Transcript Breast Cancer

Update on Breast Cancer:
ASCO 2004
Hope S. Rugo, MD
Clinical Professor of Medicine
Director, Breast Oncology Clinical Trials Program
University of California San Francisco
Comprehensive Cancer Center
ASCO Update: Breast Cancer
Chemotherapy
• Neoadjuvant therapy
– Herceptin for HER2 positive disease
• Adjuvant therapy
– Dose dense therapy for high risk node positive disease
• Metastatic disease
– Weekly vs every three week paclitaxel
– Gemcitabine plus paclitaxel vs paclitaxel
– Novel cytotoxics
• Abraxane
– Targeted therapy/surrogate endpoints
• Prognostic factors
– Gene analysis
– Circulating tumor cells
ASCO Update: Breast Cancer
Hormone Therapy
• Risk of relapse at 5 years
• Update on MA.17
• Effects of exemestane on bone and
cardiovascular endpoints
• Exemestane as first-line therapy for
metastatic disease
Neoadjuvant Chemotherapy for
Breast Cancer in HER2 Positive
BC
• Trastuzumab improves survival when added
to chemotherapy for MBC
• Remarkable synergy exists when combined
with doxorubicin
– Limited by significant cardiac toxicity
• Is there a way to capitalize on the benefits of
both agents without increasing the risk of
cardiac damage?
Significantly Higher Pathological Complete Remission
(PCR) Rate Following Neoadjuvant Therapy with
Trastuzumab [Herceptin (H)], Paclitaxel (P) and
Anthracycline-Containing Chemotherapy (CT): Initial
Results of a Randomized Trial in Operable Breast
Cancer (BC) with HER-2 Positive Disease
• Objectives
• Compare the pathologic complete
response rate in patients receiving
chemotherapy with or without trastuzumab
• Histologically confirmed invasive
breast cancer T 1-3, N 0-1, M0
• Her-2 + by FISH or IHC 3+
Buzdar et al, ASCO 2004
Trial Design
Operable Breast Cancer Her-2 +
Randomization
Paclitaxel X 4
Paclitaxel X 4 + H X 12 wkly
FEC X 4
FEC X 4 + H X 12 wkly
Local Therapy
Appropriate Endocrine Therapy for Patients
with Hormone Receptor + Disease
Paclitaxel: 225 mg/m2 over 24 h
FEC: 75mg/m2 epirubicin
Unscheduled DSMB Review – October 2003
Why: High overall complete pathological response rate
(47%)
Findings:
Treatment
Pathological CR
P FEC alone (N=16)
25%
P FEC + H (N=18)
66.7%
Additional 8 patients were still on study – final N = 42
DSMB decision: Trial should be closed – evident superiority
of P
FEC + H.
Rationale: If accrual to 164 patients - 95% probability
P FEC + H superior (Bayesian predictive probability)
Pathological Complete Response Rates
95% CI (41%-87%)
95% CI (43%-84%)
70
60
50
66.7%
N=18
40
65.2%
N=23
30
20
10
25%
N=16
26.3%
N=19
0
DSMB Reviewed Data
Final Results
P=0.016
P+FEC alone
P+FEC + H
Pathological Complete Response Rates
by Hormonal Receptor Status
70
60
50
40
61.5%
N=13
30
70%
N=10
20
10
27.2%
N=11
25%
N=8
0
P os itiv e
N e ga tiv e
P + FE C a lon e
P + FE C + H
Adverse Events
Cardiac Safety Data
Events
P
FEC alone
N=19
P
FEC + H
N=23
CHF
0
0
>10% Decrease in ejection fraction
- Decrease on paclitaxel
- Decrease on FEC
5
0
5
7
4
3
Improvement in ejection fraction
on follow-up evaluation
2
3
Abnormal Troponin-T
0
1
Conclusion
• The addition of trastuzumab to taxane and
anthracycline-containing chemotherapy as utilized in
this trial significantly increased the pathological
complete response rates in patients with HER-2 positive
breast cancer
• Addition of trastuzumab resulted in significantly higher
incidence of neutropenia
•11 vs 21, p .03
• No clinical cardiac toxicity was observed
• Where should we go from here?
