Update on Breast Cancer: ASCO 2004

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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

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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

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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

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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?

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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
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Paclitaxel 225 mg/m2 over 24 h FEC 75mg/m2
epirubicin
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• 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

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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
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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
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Take Home Points

• Dose dense and dose intense sequential ETC is
  better than standard EC followed by T in women
  with gt 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

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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
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CALGB 9342To 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 TTP OS
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26
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NS
0.12
3.9 mos
4.1 mos
4.9 mos
0.30
11 mos
12 mos
14 mos
Winer E et al. J Clin Oncol 22 2061-2068, 2004
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CALGB 9840 Design MBC with 0-1 Prior
Chemotherapy for MBC, gt 12 mo Since Adjuvant
Taxane
1998-2000 (n171 HER2 unknown)
q3w P
q1w P
paclitaxel 80 mg/m2 qw vs 175 mg/m2 q 3w
trastuzumab 4mg/kg load, 2 mg/kg/w
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
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CALGB 9840Tumor Response
(all patients)
(HER2 normal patients)
(OR1.61, p0.017)
(p0.34)
100 80 60 40 20 0
40 28
35 29
Percentage
q1w P q3w P
T No T
n
344 373
112 111
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CALGB 9840Time to Progression
(Adjusted HR1.45, p0.0008)
(p0.09)
12 11 10 9 8 7 6 5 4 3 2 1
9 mos 5 mos
7 mos 6 mos
(all patients)
(HER2 normals)
months
q1w P q3w P
T No T
74/113
82/115
221/350
324/385
n (events/pts)
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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

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Phase III Study of Gemcitabine plus Paclitaxel
versus Paclitaxel as Frontline Therapy for MBC
Albain et al, ASCO 2004
Treat until documented PD All sites of disease
assessed every 8 weeks
GT arm (21-day cycle)
R A N D O M I Z E
Day 1

Paclitaxel 175 mg/m2 (3 hr) Gemcitabine 1250
mg/m2






Day 8


Gemcitabine 1250 mg/m2
ELIGIBILITY Unresectable, locally recurrent or
metastatic measurable disease No prior
chemotherapy for advanced disease Prior adjuvant
chemotherapy (anthracycline-based, unless
contraindicated)




T arm (21-day cycle)



Day 1
Paclitaxel 175 mg/m2 (3 hr)

Standard paclitaxel premedications
98 centers, 19 countries
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JHQG Planned Interim Analysis

• Endpoint GT
  T p-value
• Response rate 40.8 22.1
  lt0.0001 (HR 0.65)
• Median TTP 5.2 2.9
  lt0.0001
• 6-month 37 23
  0.0027
• progression-free
• 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

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JHQG Interim Overall Survival
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JHQG Subsequent Chemotherapy

• Treatment Post-study GT T
• Total
  44.2 49.2
• Number of regimens
• 1 2
  29.5 35.1
• 3
  14.6 14.1
• Regimens or single agent
• Vinorelbine 24.7
  27.9
• Capecitabine 17.6
  14.9
• Docetaxel 10.5
  10.3
• Gemcitabine 3.8
  14.1
• At time of interim data lock

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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

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ABRAXANE Transport From Blood Circulation,
through Endothelial Cells and into TUMORS
Leaky junction
Tumor Interstitium
(A) Enhanced Penetration Retention of nab
particles and macromolecules
Lumen of Tumor microvessel
Albumin-receptor (gp60, albondin)
Endothelial Cell
Caveolae (vesicles)
(B) Receptor-mediated Transcytosis
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Phase II Weekly ABI-007 (Abraxane) in Taxane
Refractory MBC. Blum et al
Evaluable Patients, n () 106 (100) Objective
Partial Response(PR) 16
(15) 95 CI 8.3 -
21.9 Disease Control(PRSD ? 16 weeks)
32 (30)95 CI 21.4 -
38.9 Objective Disease Tumor Growth
After n RR Control Taxotere
alone 33 24 35 Taxol alone 31 16 37 Both 28
7 27
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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

