Endocrine Therapy of Breast Cancer

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Endocrine Therapy of Breast Cancer

• Grand Rounds June 3, 2005
• Coy Heldermon

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Breast cancer

• Most common malignancy in U.S. women with 217,440
  cases diagnosed in 2004.
• 2nd leading cause of cancer death in U.S. women
  with 40,580 deaths in 2004.
• 12.5 lifetime risk of diagnosis.
• Median age is 63yo.
• Jemal A, Tiwari R, Murray T, et al. Cancer
  statistics, 2004. CA Cancer J Clin.
  200454(1)8-29.

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5 year survival by stage
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Rationale for endocrine therapy of breast cancer

• Oopherectomy was shown as early as 1896 by
  Beatson, et. al. to result in breast tumor
  regression.
• Subsequent responses were seen after removal of
  pituitary and adrenal glands.
• Risk factors for Br Ca include prolonged estrogen
  exposure states such as early menarche, late
  menopause, nulliparity and estrogen replacement
  therapy.

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Rationale for endocrine therapy of breast cancer

• Estrogen and/or progesterone receptor expression
  is found in 85 of breast cancers. This
  proportion increases with age.

Daidone MG, Coradini D, Martelli G, Veneroni S.
Primary breast cancer in elderly women
biological profile and relation with clinical
outcome. Crit Rev Oncol Hematol 200345313325
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Rationale for endocrine therapy of breast cancer

• 70 of breast cancers express high local levels
  of aromatase, the enzyme responsible for
  production of estrone and estradiol.

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Endocrine agents
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Agent history - tamoxifen

• Initially developed in 1966.
• Designed to be an oral contraceptive.
• Actually induced ovulation.
• Found to be at least equivalent to oopherectomy
  or CMF in 1986 and similar to megace with less
  toxicity in 1985 for metastatic disease.

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Tamoxifen adjuvant tx
Mortality From Any Cause
Recurrence as First Event
100
100
91.8
Tamoxifen (5 y)
Tamoxifen (5 y)
87.4
90
90
89.3
Control
Control
78.9
79.2
80
80.1
80
74.9
Tamoxifen (5 y)
Tamoxifen (5 y)
Node -ve
73.3
Node -ve
70
70
75.6
Control
Control
64.3
74.2
61.4
60
60
59.7
Node ve
58.3
Node ve
Alive
50
50
Recurrence-free
50.5
40
40
44.5
30
30
Absolute Mortality Reduction
Absolute Recurrence Reduction
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Node -ve 5.6 SD 1.3 2Plt0.00001 Node ve
10.9 SD 2.5 2Plt0.00001
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Node -ve 14.9 SD 1.4 2Plt0.00001 Node ve
15.2 SD 2.5 2Plt0.00001
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10
0
0
5
10
0
5
10
0
Years
Years
Early Breast Cancer Trialists Collaborative
Group. Lancet. 19983511451.
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Tamoxifen beyond 5y adjuvant treatment
DFS
OS
P0.07
100
100
P0.03
94
90
90
91
82
80
80
of patients
of patients
78
70
70
60
60
50
50
0
5
7
0
5
7
1
2
4
6
3
1
3
2
4
6
Years
Years

• Tamoxifen demonstrated higher rates of
  endometrial cancer, ischemicheart disease, and
  cerebrovascular disease.

Fisher et al. J Natl Cancer Inst. 200193684.
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Aromatase inhibitor history

• Aminoglutethimide was developed as an
  anti-epileptic and was shown to inhibit estrogen
  production in 1977.
• Subsequently more specific and potent inhibitors
  have been developed.
• The non-steroidal class reversibly bind the
  substrate binding site and the iron core.
• The steroidal class irreversibly bind the
  substrate binding site.

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Aromatase inhibitors (AI) in the metastatic
setting.

• AI established as similar or superior to
  tamoxifen for metastatic disease in the early
  1990s.

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2nd and 3rd line in metastatic disease

• Switching class of AI or switching to direct ER
  inhibitor continues to produce clinical response.

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Neoadjuvant therapy with AI

• 4 months of AI has efficacy before surgery.

Eiermann W, Paepke S, Appfelstaedt J, et al.
Preoperative treatment of postmenopausal breast
cancer patients with letrozole a randomized
double-blind multicenter study. Ann Oncol
20011215271532.
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Extended adjuvant therapy

• 5y tamoxifen is superior to 7y or 10y
• Would further therapy with an AI improve
  outcomes?
• MA-17 evaluated letrozole vs placebo for 5y after
  tamoxifen for 5y.
• This trial has now been extended to evaluate an
  additional 5y of letrozole vs placebo.

