Challenging Cases in Cancer:Advanced Breast Cancer

Linda T. Vahdat, MD

Medical Director, Breast Cancer Program

Weill Medical College of Cornell University

New York Presbyterian Hospital

New York, NY

Goals of Program

• Review approach to goals of therapy in advanced breast cancer

• Integrate existing clinical data in the day-to-day management of advanced breast cancer

Management of Advanced Breast Cancer: Efficacy vs. Toxicity

Options for Advanced Breast Cancer

Chemotherapy Hormonal Therapy

Biologics

Oral meds- capecitabine, Vincas, taxanes, camptothecins, liposomal preparations, nanoparticle preparations (ixabepilone, eribulin)

Tamoxifen, SAIs, fulvestrant (2ME)

Trastuzumab, bevacizumab, Lapatinib (sunitinib, tipifarnib)

Non-FDA approved drugs in parentheses

Advanced Breast Cancer

• No standard approach

• Many options

• QOL important endpoint

• Site specific palliation (i.e. VAT, bisphosphonates)

• Many clinical trials available

• Improvement in survival

– Median 4.3 years

Chemotherapy for Stage IV Breast Cancer

• Options:

– Taxanes- vary the schedule to re-induce response, use of different delivery systems

– Capecitabine +

– Vinorelbine +

– Anthracyclines + liposomal preparations, epirubicin

– Gemcitabine +

– Irinotecan

Stage IV Breast Cancer Chemotherapy

• Modest differences in response rates

• No real effect on overall survival

• Toxicity issues important when palliation the goal

Common Regimens for Stage IV Breast Cancer

Agent CR (%) PR (%) ORR (%) TTP (mos)

Paclitaxel 5 20 25 4.6

Docetaxel 2 30 32 7.5

Nab-paclitaxel

NR NR 34 5.2

Capecitabine 2 18 20 8.1

Vinorelbine 5 20 25 3.0

Gemcitabine 6 6 12 3.0

Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005

Common Regimens Used in MBC: Grade 3/4 Hematologic Toxicity

2

15

2 0 0 1

0

10

20

30

40

50

60

70

80

90

100

pacli

taxe

l

doce

taxe

l

nab-

pacli

taxe

l

cape

citab

ine

gem

citabin

e

vinor

elbine

% p

atie

nts Neutropenia

Febrile neutropenia

Platelets

Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005

Common Regimens Used in MBC: Grade 3/4 Non-hematologic Toxicity

0

5

10

15

20

25

30

PN- Sen

sory

PN-Moto

r

Asthen

iaN/V

stomati

tis

paclitaxel

docetaxel

nab-paclitaxel

capecitabine

gemcitabine

navelbine

Jones, JCO 2005, Gradishar, JCO 2005, Blum, JCO 1999, Livingston, JCO 1997, Modi, Clin Breast Cancer 2005

Case Studies

• Real patients

• No wrong answer

• Integrate goals of patients and physician into final decision

Case #1: DG

• 72-year-old woman with a h/o bilateral breast cancer

– 1978 RMRM: T = 2.cm, N = 0/24, ER/PR+

• No further therapy

– 1990 LMRM: T = 1.0 cm, N = 0/12, ER/PR+

• Tamoxifen x 5 years

– 1998 CW nodule excised: c/w ILC, ER/PR+, HER2-

– EOD: sub-centimeter pulmonary nodules

– Anastrazole started with resolution of pulmonary nodules

Case #1: DG

• 2006: routine follow-up physical exam:

– Noted to have large pre-sternal mass

– Asymptomatic

– CT chest abd pelvis: 8 cm mass adjacent to sternum abutting but not invading pericardium

Case #1: DG

What treatment would you recommend? Hormonal therapy Chemotherapy Radiation therapy Hospice

Case #1: DG

What treatment would you recommend? Hormonal therapy Chemotherapy Radiation therapy Hospice

Recommended Approach:

• All options are appropriate but would favor hormonal therapy

Reasons to Consider Hormonal Therapy for This Patient

• Elderly

• Asymptomatic from current cancer

• Long natural history of breast cancer

• 9-years of benefit from an aromatase inhibitor

• RT will only manage CW mass and large area to irradiate

Hormonal Options

• Another aromatase inhibitor

– Exemestane

– Letrozole

• Estrogen receptor down-regulator

– Fulvestrant

Clinical Data

• Use of fulvestrant after an aromatase inhibitor:

– Fulvestrant in women with advanced breast cancer after progression of prior aromatase inhibitor: NCCTG Trial 0032. Ingle JN et al. JCO 2006

• Use of an aromatase inhibitor after failure of an aromatase inhibitor:

– Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors. Lonning et al. JCO 2000

– Sequential use of aromatase inactivators and inhibitors in advanced breast cancer. Bertelli et al. Proc Amer Soc Clin Oncol 2002

Fulvestrant in Women with Advanced Breast Cancer After Progression of Prior Aromatase Inhibitor:

NCCTG 0032

Eligibility criteria

• ER and/or PR+ breast cancer

• Measurable disease

• Progressive disease after a 3rd generation AI in addition to another hormonal agent

• One prior chemo regimen for MBC

Treatment: Fulvestrant 250 mg IM Q 28 days

Evaluation on study: Month 1 and then Q 3 months

Ingle JN et al. JCO 2006

NCCTG 0032

• Entered: 80 patients

• Evaluable: 77 patients

• Disease sites:

– 88% visceral predominant disease

– 73% 2 prior hormone therapies

– 32% prior chemotherapy

Ingle JN et al. JCO 2006

NCCTG 0032: Results

• Partial responses: 11/77= 14.3%

• Stable disease ≥ 6 months16/77 = 20.8%

• Clinical benefit rate: 35%

• Median TTP = 3 months

• Median duration of response 11.4 months

• Clinical benefit rate 54% in those who had not received prior tamoxifen

Ingle JN et al. JCO 2006

Clinical Benefit of Fulvestrant in Post Menopausal Women with Primary or Acquired Resistance to Aromatase Inhibitors:

Final Results of Phase II Swiss Group for Clinical Research Trial (SAKK 21/00)

• Two groups of patients:

– Group A (N = 70)AI responsive disease

– Group B (N = 20) AI resistant disease

• Treatment: fulvestrant 250 mg IM Q 28 days

Perey et al. Annals of Oncology 2007

SAKK 21/00: Results

• Patient characteristics:

– AI pretreatment: 100%

– Tam/toremifene pretreatment: 84%

– Bone mets: 64%

– Liver mets: 45%

• Clinical Benefit rate (CR,PR, SD ≥ 6 months): 30%

• No difference by prior AI response

Perey et al. Annals of Oncology 2007

Activity of Exemestane in Metastatic Breast Cancer After Failure of Nonsteroidal Aromatase Inhibitors

• Phase II trial: N = 242 pt

• Exemestane: 25 mg QD after failure of AI

• Response rate: 16/242 6.6%

• Stable disease rate ≥ 6 months: 42/242 (17%)

• Clinical benefit rate: 24.3%

• Median duration of response: 54 weeks

• Median duration of treatment: 10 weeks

Lonning PE et al, JCO 2000

Summary of Fulvestrant or Aromatase Inhibitor After Failure of an AI

Treatment NRR

(%)

SD ≥ 6 mos

(%)

CBR

(%)

Med. TTF

(mos.)

Fulvestrant after AI  

NCCTG 0032 80 14.3 20.8 35 11.4

SAKK 21/00 90 30

Exemestane after AI

 

Lonning 242 6.6 17 24.3 12.2

AI= aromatase inhibitor, RR= response rate, SD= stable disease, CBR= clinical benefit rate ( CR,PR and SD≥6 mos); TTF= Time to treatment failure (ie. median duration of

response)

Case #1: Outcome

• Patient in an ongoing response to fulvestrant for 1 year at present

Case #2: DCR

• 45-year-old AA woman vocalist with stage 2 breast cancer

– 1999: LMRM

– T = 3.2 cm, N = 0/10, ER/PR/HER2-

– AC q 3 w x 4

• 2006: difficulty hitting the high notes and DOE during dance routines

Case #2: DCR

• 2006: biopsy of CW mass: c/w BC (ER/PR/HER2-)

