HOT TOPICS IN BREAST CANCER FROM HOT TOPICS IN BREAST CANCER FROM ASCO 2002ASCO 2002

Controversies in Endocrine Therapy of Early Controversies in Endocrine Therapy of Early Breast Cancer:Breast Cancer:

Adjuvant CT and tamoxifen: Concurrent or sequential?Adjuvant CT and tamoxifen: Concurrent or sequential?

Miguel MartinMiguel MartinMedical Oncology DptmentMedical Oncology Dptment

Hospital Universitario San CarlosHospital Universitario San CarlosMadrid (Spain)Madrid (Spain)

3rd International BCIRG Conference3rd International BCIRG Conference

Anaheim, June 20 to 22, 2002Anaheim, June 20 to 22, 2002

Tamoxifen and CT: Concurrently or sequentally?

• Preclinical data

• Clinical data:– Intergroup 0100 (abstract 143)

– GEICAM 9401 (abstract 144)

• Clinical implications

Tamoxifen and CT: Concurrently or sequentally?

• Preclinical data• Clinical data:

– Intergroup 0100 (abstract 143)

– GEICAM 9401 (abstract 144)

• Clinical implications

CT-tamoxifen interactions:CT-tamoxifen interactions:preclinical data (1)preclinical data (1)

• Tamoxifen induces a G1/G0 cell cycle Tamoxifen induces a G1/G0 cell cycle blockade of MCF-7 cells in vitroblockade of MCF-7 cells in vitro11

• Tamoxifen inhibits the cytotoxic effects Tamoxifen inhibits the cytotoxic effects of melphalan and fluorouracil in estrogen of melphalan and fluorouracil in estrogen receptor-negative breast cancer cell lines receptor-negative breast cancer cell lines in vitroin vitro2 2

• Both additiveBoth additive2 2 and antagonicand antagonic3 3 effects have effects have been described with doxorubicinbeen described with doxorubicin

1. Clarke R et al, Biochem Soc Trans 15:243,19872. Osborne CK et al, J Clin Oncol 7:710,19893. Woods KC et al, Biochem Pharmacol 47:1449,1994

CT-tamoxifen interactions:CT-tamoxifen interactions:preclinical data (2)preclinical data (2)

• Tamoxifen revers in vitro the multidrug Tamoxifen revers in vitro the multidrug resistance to certain drugs such as resistance to certain drugs such as doxorubicindoxorubicin11

• Tamoxifen and taxotere are synergistic in Tamoxifen and taxotere are synergistic in estrogen receptor-negative cell linesestrogen receptor-negative cell lines22

1. Greenberg DA et al, Cancer Res 47:70,19872. Ferlini C et al, Br J Cancer 75: 884,1997

Preclinical data onPreclinical data onCT-tamoxifen interactions:CT-tamoxifen interactions:

SummarySummary

• The interaction (antagonistic or ever The interaction (antagonistic or ever synergistic) of CT and tamoxifen seems to be synergistic) of CT and tamoxifen seems to be drug-specificdrug-specific

• The NET interaction between a The NET interaction between a polichemotherapy regimen and tamoxifen polichemotherapy regimen and tamoxifen results difficult to predictresults difficult to predict

• In vitro data is only useful for developing In vitro data is only useful for developing hypothesis that can be tested in clinical trialshypothesis that can be tested in clinical trials

Tamoxifen and CT: Concurrently or sequentally?

• Preclinical data

• Clinical data:–Intergroup 0100 (abstract 143)

–GEICAM 9401 (abstract 144)• Clinical implications

Adjuvant Chemohormonal Therapy for Primary Breast Cancer Should Be Sequential Instead of Concurrent

Initial Results from North American Intergroup Trial 0100 (SWOG-8814)

• Southwest Oncology Group (coordinator)• Eastern Cooperative Oncology Group• Cancer and Leukemia Group B• North Central Cancer Treatment Group• NCI Canada Clinical Trials Group

Proc ASCO 21: 143,2002

Breast Intergroup Trial 0100 Study Design

STRATIFYNodes 1-3+ vs 4+

PgR+(ER+ or ER-) vs PgR-(ER+) Time from surgery 6 vs >6-12 weeks

RANDOMIZE

Tamoxifen CAFx6, then CAFx6,concurrent tamoxifen tamoxifen

Breast Intergroup Trial 0100Postmenopausal, Node (+), Receptor (+)

Objectives

1. Determine if anthracycline-based adjuvant therapy with CAF plus T is superior to T alone

Results: Significant DFS and S advantage to the combination (Proc. ASCO 2001)