• Not a regimen to take home yet!
• Consider use of Herceptin off protocol for LABC
• Adjuvant data to follow……
Dose Dense Sequential Chemotherapy
with ETC: The AGO Trial. Mobus et al, #513
26.4% required transfusions in the phase I/II study of dose density
Time to Relapse and
RFS Subgroup Analysis
• Time to relapse
127 vs 94 mo (p
= .0009)
• No impact on
TTR of epoietin
– Less
transfusions
– 28 v 12%
• One patient died
of AML in the
ETC arm
Hazard ratio 0.64
Take Home Points
• Dose dense and dose intense sequential ETC is better
than standard EC followed by T in women with > 4 +
axillary lymph nodes
– This is the first large study to show survival benefit in patients
with high risk node positive disease
– Short follow-up (28 months)
– Unclear whether benefits are due to the dose-density or the
dose-intensity of the regimen
• Superior arm had higher doses as well as higher density
• Treatment is reasonably well tolerated with growth
factor support
• Chemotherapy can be given safely every 2 weeks, this
shortens duration of treatment
• Epo had no effect on survival
– Contrary to prior studies suggesting worse outcome with epo
CALGB 9840: Phase III study of weekly vs. every third
week paclitaxel in the treatment of metastatic breast
cancer, with trastuzumab for HER2 + MBC and
randomized for trastuzumab for HER2 normal MBC
• Primary objectives
– Weekly (q1w) paclitaxel (P) improves response in MBC
as compared to q3w P
– Adding trastuzumab (T) to q1w or standard (q3w) P
improves response for HER2 normal MBC
• Secondary objective
– TTP and OS are better with weekly paclitaxel compared
with every three week dosing
Seidman et al, ASCO 2004
CALGB 9342
To reduce patients required for study endpoints, and
study costs, 158 patients were ‘borrowed’ (total 738)
250 mg/m2
210 mg/m2
175 mg/m2
Multivariate
p=
Response
23%
26%
21%
NS
TTP
3.9 mos
4.1 mos
4.9 mos
0.12
OS
11 mos
12 mos
14 mos
0.30
Winer E et al. J Clin Oncol 22: 2061-2068, 2004
CALGB 9840: Design
MBC with 0-1 Prior Chemotherapy for MBC,
> 12 mo Since Adjuvant Taxane
1998-2000
(n=171; HER2 unknown)
2000-2003
(n=406; HER2 known)
q3w P
q1w P
= paclitaxel 80 mg/m2* qw vs
175 mg/m2 q 3w
q3wP+T
= trastuzumab 4mg/kg load,
2 mg/kg/w**
q1wP+T
*first 116 pts at 100 mg/m2 x 6, then all pts 80 mg/m2 qw
**Her 2 + receive trastuzumab, Her 2 – randomized to T
or no T
H
E
R
2
(+)
H
E
R
2
(-)
CALGB 9840
Tumor Response
(all patients)
(OR=1.61, p=0.017)
(HER2 normal patients)
(p=0.34)
100
80
40%
28%
35%
29%
60
40
20
0
q1w P q3w P
n=
344
373
T
No T
112
111
CALGB 9840
Time to Progression
(Adjusted HR=1.45, p=0.0008)
12
11
10
9
8
7
6
5
4
3
2
1
9 mos
5 mos
(p=0.09)
7 mos
(all patients)
q1w P
n (events/pts) = 221/350
q3w P
324/385
6 mos
(HER2 normals)
T
74/113
No T
82/115
CALGB 9840: Conclusions
• Weekly P is superior to every 3 week P for response
and time to progression in MBC , there was no
difference in overall survival (24 vs 16 mo)
• Trastuzumab does not improve outcome when added to
P for HER2 normal MBC
• Companion correlative studies are pending
• Less neutropenia in the weekly arm
– 5 vs 15% grade 3-4
• More sensory neuropathy in the weekly arm
– 30% - 100 mg weekly (n116); 19% - 80 mg weekly (n228)
– 12% - q 3 weeks (n224)
• Do the borrowed patients affect the observed outcome?
