable Breast CancerOperable Breast Cancer

RandomizationRandomization

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs

AC x 4 AC x 4 Tam X 5 YrsTam X 5 Yrs

SurgerySurgery Docetaxel x 4Docetaxel x 4 SurgerySurgery

SurgerySurgery Docetaxel x 4Docetaxel x 4

B-27B-27Pathologic Response (pCR) in BreastPathologic Response (pCR) in Breast

P < 0.001P < 0.001

AC DocetaxelAC Docetaxel(718 pts)(718 pts)

ACAC(1,492 pts)(1,492 pts)

3.9%

9.8%

No TumorNo Tumor Non-InvasiveNon-Invasive

6.9%

18.7%

13.7%13.7% 25.6%25.6%

20%20%

10%10%

00

30%30%

B-27: Nodal Down-stagingB-27: Nodal Down-staging

Rastogi P, et al. J Clin Oncol 2008;26:778-85

EORTC-NCIC-SAKK Multi-centre Trial EORTC-NCIC-SAKK Multi-centre Trial in LABC:in LABC:

Patient Population(n = 448)

– 40% T4a-c

– 45% T4d

– Locoregional treatment variable

RRAANNDDOOMMIIZZAATTIIOONN

C 75 mg/m2 po q d days 1–14E 60 mg/m2 IV days 1 and 8 q 4 wk x 6 F 500 mg/m2 IV days 1 and 8

E 120 mg/m2 IV day 1 q 2 wk x 6 C 830 mg/m2 IV days 1 with G-CSF day 2-13

Therasse P et al. J Clin Oncol 2003;21:843-50

Adapted from Therasse P, et al. J Clin Oncol 2003;21:843-50

•In exploratory analysis: DFS worse in IBC (median 23.5 m) vs LABC (median 44 m)

Current “standard” neoadjuvant chemotherapy regimens:anthracycline & taxane combination – Her2 neg

• Regimen Trial pCR (%)

• Anthracycline (adriamycin / epirubicin) 15

• Anthracycline plus taxane (taxol or taxotere) 28

What is the “standard” Her2- at PMH?

AC-T (dose dense) 8 (16%)

FEC-D 38 (79%)

Endocrine 2 (4%)

In Ontario:AC-taxotere

FEC-taxotere

Dose dense AC-Taxol

Breast Cancer Biological Subtypes as Predictive Subtypes

NOAH: the largest neoadjuvant trial in HER2-positive breast cancer

aHormone receptor-positive patients receive adjuvant tamoxifen; LABC, locally advanced breast cancer; H, trastuzumab (8 mg/kg loading then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); T, paclitaxel (175 mg/m2); CMF, cyclophosphamide, methotrexate, fluorouracil

HER2-positive LABC(IHC 3+ and / or FISH+)

n=113

H + ATq3w x 3

H + Tq3w x 4

H q3w x 4 + CMF q4w x 3

Surgery followed byradiotherapya

H continued q3wto Week 52

Tq3w x 4

CMFq4w x 3

Surgery followed byradiotherapya

n=115

ATq3w x 3

ATq3w x 3

Tq3w x 4

CMFq4w x 3

Surgery followed byradiotherapya

n=99

HER2-negative LABC(IHC 0/1+)

Patient characteristicsPatient characteristics

HER2-negative IBC, %

Total pop IBC pop(n=99) (n=14)

ER, oestrogen receptor; PgR, progesterone receptor

Characteristic

4357

5050

6436

295021

1000

Age group<50 years>50 years

Menopausal statusPrePost

Hormonal receptorsER+ and / or PgR+Both negative

Axillary nodesN0N1N2

Ipsilateral supraclavicular nodesNoYes

HER2-positive IBC, %-H

Total pop IBC pop(n=113) (n=31)

+HTotal pop IBC pop(n=115) (n=31)

