Update on Breast Cancer: ASCO 2004 Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast...
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Update on Breast Cancer: Update on Breast Cancer: ASCO 2004 ASCO 2004 Hope S. Rugo, MD Hope S. Rugo, MD Clinical Professor of Medicine Clinical Professor of Medicine Director, Breast Oncology Clinical Director, Breast Oncology Clinical Trials Program Trials Program University of California San Francisco University of California San Francisco Comprehensive Cancer Center Comprehensive Cancer Center
Update on Breast Cancer: ASCO 2004 Hope S. Rugo, MD Clinical Professor of Medicine Director, Breast Oncology Clinical Trials Program University of California
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
Slide 2
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
Slide 3
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 ASCO Update: Breast
Cancer Hormone Therapy
Slide 4
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?
Slide 5
ObjectivesObjectives Compare the pathologic complete response
rate in patients receiving chemotherapy with or without trastuzumab
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, M 0 Histologically confirmed
invasive breast cancer T 1-3, N 0-1, M 0 Her-2 + by FISH or IHC 3+
Her-2 + by FISH or IHC 3+ 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 Buzdar et al, ASCO 2004
Slide 6
Paclitaxel: 225 mg/m 2 over 24 h FEC: 75mg/m 2 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 cancerThe 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 neutropeniaAddition of trastuzumab resulted in
significantly higher incidence of neutropenia 11 vs 21, p.0311 vs
21, p.03 No clinical cardiac toxicity was observedNo clinical
cardiac toxicity was observed Where should we go from here?Where
should we go from here? Not a regimen to take home yet! Not a
regimen to take home yet! Consider use of Herceptin off protocol
for LABC Consider use of Herceptin off protocol for LABC Adjuvant
data to follow Adjuvant data to follow
Slide 12
26.4% required transfusions in the phase I/II study of dose
density Dose Dense Sequential Chemotherapy with ETC: The AGO Trial.
Mobus et al, #513
Slide 13
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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
Slide 15
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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 > 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
Slide 17
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
Slide 18
CALGB 9342 To reduce patients required for study endpoints, and
study costs, 158 patients were borrowed (total 738) 175 mg/m 2 210
mg/m 2 250 mg/m 2 Response TTP OS Winer E et al. J Clin Oncol 22:
2061-2068, 2004 23%26% 21% Multivariate p = NS 0.12 0.30 3.9 mos4.1
mos4.9 mos 11 mos12 mos14 mos
Slide 19
= paclitaxel 80 mg/m 2 * qw vs 175 mg/m 2 q 3w = trastuzumab
4mg/kg load, 2 mg/kg/w** CALGB 9840: Design CALGB 9840: Design MBC
with 0-1 Prior Chemotherapy for MBC, > 12 mo Since Adjuvant
Taxane q3w P q1w P 1998-2000 (n=171; HER2 unknown) q3wP+T q1wP+T
2000-2003 (n=406; HER2 known) H E R 2 (+) H E R 2 (-) *first 116
pts at 100 mg/m 2 x 6, then all pts 80 mg/m 2 qw **Her 2 + receive
trastuzumab, Her 2 randomized to T or no T
Slide 20
CALGB 9840 Tumor Response 100 80 60 40 20 0 q1w P q3w PT No T
40% 28%35% 29% (OR=1.61, p=0.017)(p=0.34) Percentage n = 344 373
112 111 (all patients) (HER2 normal patients)
Slide 21
CALGB 9840 Time to Progression 12 11 10 9 8 7 6 5 4 3 2 1 q1w P
q3w PT No T 9 mos 5 mos7 mos 6 mos (Adjusted HR=1.45,
p=0.0008)(p=0.09) months 74/11382/115221/350324/385 n (events/pts)
= (all patients)(HER2 normals)
Slide 22
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
Slide 23
Treat until documented PD All sites of disease assessed every 8
weeks Paclitaxel 175 mg/m 2 (3 hr) Gemcitabine 1250 mg/m 2
Paclitaxel 175 mg/m 2 (3 hr) GT arm (21-day cycle) T arm (21-day
cycle) Day 1: Gemcitabine 1250 mg/m 2 Day 8: RANDOMIZERANDOMIZE
Standard paclitaxel premedications Phase III Study of Gemcitabine
plus Paclitaxel versus Paclitaxel as Frontline Therapy for MBC:
Albain et al, ASCO 2004 ELIGIBILITY Unresectable, locally recurrent
or metastatic measurable disease No prior chemotherapy for advanced
disease Prior adjuvant chemotherapy (anthracycline-based, unless
contraindicated) 98 centers, 19 countries