– 75 v 20% second line
– Without those patients, trend toward improved response, significant
improvement in TTP
Phase III Study of Gemcitabine plus Paclitaxel
versus Paclitaxel as Frontline Therapy
for MBC: Albain et al, ASCO 2004
R
A
N
D
O
M
I
Z
E
GT arm (21-day cycle)
Day 1:
Paclitaxel 175 mg/m2 (3 hr)
Gemcitabine 1250 mg/m2
Day 8:
Gemcitabine 1250
mg/m2
T arm (21-day cycle)
Day 1:
Paclitaxel 175 mg/m2 (3
hr)
Standard paclitaxel premedications
98 centers, 19 countries
Treat until
documented PD
All sites of
disease
assessed every
8 weeks
ELIGIBILITY
Unresectable, locally
recurrent or metastatic
measurable disease
No prior chemotherapy for
advanced disease
Prior adjuvant
chemotherapy
(anthracycline-based,
unless contraindicated)
JHQG Planned Interim Analysis
Endpoint
GT
Response rate
40.8%
T
p-value
22.1%
<0.0001 (HR 0.65)
Median TTP
5.2
2.9
<0.0001
6-month
progression-free
37%
23%
0.0027
Deaths
160
183
Censored
40.1%
30.2%
Median OS, mos
18.5
15.8
12-month survival
70.7%
60.9%
18-month survival
50.7%
41.9%
JHQG Interim Overall Survival
Overall Survival Probability
1.0
0.8
Log rank
p=0.018
Hazard Ratio
0.78 (0.63, 0.96)
GT
0.6
0.4
T
0.2
0.0
0
6
12
18
24
30
Overall Survival Time (Months)
36
42
JHQG Subsequent Chemotherapy*
Treatment Post-study
GT
Total
44.2%
49.2%
29.5%
14.6%
35.1%
14.1%
24.7%
17.6%
10.5%
3.8%
27.9%
14.9%
10.3%
14.1%
Number of regimens
1–2
3
Regimens or single agent
Vinorelbine
Capecitabine
Docetaxel
Gemcitabine
*At time of interim data lock
T
Conclusions
• Gemcitabine/paclitaxel doublet joins
capecitabine/docetaxel and trastuzumab/taxane in
providing superior outcomes to taxane monotherapy
• GT is very well-tolerated, and thus can be studied in the
adjuvant setting
– The major difference in toxicity is hematologic
• 48 vs 11% grade 3-4 neutropenia
• 10 vs 4 RBC transfusions
– Two ongoing trials (Tango, NSABP), neoadjuvant planned
(NSABP)
• The risk-benefit profile favors GT and offers a new option
for frontline treatment in women with MBC
ABRAXANE Transport From Blood Circulation, through
Endothelial Cells and into TUMORS
Leaky junction
Tumor Cell
Tumor
Interstitium
(A) Enhanced
Penetration &
Retention of nab
particles and
macromolecules
Lumen of
Tumor
microvessel
(C) High uptake
by tumors
(A) Enhanced
Albumin-receptor
(gp60, albondin)
Endothelial Cell
Caveolae
(vesicles)
Tumor Cell
(B) Receptor-mediated
Transcytosis
Phase II Weekly ABI-007 (Abraxane)
in Taxane Refractory MBC. Blum et al
Evaluable Patients, n (%)
106 (100%)
Objective Partial Response
(PR)
95% CI
Disease Control
(PR+SD  16 weeks)
95% CI
16 (15%)
8.3% - 21.9%
32 (30%)
21.4% - 38.9%
Objective Disease Tumor Growth After:
Taxotere alone
Taxol alone
Both
n
33
31
28
RR Control
24%
35%
16%
37%
7%
27%
Conclusions
• Long-term disease control was achieved with a well tolerated
weekly regimen of Abraxane
• ABI-007 (100 mg/m2 weekly) compares favorably to reported data
1,2 using weekly Taxol 80 mg/m2
– G-4 neutropenia (1% vs 5%)
– G-3 neuropathy (4% vs 23% sensory, 0% vs 8% motor
respectively)
• In light of the very low incidence of grade 3 or 4 toxicities, further
studies of ABI-007 are focusing on neoadjuvant and adjuvant
breast cancer, higher weekly doses (125 and 150 mg/m2), and
combinations with other drugs
1.