4258

5050

3565

164737

964

3268

5545

1684

195526

9010

4654

5248

3565

134443

946

5545

4258

2377

265223

1000

5149

5545

6436

173844

964

Significant improvement of pCR in IBC by adding trastuzumab

+H-H0

10

20

30

40

50

60Patients(%)

HER2negative

+H HER2negative

-H

p=0.004p=0.002

HER2 positive HER2 positive

tpCRpCR

4(29%)

6(19%)

17(55%)

4(29%)

4(13%)

15(48%)p=0.49 p=0.20

eradication of invasive cancer in the breast

eradication of invasive cancer in the breast plus axillary nodes

Good cardiac safety profile

No change (LVEF >55%)

Absolute decrease >10-<20%

Absolute decrease >20%

CHF responsive to treatment

+H(n=31)

77

23

0

0

-H(n=31)

84

13

3

0

86

14

0

0

HER2-positive IBC, %

CHF, congestive heart failure;LVEF, left ventricular ejection fraction

HER2-negative IBC, %

(n=14)

LVEF worst value

Pathologic Complete Response (pCR)

Untch M et al. EBCC 2008

What is the “standard” Her2+ at PMH?

MUGA

FEC

MUGA

Taxotere + herceptin

In Ontario:AC-TaxotereH

FEC-TH

AC-TaxolH

TCH

Anything new in 2010?Anything new in 2010?

Baselga J et al, SABCS 2010

Gianni L et al, SABCS 2010

Gianni L et al, SABCS 2010

Gianni L et al, SABCS 2010

Gianni L et al, SABCS 2010

Winer EP, SABCS 2010

Winer EP, SABCS 2010

Should patients with LABC have a lumpectomy if good response to chemotherapy?

Challenges in the Management of LABC

Pre-Treatment MRI of Breast Cancer with Septal Spread

After Neo-Adjuvant ChemotherapyTumour shrunk to lesser volume along septa

Pathologic Response to Neoadjuvant Chemotherapy (TSRCC)

Study Definition pCR rate (n=117) (%)

NSABP pCR in breast only

No microinvasive disease

Can have DCIS

10.3

Aberdeen pCR in breast/axilla

No microinvasive disease

Can have DCIS

8.6

TSRCC pCR in breast and axilla

No microinvasive disease

Can have DCIS

8.6

Chevallier pCR in breast and axilla

No microinvasive disease

No DCIS

4.3

Why such low pCR rates?

1)Advanced nature of patients selected for neoadjuvant chemotherapy in a LABC dedicated program1)this is a VERY different pt population than

preoperative systemic therapy for Stage I and II pts that is becoming more common in USA

2)High incidence of ER + tumors (71%)

3)Strict definition of pCR

How effective is Neoadjuvant Chemotherapy in ER+ Breast Cancer

• Chemotherapy is less effective in ER+ disease vs ER- disease (but doesn’t mean some patients don’t benefit)

• Luminal A cohort do not benefit vs luminal B?

• Other predictive markers needed

Phase III SWOG 8814 (TBCI 0100) Postmenopausal, N+, ER+

RANDOMIZE n = 1477

tamoxifen x 5 yrs

CAF x 6, then tamoxifen

CAF x 6, with concurrent tam

Albain, et al. Breast Cancer Res Treat 2007

Superior Disease-Free Survival (DFS) and Overall Survival (OS)

over 10 Years

(n = 361)(n = 550) (n = 566)

0.0

00

.25

0.5

00

.75

1.0

0D

ise

as

e-f

ree

su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (n=55, 15 events)CAF-T (n=91, 26 events)

Stratified log-rank p = 0.97 at 10 years

Low risk (RS < 18)

Disease-Free Survival by TreatmentNo benefit to CAF over time if low RS (n=146)

Strong benefit if high RS

0.0

00.

25

0.5

00.

75

1.0

0

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (n=47, 26 events)CAF-T (n=71, 28 events)

Stratified log-rank p = 0.033 at 10 years

High risk (RS ≥31)

Disease-Free Survival by Treatment

0.0

00.