Breast Intergroup Trial 0100Postmenopausal, Node (+), Receptor (+)

Objectives

2. Assess if CAF followed by T (CAFT) is superior to concurrent therapy followed by T (CAFTT)

Results: This report

Breast Intergroup Trial 0100

Acute Toxicity and Late Effects CAF T vs CAFTT

• No difference in recorded grade 2, 3, or 4 acute toxicities

• Rates of congestive heart failure, thromboembolic events, uterine cancer and secondary AML/MDS were very similar

0 24 48 72 96

0%

20%

40%

60%

80%

100%

120 144

Months After Registration

Breast INT 0100

8-year disease-free survival

CAF T 67%CAFT T 62%

p = .03(log rank)

Median follow-up: 8.5 y

RR: 1.18

0 24 48 72 96

0%

20%

40%

60%

80%

100%

Months After Registration

Breast INT 0100

8-year overall survival

120 144

CAF T 73%CAFT T 71%

P=0.23

Breast Intergroup Trial 0100

Conclusions• There is an estimated 18% improvement

in DFS by delaying tamoxifen until the completion of CAF

• Long follow-up of a large cohort was necessary to ascertain this benefit

• Data consistent with hypothesis that tamoxifen may antagonize drugs used in this or similar regimens

GEICAM 9401 (Spanish Breast Cancer Research Group)

• Adjuvant Epirubicin-Cyclophosphamide Chemotherapy Plus Tamoxifen Administered Concomitant vs. Sequential: Randomized Phase III Trial in Postmenopausal Node-Positive Breast Cancer Patients

Proc ASCO 21:144,2002

GEICAM 9401: Clinical Trial Design

• Primary End-point: 5-year DFS

ECx4 TamSurgery RR

ECx4 + Tam

Postmenopausal patientsStage II and III-A (node positive)Up to 70 years oldHR positive & negative

Recruitment• Number of randomized patients: 485*

• Recruitment period:– June 1995 / July 2000

• A decision was made to stop enrollment due to persistent low accrual and delay in planned recruitment

*planned sample size: 762

Results

• Median follow-up: 54 mo• No difference in prognostic factors between

arms• No difference in toxicity • Non-statistically significant trend toward

better outcome with sequential administration

Number of Events

Concomitant Sequential

Metastases 43 36

Skin & Nodes 5 2

2nd Breast 1 0

TOTAL 49 38

Median follow-up: 54 months

GEICAM 9401: Disease Free Survival

60483624120

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

Concomitant

Sequential

Log Rank; p=0.43

Seq 219 127 42

Con 220 145 33Patients at risk

Hazard Ratio

0 0.5 1 1,5 2

p = 0.5

Concomitant better Sequential better

HR (95% C.I.) = 1.147 (0.769- 1.709)

No difference or not enough power?

5-year DFS

Patient

number

Power

Assumptions 50% 10% 762 80%

Actual 70% 5% 474 35%

= 5%

Conclusions

• No statistically significant difference

• However, a 5% difference, if true, would be clinically relevant

• This extra-benefit does not require any extra effort, toxicity, or cost

• Our results are still immature, and further follow-up is needed to get less uncertain data

INT 0100 and GEICAM 9401:Summary

• Both trials have similar design:– Potmenopausal

– Anthracycline-containing chemotherapy

• Toxicity in both arms was similar• Results favouring the sequential arm:

– Statistically significant difference in DFS in the INT 0100 trial

– Clear trend of similar amount in DFS in GEICAM 9401 trial

Hazard Ratio

0 0.5 1 1,5 2

Concomitant better

Sequential better

Intergroup INT 0100

GEICAM 9401

1.18 (1.01-1.39)

1.147 (0.769-1.709)

Clinical Implications

• Concurrent chemo-hormonal therapy may result in suboptimal benefit from the chemotherapy

• Unless new data became available, we should use CT and tamoxifen sequentially

• Are these results extrapolable to all chemotherapy regimens?– CMF?

– Taxanes? (NSABP B-28 trial?)

NSABP B-28 Stage II-IIIA

Paclitaxel 225 mg/m2

Doxorubicin

Cyclophosphamide

No additional chemotherapy

Concomitant tamoxifen (x 5 years) in tamoxifen-sensitive patients

AC 1525 pts

AC P 1528 pts

RR (95% IC)

p

Events

282

269

0,93

(0,78 – 1,10)

0,38

Deaths

133

136

1,00

(0,78 – 1,27)

0,98

Med. Follow-up: 34 m

• Special thanks to:

• Dr. S. Albain (SWOG)

• Dr C. Picó (GEICAM)