Challenging Cases in Cancer: Advanced Breast Cancer
description
Transcript of Challenging Cases in Cancer: Advanced Breast Cancer
![Page 1: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/1.jpg)
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
![Page 2: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/2.jpg)
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
![Page 3: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/3.jpg)
Management of Advanced Breast Cancer: Efficacy vs. Toxicity
![Page 4: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/4.jpg)
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
![Page 5: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/5.jpg)
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
![Page 6: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/6.jpg)
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
![Page 7: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/7.jpg)
Stage IV Breast Cancer Chemotherapy
• Modest differences in response rates
• No real effect on overall survival
• Toxicity issues important when palliation the goal
![Page 8: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/8.jpg)
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
![Page 9: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/9.jpg)
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
![Page 10: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/10.jpg)
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
![Page 11: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/11.jpg)
Case Studies
• Real patients
• No wrong answer
• Integrate goals of patients and physician into final decision
![Page 12: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/12.jpg)
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
![Page 13: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/13.jpg)
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
![Page 14: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/14.jpg)
Case #1: DG
What treatment would you recommend? Hormonal therapy Chemotherapy Radiation therapy Hospice
![Page 15: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/15.jpg)
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
![Page 16: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/16.jpg)
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
![Page 17: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/17.jpg)
Hormonal Options
• Another aromatase inhibitor
– Exemestane
– Letrozole
• Estrogen receptor down-regulator
– Fulvestrant
![Page 18: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/18.jpg)
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
![Page 19: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/19.jpg)
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
![Page 20: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/20.jpg)
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
![Page 21: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/21.jpg)
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
![Page 22: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/22.jpg)
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
![Page 23: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/23.jpg)
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
![Page 24: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/24.jpg)
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
![Page 25: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/25.jpg)
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)
![Page 26: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/26.jpg)
Case #1: Outcome
• Patient in an ongoing response to fulvestrant for 1 year at present
![Page 27: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/27.jpg)
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
![Page 28: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/28.jpg)
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
![Page 29: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/29.jpg)
Case #2: DCR
What treatment would you recommend:
Chemotherapy alone
Chemotherapy + biologic
Hospice
![Page 30: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/30.jpg)
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
![Page 31: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/31.jpg)
Case #2: DCR
• Chemotherapy: single agent or combination
• Chemotherapy + biologic
– Paclitaxel + bevacizumab
– Capecitabine + bevacizumab
![Page 32: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/32.jpg)
Treatment Issues
• Single agent vs. combination?
• Rapid response rate?
• Any special considerations for triple negatives?
![Page 33: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/33.jpg)
Single Agent vs. Combination
• Response rates higher with combination therapy
• Time to progression better
• Overall survival similar
• Toxicity increased with combination
![Page 34: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/34.jpg)
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
![Page 35: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/35.jpg)
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
![Page 36: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/36.jpg)
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
![Page 37: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/37.jpg)
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
![Page 38: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/38.jpg)
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
![Page 39: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/39.jpg)
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
![Page 40: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/40.jpg)
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
![Page 41: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/41.jpg)
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
![Page 42: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/42.jpg)
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
![Page 43: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/43.jpg)
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)
![Page 44: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/44.jpg)
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
![Page 45: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/45.jpg)
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
![Page 46: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/46.jpg)
Case #3: RS
What treatment would you recommend:
Hormonal therapy
Chemotherapy
Clinical trial
Hospice
![Page 47: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/47.jpg)
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
![Page 48: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/48.jpg)
• 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
![Page 49: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/49.jpg)
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
![Page 50: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/50.jpg)
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
![Page 51: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/51.jpg)
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
![Page 52: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/52.jpg)
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
![Page 53: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/53.jpg)
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
![Page 54: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/54.jpg)
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
![Page 55: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/55.jpg)
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
![Page 56: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/56.jpg)
Case #4: IHA
What treatment would you recommend:
Hormonal therapy
Radiation therapy
Chemotherapy
Hospice
![Page 57: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/57.jpg)
Case #4: IHA
What treatment would you recommend:
Hormonal therapy
Radiation therapy
Chemotherapy
Hospice
Treatment Recommendation
• Chemotherapy
![Page 58: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/58.jpg)
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
![Page 59: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/59.jpg)
Chemotherapy Options
• Anthracyclines
• Taxanes: paclitaxel, docetaxel, nab-paclitaxel
• Capecitabine
• Gemcitabine
• Vinorelbine
![Page 60: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/60.jpg)
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
![Page 61: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/61.jpg)
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
![Page 62: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/62.jpg)
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
![Page 63: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/63.jpg)
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
![Page 64: Challenging Cases in Cancer: Advanced Breast Cancer](https://reader035.fdocuments.us/reader035/viewer/2022062410/56815734550346895dc4d285/html5/thumbnails/64.jpg)
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