25

0.5

00.

75

1.0

0

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (n=46, 22 events)CAF-T (n=57, 20 events)

Stratified log-rank p = 0.48 at 10 years

Intermediate risk (RS 18-30)

Disease-Free Survival by TreatmentTest for interaction p=0.053

0.00

0.25

0.50

0.75

1.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10

Years since registration

Tamoxifen (n=57, 20 events)

CAF-T (n=85, 30 events)

Stratified log-rank p = 0.81 at 10 years

HER2 Negative and ER Allred 7-8

0.00

0.25

0.50

0.75

1.00

Dis

ease

-fre

e su

rviv

al

0 2 4 6 8 10Years since registration

Tamoxifen (n=73, 36 events)CAF-T (n=112, 39 events)

Stratified log-rank p = 0.011 at 10 years

HER2 Positive or ER Allred <7

No DFS Benefit from CAF if Central IHC is Both HER2 Negative and ER Level High* (n=142)

*Test for Interaction p=0.052

Our most successful therapies target self-sufficiency in growth signals

Growth Factor• Estrogen/ER• HER2

Therapy• SERMs, AIs,

oophorectomy, fulvestrant

• Trastuzumab– Lapatinib

Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy?

Challenges in the Management of LABC

Should we treat patients with residual lymph node involvement after neoadjuvant chemotherapy with further adjuvant chemotherapy?

0

20

40

60

80

100

0 1 2 3 4 5

% S

urv

ivin

g

Years after Surgery

•Nodal Status NDeaths•Negative 884 112•1-3 Positive 587 113•4-9 Positive 308 107•10+ Positive 102 54

3-31-04NSABP B-27: Overall Survival nodal Status; Patients without pCR(Bear JCO 2003)(Bear JCO 2003)

Systemic therapy – when more is less!

• LABC patients not responding to chemotherapy – More or different chemo is not always the answer– Chemo is toxic– Importance of multidisciplinary team– Unique area for further study:

• Role of RT• Role of biologics• Understanding chemo-resistance• Response predictors• Response Assessment Tools

Our most successful therapies target self-sufficiency in growth signals

Growth Factor• Estrogen/ER• HER2

Therapy• SERMs, AIs,

oophorectomy, fulvestrant

• Trastuzumab– Lapatinib

Surely neoadjuvant chemotherapy is the best?

• Semiglazov et al. 2004– Neoadjuvant treatment in women aged >70 with ER + breast cancer

• Doxorubicin and Paclitaxel (q3 weeks, 4 cycles) (n=60)• 3 months treatment with anastrozole or exemestane (n=59)

• There was a trend towards more breast conservation in the AI arms.

chemotherapy anastrozole exemestane

pathological CRs

7.4% 3.3% 6.8%

overall clinical RRs

76% 75% 81%

SummaryPreoperative vs. Postoperative

– OS = DFS = BCS

Clinical and pathologic response predicts overall survival

Standard chemo is an anthracycline & taxane regimen

For older HR+ pts consider endocrine therapy

Currently no role for more chemo for patients with residual disease after preoperative therapy

Challenges in the Management of Locally Advanced Breast Cancer

Surgical oncology• Who to send for preoperative therapy?

– In the setting of LABC – we are hoping to make surgery feasible– This is different from using NAT as the standard for ALL patients

• Role of breast conservation– Not common for LABC population– Can be done when feasible

• Role of SLN surgery– Very high rate of nodal involvement

• Surgery on relapse– Palliation in the setting of very poor prognosis

Challenges in the Management of Locally Advanced Breast Cancer

Medical oncology• What drugs to give for preoperative therapy?

– Anthracycline and taxane (± herceptin)– Endocrine therapy

• How can we improve response rates?– More than chemo!– radiotherapy, biological agents

• What to give on relapse?– Very difficult as survival is often short