2.
Perez EA, Vogel CL, Irwin DH, Kirshner JL, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic
breast cancer. J Clin Oncol 19:4216-23, 2001
Seidman, ASCO 2004
Role for Bisphosphonates in the
Treatment of Breast Cancer
• 3 trials on the use of clodronate (1600 mg/day) in breast
cancer pts
– Finnish study (N = 282): DECREASED disease-free survival
• 10-year follow-up
• Primary node-positive breast cancer
– German study (N = 290): PROLONGED overall survival
• 8.5-year follow-up
• Primary breast cancer with micrometastases to bone marrow
– English study (N = 1069): IMPROVED survival; ↓ bone
metastases
• 5-year follow-up
• Primary operable stage 1-3 breast cancer
• NSABP trial will help to clarify role of clodronate in the
treatment of breast cancer
• Intergroup trial to open soon
1. Saarto T, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 527.
2. Jaschke A, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 529.
3. Powles T, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 528.
ASCO 2004 #522 Verification of Adjuvant! on an
Independent Data Set
• Adjuvant! is a Web-based computer model based on clinical trial
data
• Predicts 10 year DFS and OS based on
– Age
– Tumor size, #LN
– ER/PR status
– Hormonal and chemotherapy administered
• Continually updated (last revision 8/04)
• Clinical and treatment data obtained from British Columbia cancer
registry
– 4083 women treated from 1989-1993
– T1-2N0-1 BCa, 66% T1, 34% N1, 58% ER(+)
– No tx 45%, tam 30%, chemo 16%, T +CT 9%
• Data entered into adjuvant and compared to observed 10 year DFS
and OS
Olivetto et al.
ASCO 2004 #522
Verification of Adjuvant! on an Independent
Data Set
• Adjuvant! Predicted overall DFS and OS within 1% of
observed:
– For OS (71.7% pred, 72% obs)
– For DFS (71% pred, 70.1% obs)
• Adjuvant was overly optimistic in:
– DFS in women <35 years (pred 67%, obs 54%, p<0.002)
– DFS in women on CT (pred 65%, obs 61%, p=0.056)
– DFS in women on CT + tam (pred 68%, obs 61.7%, p=0.012)
• Conclusion:
– Adjuvant! Works reliably well in large test dataset, likely useful
for clinical practice
– Caution in interpreting benefit of CT and CT + tam
– ‘Toggle’ switch allows increase or decrease in risk based on
known additional risk factors (e.g. HER2, LVI, age)
Neoadjuvant Therapy: Prediction of
pCR using Genomics
•
Background:
Pathologic eradication of invasive breast cancer (pCR) is an
independent predictor of outcome (DFS and OS) in women
undergoing primary chemotherapy
•
Can genes be identified whose expression correlates with the
likelihood of pCR to primary chemotherapy (doxorubicin and
paclitaxel)?
