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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 - PowerPoint PPT Presentation
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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