• EOD: multiple pulmonary nodules and extensive hilar and subcarinal adenopathy compressing bronchi

Case #2: DCR

What treatment would you recommend:

Chemotherapy alone

Chemotherapy + biologic

Hospice

Case #2: DCR

What treatment would you recommend:

Chemotherapy alone

Chemotherapy + biologic

Hospice

Recommend Approach

• Would favor a regimen that would give the highest response in the quickest amount of time because she is symptomatic

Case #2: DCR

• Chemotherapy: single agent or combination

• Chemotherapy + biologic

– Paclitaxel + bevacizumab

– Capecitabine + bevacizumab

Treatment Issues

• Single agent vs. combination?

• Rapid response rate?

• Any special considerations for triple negatives?

Single Agent vs. Combination

• Response rates higher with combination therapy

• Time to progression better

• Overall survival similar

• Toxicity increased with combination

Trials of Combination vs. Monotherapy in Advanced Breast Cancer

Author NRR

(%)

TTP

(mos.)

OS

(mos.)

Sledge (E1193)

Doxorubicin 224 36 5.6 19

Paclitaxel 229 34 5.8 22

Combination 230 47 8 22

Bonneterre

Docetaxel 86 43 6.5 NA

5FU/Vinorelbine 90 34 5.1 NA

O’Shaughnessy

Docetaxel 256 30 4.2 11.5

Docetaxel + Capecitabine 255 42 6.1 14.5

Albain

Paclitaxel 262 26 2.9 15.8

Paclitaxel + gemcitabine 267 32 5.2 18.5

Significant differences in bold, RR = response rate; TTP = time to progression; OS = overall survival.

Sledge, JCO 2003; Bonneterre, Br J Ca 2002; O’Shaughnessy, JCO 2002; Albain, Proc Amer Soc Clin Oncology 2004

Capecitabine Data

• Oral 5FU prodrug*

• Response Rate first-line1,2: 30-58%

• Response Rate for anthracycline and taxane pretreated3,4: 14 to 29%

• Median time to response: 12 weeks

1O’Shaughnessy, Ann Oncol 20012 Reynoso, Breast Ca Res Treat 2005 Suppl(S219)

3 Blum, JCO 19984Vahdat, Proc Amer Soc Clin Oncol 2007

*Good review: Seidman A, The Oncologist 2002;7(suppl 6):20-28 www.TheOncologist.com

Docetaxel Data

• Antimicrotubule agent*

• Response Rate first-line1,2: 32 to 54%

• Median time to response: 12 weeks

1Hudis C, J Clin Onc 1996; 2 Jones S J Clin Oncol 2005

*Good review: Nabholtz JM, Semin Oncol. 2002 Jun;29(3 Suppl 12):28-34

Bevacizumab Data

• Humanized monoclonal antibody to VEGF-A*

• Improves survival when added to chemotherapy in colon and NSCLC

• Single-agent activity in breast cancer1

1Cobleigh, M Semin Oncol. 2003 Oct;30(5 Suppl 16):117-24

*Good review: Traina, T et al Hematol Oncol Clin N Am (21)2007, 303-319

Chemotherapy and Bevacizumab for MBC

• Capecitabine: first and second-line therapy1,2

• Metronomic cyclophosphamide + mtx3

• Paclitaxel: first-line therapy4

1Sledge Proc Amer Soc Clin Oncol 20072Miller JCO 2005

3Burstein Breast Ca Res Treat 2005 Suppl 4Miller Proc Amer Soc Clin Oncol 2005

ECOG 2100

RRAANNDDOOMMIIZZEEDD

PaclitaxelPaclitaxel

N = 350N = 350

Paclitaxel + Bevacizumab Paclitaxel + Bevacizumab

N = 365 N = 365

Paclitaxel dose: 90 mg/mPaclitaxel dose: 90 mg/m22 on day 1,8,15 Q 28 days on day 1,8,15 Q 28 days

Bevacizumab dose: 10 mg/kg on Day 1, 15Bevacizumab dose: 10 mg/kg on Day 1, 15

First-line First-line MBCMBC

Miller, K et al. ASCO 2005Miller, K et al. ASCO 2005

ECOG 2100

Treatment PaclitaxelPaclitaxel +

BevacizumabP-value

Response rate (%)

