Download Challenging cases in breast cancer

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
Hormonal
Therapy
Chemotherapy
Oral meds- capecitabine,
Vincas, taxanes, camptothecins,
liposomal preparations,
nanoparticle preparations
(ixabepilone, eribulin)
Tamoxifen, SAIs,
fulvestrant (2ME)
Biologics
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
100
90
80
% patients
70
60
Neutropenia
Febrile neutropenia
50
Platelets
40
30
20
10
15
2
2
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0
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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
30
25
20
paclitaxel
15
docetaxel
nab-paclitaxel
10
capecitabine
gemcitabine
5
navelbine
0
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
N
RR
(%)
SD ≥ 6 mos
(%)
CBR
(%)
Med. TTF
(mos.)
NCCTG 0032
80
14.3
20.8
35
11.4
SAKK 21/00
90
Treatment
Fulvestrant after AI
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
N
RR
(%)
TTP
(mos.)
OS
(mos.)
Doxorubicin
224
36
5.6
19
Paclitaxel
229
34
5.8
22
Combination
230
47
8
22
Docetaxel
86
43
6.5
NA
5FU/Vinorelbine
90
34
5.1
NA
Docetaxel
256
30
4.2
11.5
Docetaxel + Capecitabine
255
42
6.1
14.5
Paclitaxel
262
26
2.9
15.8
Paclitaxel + gemcitabine
267
32
5.2
18.5
Author
Sledge (E1193)
Bonneterre
O’Shaughnessy
Albain
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 2001
Reynoso, Breast Ca Res Treat 2005 Suppl(S219)
3 Blum, JCO 1998
4Vahdat, Proc Amer Soc Clin Oncol 2007
*Good review: Seidman A, The Oncologist 2002;7(suppl 6):20-28 www.TheOncologist.com
2
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 2007
2Miller
3Burstein
JCO 2005
Breast Ca Res Treat 2005 Suppl
4Miller
Proc Amer Soc Clin Oncol 2005
ECOG 2100
First-line
MBC
R
A
N
D
O
M
I
Z
E
D
Paclitaxel
N = 350
Paclitaxel + Bevacizumab
N = 365
Paclitaxel dose: 90 mg/m2 on day 1,8,15 Q 28 days
Bevacizumab dose: 10 mg/kg on Day 1, 15
Miller, K et al. ASCO 2005
ECOG 2100
Treatment
Paclitaxel
Paclitaxel +
Bevacizumab
P-value
Response
rate (%)
14.2
28.2
P < 0.0001
Median time
to
progression
(months)
6.1
11
P < 0.0001
HR = 0.51
Overall
survival
ns
ns
HR = 0.84
Miller, K et al. ASCO 2005
Phase III Trial Capecitabine ± Bevacizumab
Treatment
Capecitabine
Capecitabine +
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 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: RS
What 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
Epothilones: Ixabepilone (BMS-247550)
• New antineoplastic class - the natural epothilones and their analogs
S. cellulosum
Epothilone B
Ixabepilone
• Low susceptibility to tumor resistance mechanisms
– MRP-1 and P-gp efflux pumps
– b (III) tubulin overexpression
– b tubulin mutations
• Activity in multiple tumor models
• Demonstrated pre-clinical synergy with capecitabine
Ixabepilone Phase II Data in Breast Cancer
45
42
ORR (%)
30
22
15
19
18 pCR
Thomas4
Multiresistant
(anthra / tax /
cape) MBC
Baselga5
Neoadjuvant
T2-4, N0-3,
M0
12
0
Roché1
After
adjuvant
anthra
Low2
Conte3
TaxaneTaxane-resistant
pretreated MBC
MBC
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.
Study Design: International, Randomized,
Open-label, Phase III Trial
Ixabepilone
(40 mg/m2 IV over 3 hr d1 q3wk)
+
Capecitabine
Metastatic or locally
advanced breast cancer
RESISTANT
to anthracyclines
and taxanes
N=752
Stratification
• Visceral metastases
• Prior chemotherapy for MBC
(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
• Anthracycline resistance
• Study site
Response Rate
% Response
ORR (CR + PR)
Investigator
Ixabepilone
Capecitabine
+
Capecitabine
N = 377
N = 375
42
23
IRR
Ixabepilone
Capecitabine
+
Capecitabine
N = 377
N = 375
35
P < 0.0001
14
P < 0.0001
Stable disease
36
38
41
46
Progressive disease
14
29
15
27
Unable to determine
8
10
9
12
Progression-free Survival
by Independent Radiologic Review
Proportion Progression Free
1.0
0.8
Median
95% CI
Ixabepilone + Capecitabine
5.8 mos
(5.5–7.0)
Capecitabine
4.2 mos
(3.8–4.5)
0.6
HR: 0.75 (0.64–0.88)
P = 0.0003
0.4
0.2
0
0
4
8
12
16
20
Months
24
28
32
36
Grade 3/4 Non-hematologic Toxicities
80
Ixabepilone + Capecitabine (N = 369)
% of Patients
Capecitabine (N = 368)
60
40
23
18 17
20
9
0
0
8
3
6
0.3
9
4
2
3
2
3
2
3
0
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
1st line
125 mg/m2 QW
(3 out of 4 wks)
57
NR
1st line
260 mg/m2 vs.
175 mg/m2 Q
3W
33 vs. 19
23 vs. 17
Mirtschung2
23
Gradishar3
nab-paclitaxel
vs. paclitaxel
460
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 nabpaclitaxel 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 Cancer
Conclusions
• Many varied approached to managing advanced
breast cancer
• Input from patient important in selecting a treatment
• Many new drugs being developed