• 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 194216-23, 2001
• Seidman, ASCO 2004

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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.
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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.
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ASCO 2004 522Verification 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 lt35 years (pred 67, obs 54,
  plt0.002)
• DFS in women on CT (pred 65, obs 61, p0.056)
• DFS in women on CT tam (pred 68, obs 61.7,
  p0.012)
• 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)

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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
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Results - Univariate analysis of Gene Expression
and pCR

• 86 genes correlated with likelihood of pCR (p lt
  0.05 unadjusted)
• 30 genes correlated p lt 0.01
• 18 genes correlated p lt 0.005
• 2 genes correlated p lt 0.0001
• 20 genes would have been expected by chance alone
  (p lt 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
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CTC at 1st Follow-up predict PFS
Detection of Circulating Tumor Cells Predicts
Rapid Progression in Metastatic Breast
CancerResults of a Prospective Clinical Trial
Hayes et al
1st Follow-up (3 - 4 wk) N 163 Logrank p lt
0.0001
100
90
80
70
lt5 CTC (n114) 5 CTC (n49)
60
7-8 mos
50
5-6 WEEKS
Probability of Progression Free Survival
40
30
20
10
0
0
5
10
15
20
25
30
35
40
45
55
60
65
70
75
80
50
Time from Baseline (Weeks)
Baseline CTC predict PFS
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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

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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 7/98with
  anthracycline and endocrine therapy as indicated
  were relapse free at 5 years
• Median follow-up 74 months
• Majority were stage II, 50 ER

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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

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NCIC CTG Intergroup Trial MA.17 Design
Goss PE et al., ASCO 2004 and N Engl J Med
2003349
All Patients Disease-free
Letrozole
0 3 months
n 2575
Tamoxifen
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
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MA17 Final Analysis
Toxicity - Efficacy
2003
March
Aug
Oct
1998
2003
2004

• Interim Analysis
• DFS events 207
• Deaths 73
• pts at 40 months 384
• Median follow-up 2.4 yrs

• Final Analysis
• DFS events 247
• Deaths 113
• pts at 40 months 1115
• Median follow-up 2.5 yrs

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Total Recurrences of Breast Cancer
155
Node
Node -
102
92
63
50
23
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Summary of Key Endpoints in Nodal Subgroups
HR0.45 (0.27-0.75)
HR0.63 (0.31-1.27)
HR1.52 (0.76-3.06)
Node -ve
Node -ve
Node -ve
Distant DFS
DFS
OS
Node ve
Node ve
Node ve
HR0.61 (0.45-0.84)
HR0.61 (0.38-0.98)
HR0.53 (0.36-0.78)
Statistically significant
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MA.17 Incidence of Adverse Events (All Grades)

• Letrozole () Placebo () P value
• Hot Flashes 58 54 0.003
• Arthritis/Arthralgia 25 21 lt 0.0001
• Muscle pain 15 12 0.04
• Vaginal bleeding 6 8 0.005
• Hypercholesterolemia 16 16 0.79
• Cardiovascular Events 6 6 0.76
• Osteoporosis 8 6 0.003
• Bone fractures 5.3 4.6 0.25
• Discontinuations due to adverse events 5 4 0.02
• Discontinuations for other reasons 4 5 0.1

90 of AEs Grade 1 or 2
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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 lt 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

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Summary of First Line Hormonal Treatment for MBC
with Exemestane or Tamoxifen in PM Women The
EORTC Randomized Phase III Trial
Exemestane
Letrozole
Anastrozole
Anastrozole
Patients, N 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
Significantly different from Tamoxifen ()
Nabholtz et al. J Clin Oncol.
2000183758-3767 Bonneterre et al. J Clin
Oncol. 2000183748-3757 Mouridsen et al. J
Clin Oncol. 2001192596-2606 Mouridsen et al.
Breast Cancer Res Treat. 200169211, abst 9
Paridaens et al, 515
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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.