14.2 28.2 P < 0.0001

Median time to

progression (months)

6.1 11P < 0.0001 HR = 0.51

Overall survival

ns ns HR = 0.84

Miller, K et al. ASCO 2005Miller, K et al. ASCO 2005

Phase III Trial Capecitabine ± Bevacizumab

Treatment CapecitabineCapecitabine + Bevacizumab

P-value

Response rate (%)

9.1 19.8 P = 0.001

Median time to progression

(months)4.17 4.86 HR = 0.98

Overall survival

15.1 14.5 NS

Miller, K et al. ASCO 2005Miller, K et al. ASCO 2005

Metronomic Cyclophosphamide + Methotrexate (CM) ± Bevacizumab(b):

Randomized Phase II Study

Treatment No. pts RR(%)TTP

(mos)

CM 21 10 2.2

CMB 34 29 5.5

RR = response rate; TTP = time to progression

Burstein et al, Breast Cancer Res Treat Suppl 2005

Any Role in Special Populations?

• Preliminary data from E2100 suggests a PFS benefit in triple negative population

– ER/PR +, HR = 0.30 (CI 0.29 - 0.53)

– ER+/PR -, HR = 0.86 (CI 0.52 - 1.43)

– ER/PR -, HR = 0.47 (CI 0.35 - .63)

Case #2: Outcome

• Had more than a partial response in lungs and a CR in chest wall

• Opted to come off treatment because of fatigue and neuropathy a year ago and has stable disease and no therapy since that time

Case #3: RS

• 52-year-old woman diagnosed with an IBC in 1/2003

• Neoadjuvant chemotherapy with AC followed by paclitaxel q 2 w (clinical partial response)

• LMRM, T = 6 cm, N = 12, ER/PR+, HER2- by FISH

• 11/2003: lung, liver, bone, and regional nodal metastases, ER/PR+ and HER2-

• Pain from bone mets

Case #3: RS

What treatment would you recommend:

Hormonal therapy

Chemotherapy

Clinical trial

Hospice

Case #3: RSWhat treatment would you recommend:

Hormonal therapy

Chemotherapy

Clinical trial

Hospice

Issues to Considers

• Heavily pre-treated, symptomatic, large disease burden and short disease free interval

Treatment Recommendation

• Clinical trial

• New antineoplastic class - the natural epothilones and their analogs

• Low susceptibility to tumor resistance mechanisms– MRP-1 and P-gp efflux pumps

– (III) tubulin overexpression– tubulin mutations

• Activity in multiple tumor models

• Demonstrated pre-clinical synergy with capecitabine

Epothilones: Ixabepilone (BMS-247550)

S. cellulosum Epothilone B Ixabepilone

Ixabepilone Phase II Data in Breast Cancer

1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol 2005;23:2726–34. 3. Conte P et al. J Clin Oncol 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol 2006;24(18S):abstr 660.

5. Baselga J et al Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.

Roché1

After adjuvant anthra

OR

R (

%)

Low2

Taxane-pretreated MBC

Conte3

Taxane-resistant MBC

Thomas4

Multiresistant(anthra / tax / cape) MBC

Baselga5

Neoadjuvant T2-4, N0-3,

M0

42

22

12

18 pCR19

0

15

30

45

Ixabepilone(40 mg/m2 IV over 3 hr d1 q3wk)

+Capecitabine

(2000 mg/m2/day PO 2 divided doses d1-d14 q3wk)

N = 375

Capecitabine(2500 mg/m2/day PO 2 divided doses

d1-d14 q3wk)N = 377

Metastatic or locally advanced breast cancer

RESISTANT to anthracyclines

and taxanesN=752

Stratification •Visceral metastases•Prior chemotherapy for MBC

•Anthracycline resistance•Study site

Study Design: International, Randomized, Open-label, Phase III Trial

Response Rate

% Response

Investigator IRRIxabepilone

+ Capecitabine

N = 375

Capecitabine

N = 377

Ixabepilone +

Capecitabine N = 375

Capecitabine

N = 377

ORR (CR + PR) 42 23 35 14

P < 0.0001 P < 0.0001

Stable disease 36 38 41 46

Progressive disease 14 29 15 27

Unable to determine 8 10 9 12

Median 95% CI

Ixabepilone + Capecitabine 5.8 mos (5.5–7.0)