89 evaluable patients
– 11 patients with pathologic complete response (pCR)
•
•
4 pts ER+ by IHC
– pCR rate in ER+ pts = 8% (95% CI, 1%, 15%)
7 pts ER- by IHC
– pCR rate in ER- pts = 23% (95% CI, 8%, 37%)
– Overall, pCR rate = 12%
Gianni et al, ASCO 2004
Results - Univariate analysis of Gene
Expression and pCR
•
86 genes correlated with likelihood of pCR (p < 0.05; unadjusted)
–
–
–
–
•
30 genes correlated p < 0.01
18 genes correlated p < 0.005
2 genes correlated p < 0.0001
20 genes would have been expected by chance alone (p < 0.05)
Higher likelihood of pCR associated with:
– HIGHER expression of PROLIFERATION genes
CDC20, MYBL2, FBXO5, MCM2, MCM6, CDC25B
– HIGHER expression of IMMUNE-RELATED genes
MCP1, CD68, CTSB, CD18, ILT, CD3z, FasL, HLA.DPB1
– LOWER expression of ESTROGEN-RELATED genes
PR, SCUBE2 (CEGP1), ER, NPD009, GATA3, IGF1R, IRS1
Gianni et al, ASCO 2004
Detection of Circulating Tumor Cells Predicts
Rapid Progression in Metastatic Breast Cancer:
Results of a Prospective Clinical Trial: Hayes et al
%
<5 CTC(n=34)
<5 CTC = 34
≥5 CTC(n=41)
>5 CTC = 41
%
%
%
~6.7
mos
~6.7 Months
%
%
~2.4 Months
~2.4
mos
%
%
Cox Hazards Ratio=1.8103
%
Cox Hazards Ratio = 1.8103
Logrank
p=0.0360
Logrank
p = 0.0360
%
(p-value = 0.0376)
(p value=0.04)
%
0
5
10
15
20
25
30
35
Baseline CTC predict PFS
40
%Probability of Progression Free Survival
Validation Set n=75
1st Follow-up (3 - 4 wk)
N = 163
Logrank p < 0.0001
100%
90%
80%
70%
<5 CTC (n=114)
60%
50%
40%
30%
20%
10%
~7-8 mos
~5-6
WEEKS
≥5 CTC (n=49)
0%
0 5 1015202530 35 40 45 50 55 6065 707580
Time from Baseline (Weeks)
CTC at 1st Follow-up predict PFS
Conclusions
In metastatic Breast Cancer:
– Baseline CTC
• 50% of patients ≥ 5CTC
• Independent prognostic indicators of favorable & unfavorable
outcomes (PFS and OS)
– 1st Follow-up CTC
• 30% of patients ≥ 5CTC
•
•
• When elevated, predict short PFS and OS and may indicate patient is
on a futile therapy
Do these data apply to all patients?
– All patients had measurable disease
– Data appear less robust for patients on endocrine therapy
Ongoing or planned clinical trials:
– Accruing patients with non-measurable disease
– A prospective randomized trial is being designed to determine if
changing therapy at 3-4 weeks improves outcomes
What Happens to Patients with Early
Stage Breast Cancer after Five Years?
#585: Hortobagyi et al
• Goal
– To determine the magnitude of residual risk of
recurrence 5 years after diagnosis of breast
cancer
• 1511 patients treated between 4/74 and 7/98
with anthracycline and endocrine therapy as
indicated were relapse free at 5 years
– Median follow-up 74 months
– Majority were stage II, 50% ER+
Conclusions
• Patients with breast cancer still have substantial residual
risk of relapse 5 years after diagnosis
– Stage II
• 13% for the next 5 years
• 21% for the next 10 years
– Stage III
• 18% for the next 5 years
• 30% for the next 10 years
– Stage I remains to be defined
• Residual risk is higher for patients with HR+ disease than
those with HR- disease
• Extended endocrine therapy may further reduce risk of
recurrence or death for patients with HR+ disease
• Additional and more effective therapy is needed for
patients with HR- breast cancer
NCIC CTG Intergroup Trial MA.17 Design
Goss PE et al., ASCO 2004 and N Engl J Med 2003;349
All Patients Disease-free
Tamoxifen
0–3
months
Letrozole
n = 2575
Placebo
n = 2582
4.5 - 6 years initial adjuvant
5 years extended adjuvant
Stratification: Receptors +ve / unknown
Lymph Node + ve, - ve, unknown
Adjuvant Chemo Y / N
MA17 Final Analysis
Toxicity - Efficacy
2003
March
1998
• Interim Analysis
–
–
–
–
DFS events: 207
Deaths: 73