Capecitabine 4.2 mos (3.8–4.5)

Progression-free Survival by Independent Radiologic Review

P = 0.0003

HR: 0.75 (0.64–0.88)

Pro

port

ion

Pro

gres

sion

Fre

e

1.0

0.8

0.6

0.4

0.2

00 4 8 12 16 20 24 28 32 36

Months

Grade 3/4 Non-hematologic ToxicitiesP

erip

hera

l

neur

opat

hy

23

0

Mya

lgia

8

0.3

Han

d-fo

ot

synd

rom

e

18 17

Dia

rrhe

a6

9

Muc

ositi

s

3 2

Vom

iting

4 2

Fatig

ue

9

3

Nau

sea

3 2

Art

hral

gia

30

0

% o

f Pa

tient

s

Ixabepilone + Capecitabine (N = 369)

Capecitabine (N = 368)

20

40

60

80

Case #3: Outcome

• Enrolled in BMS 046 and randomized to ixabepilone and capecitabine arm

• Had a partial response that was clinically significant and was on study for 13 months. Taken off for progression

Case #4: IHA

• 55-year-old woman with newly diagnosed Stage IV breast cancer with massive adenopathy in right axilla rending limited motion in her arm

• No neurologic symptoms and she ignored problem until she was unable to go to work as a operator

• Biopsy c/w metastatic breast cancer, ER+/PR -, HER2- by FISH

• Rest of evaluation unremarkable except for bone metastases

Case #4: IHA

What treatment would you recommend:

Hormonal therapy

Radiation therapy

Chemotherapy

Hospice

Case #4: IHA

What treatment would you recommend:

Hormonal therapy

Radiation therapy

Chemotherapy

Hospice

Treatment Recommendation

• Chemotherapy

Treatment Issues: IHA

• Many chemotherapy options.

– Want to accomplish rapid disease control without significant toxicity.

• Goal would be to cytoreduce to no symptoms and then place on hormonal therapy

Chemotherapy Options

• Anthracyclines

• Taxanes: paclitaxel, docetaxel, nab-paclitaxel

• Capecitabine

• Gemcitabine

• Vinorelbine

First-line Chemotherapy For MBC

Agent N RR (%) TTP (mos)

Capecitabine1 61 30 4.1

Gemcitabine2 35 37 5.1

Vinorelbine3 157 41 6

Paclitaxel4 224 25 3.6

Docetaxel4 225 32 5.7

RR = response rate; TTP = time to progression

1O’Shaughnessy, Ann Oncol 2001; 2Blackstein, Oncology 2002; 3 Fumoleau, JCO 1993; 4Jones, JCO 2005

Nab-paclitaxel

• Albumin-bound paclitaxel

• Advantages: no premeds

– Cremophor free

– Shorter infusion time

• Might make use of gp 160-albumin mediated receptor transport across endothelial cells

Nab-paclitaxel

Trial N Setting Schedule RR (%)Med TTP

(wks)

Ibrahim1 63 No limit 300 mg/m2 Q3w 48 27

Mirtschung2 23 1st line125 mg/m2 QW (3 out of 4 wks)

57 NR

Gradishar3

nab-paclitaxel vs. paclitaxel

460 1st line260 mg/m2 vs. 175 mg/m2 Q

3W33 vs. 19 23 vs. 17

Significant differences in Bold; RR = response rate, TTP = time to progression; NR = not reported

1 Ibrahim, JCO 2005; 2 Mirtschung, Breast Ca Res Treat Suppl 2006; 3 Gradishar, JCO 2005

Case #4: Outcome

• Patient had a near complete response to nab-paclitaxel and eventually came off of therapy due to toxicity (neuropathy)

– This was chosen because she wanted to minimize her time in the office (Q 3 w schedule)

• Doing well on letrozole

Treatment of Advanced Breast CancerConclusions

• Many varied approached to managing advanced breast cancer

• Input from patient important in selecting a treatment

• Many new drugs being developed