# pts at 40 months = 384
Median follow-up: 2.4 yrs
Aug Oct
2003
2004
• Final Analysis
–
–
–
–
DFS events: 247
Deaths: 113
# pts at 40 months = 1115
Median follow-up: 2.5 yrs
Total Recurrences of Breast Cancer
Distant
Locoregional
New primary only
175
155
Node +
Node -
150
125
100
94
92
102
63
75
57
50
33
18
25
28
14
39
20
18
12
13
3
7
Placebo
Letrozole
17
14
14
10
Letrozole
Placebo
Letrozole
0
Placebo
50
74
23
DFS by Treatment Duration
Letrozole
Placebo
(N=2582)
(N=2586)
(%)
(%)
0.00004
1
98.5
97.9
(Overall)
2
96.9
95.4
3
95.7
92.2
4
94.7
89.8
Year
P-value
4.8%
NNT = 21
(CI 2.1% - 6.9%)
Node – ve
96.3
93.6
2.7%
NNT = 37
Node + ve
92.3
84.8
7.5%
NNT = 13
(NNT = Number Needed to Treat)
13
Summary of Key Endpoints in Nodal
Subgroups
HR=0.45
(0.27-0.75)
Node*
-ve
Node
-ve
Distant*
DFS
DFS*
HR=1.52
(0.76-3.06)
HR=0.63
(0.31-1.27)
Node
-ve
OS
Node*
+ve
Node*
+ve
Node*
+ve
HR=0.61
(0.45-0.84)
HR=0.53
(0.36-0.78)
HR=0.61
(0.38-0.98)
*
= Statistically significant
MA.17: Incidence of Adverse Events
(All Grades)
Letrozole (%) Placebo (%) P value
Hot Flashes
58
Arthritis/Arthralgia
25
Muscle pain
15
Vaginal bleeding
6
Hypercholesterolemia
16
Cardiovascular Events
6
Osteoporosis
8
Bone fractures
5.3
Discontinuations due to adverse events5
Discontinuations for other reasons
4
90% of AE’s Grade 1 or 2
54
21
12
8
16
6
6
4.6
4
5
0.003
< 0.0001
0.04
0.005
0.79
0.76
0.003
0.25
0.02
0.1
A Randomized Placebo Controlled Feasibility Study of
Exemestane vs Placebo in Postmenopausal Women with
Early Breast Cancer at Low Risk. #518: Lonning et al
• Exemestane moderately increases bone loss in the
lumbar spine and the femoral neck.
• 0.10 reduction in bone mineral density femoral T-score on
exemestane
– Corresponds to an increase in the lifetime hazard rate of fracture
of < 1.15 (Cummings et al. JAMA 2002; 288: 1889-97).
• No patient with normal bone mineral density at baseline
became osteoporotic on either treatment.
• The frequency of fractures did not different between
exemestane and placebo.
• Bone loss was higher than expected in the placebo arm
• At 25 mg a day, exemestane does not appear to prevent
bone mineral density loss in this patient population
Summary of First Line Hormonal Treatment for MBC
with Exemestane or Tamoxifen in PM Women: The
EORTC Randomized Phase III Trial
Anastrozole
Anastrozole
Letrozole
170 vs 182
340 vs 328
453 vs 454
182 vs 189
OR, %
21 vs 17
33 vs 33
30 vs 20*
46 vs 31*
Clin. Benefit, %
59 vs 46*
56 vs 56
49 vs 38*
66 vs 49*
Med. PFS, mo
11 vs 6*
8 vs 8
9 vs 6*
10 vs 6*
ER unknown, %
11 vs 11
56 vs 54
34 vs 33
15 vs 11
Patients, N
Exemestane
Significantly different from Tamoxifen (*)
Nabholtz et al. J Clin Oncol. 2000;18:3758-3767; Bonneterre et al. J Clin Oncol. 2000;18:3748-3757;
Mouridsen et al. J Clin Oncol. 2001;19:2596-2606; Mouridsen et al. Breast Cancer Res Treat.
2001;69:211, abst 9; Paridaens
et al, #515
Conclusions
• New combinations, targeted biologic agents, and new
treatment schedules are improving options for treatment
and outcome for women with high risk and advanced
breast cancer.
– The GT combination will be compared to XT in the planned new
NSABP neoadjuvant trial
– Herceptin adjuvant trials are ongoing, neoadjuvant trials are
planned
– Genomics and CTCs may help to determine appropriate
individual therapy in the future
• Aromatase inhibitors have an established efficacy in the
treatment of early stage, hormone receptor positive
breast cancer
– MA.17 in node positive breast cancer is the first adjuvant AI trial
to show improvement in survival
– We need the data from BIG Femta to understand sequence
– Understanding duration is more of a challenge.