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• Femara Placebo
• Median age (y) 62 62
• ER and/or PgR () 98 98
• ECOG 0 () 90 90
• T1 () 58 58
• Node-negative 50 49
• Breast-conserving surgery57 57
• Radiotherapy 60 59
• Chemotherapy 46 46

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Risk of recurrence
Goss P. P1 The rise and current status of
aromatase inhibitors in breast cancer treatment.
The 27th Annual San Antonio Breast Cancer
Symposium. San Antonio, TX. Kluwer Academic
Publishers 2004.
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Primary endpoints at 2.5 years median follow-up
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Overall survival
HR 0.61
months
months
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Toxicities
Letrozole
Placebo
P value
Hot flashes Vaginal bleeding Osteoporosis Arth
ralgia Muscle pain
58 6 8 25 15
54 8 6 21 12
0.003 0.005 0.003 lt0.0001 0.04
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Should we extend adjuvant therapy?

• YES

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Should we switch earlier?

• Intergroup Exemestane Study IES

Coombes R, Hall E, Snowdon C, Bliss J. 3 The
Intergroup Exemestane Study a randomized trial
in postmenopausal patients with early breast
cancer who remain disease-free after two to three
years of tamoxifen-updated survival analysis. The
27th Annual San Antonio Breast Cancer Symposium.
San Antonio, TX. Kluwer Academic Publishers
2004.
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Demographics
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Disease free survival at median follow-up 37.4
months
88.9
85.1
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Overall Survival at median follow-up 37.4 months
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Toxicities
TgtE
T only
P value
Vaginal bleeding Osteoporosis Arthralgia Arthritis
/OA Muscle cramps Change in spine BMD Change in
hip BMD Gyn symptoms Visual disturbances Diarrhea
Thromboembolism MI
0.05 0.08 lt0.001 0.003 0.001 lt0.0001 lt0.0001 0.0
02 0.04 0.001 lt0.001 NS
4.0 8.3 19.8 16.8 3.0 2.9 2.1 14.3 7.4 5.3 1.9 0.9
5.5 6.9 13.1 13.5 5.1 0.02 0.5 17.8 5.7 3.0 3.3
0.4
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Should we switch earlier?

• Probably
• The ABCSG 8 and ARNO trials used anastrozole for
  the switch and also show an improvement in DFS.

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Should we just start with AI?
Anastrozole Tamoxifen And Combination Trial ATAC

• Schema
• Anastrozole 1mg daily for 5y placebo
• Or
• Tamoxifen 20mg daily for 5y placebo
• Or
• Both anastrozole and tamoxifen for 5y (closed at
  first interim analysis due to equivalence to
  tamoxifen alone)

Howell, A on behalf of the ATAC trialists group.
ATAC (Arimidex, Tamoxifen, Alone or in
Combination) completed treatment analysis
Anastrozole demonstrates superior efficacy and
tolerability compared with tamoxifen. The 27th
Annual San Antonio Breast Cancer Symposium. San
Antonio, TX. Kluwer Academic Publishers 2004.
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DFS at median follow-up of 68 months

• Anastrozole vs Hazard or
  Tamoxifen Population Odds
  Ratio 95 CI P Value
• Disease-free survival ITT
  0.87 0.78-0.97 0.01
  HR
  0.83 0.73-0.94 0.005
• Incidence of cBC ITT
  0.58 0.38-0.88 0.01
  HR 0.47
  0.29-0.75 0.001
• Time to recurrence ITT 0.79
  0.70-0.90 0.0005
  HR 0.74
  0.64-0.87 0.0002
• Time to distant ITT
  0.86 0.74-0.99 0.04
  recurrence HR
  0.84 0.70-1.00 0.06

Howell, A on behalf of the ATAC trialists group.
ATAC (Arimidex, Tamoxifen, Alone or in
Combination) completed treatment analysis
Anastrozole demonstrates superior efficacy and
tolerability compared with tamoxifen. The 27th
Annual San Antonio Breast Cancer Symposium. San
Antonio, TX. Kluwer Academic Publishers 2004.
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OS at median follow-up of 68 months

• 5y OS 84.3 on anastrozole
• 83.8 on tamoxifen
• P value 0.7
• No difference!

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Toxicities
Anastrozole
Tamoxifen
P value
Hot flashes Vaginal bleeding Vaginal
discharge Endometrial Cancer CVA DVT Joint
symptoms Fractures Hysterectomy Cardiac event
35.7 5.4 3.5 0.2 2.0 2.8 35.6 11.0 1.3 4.1
40.9 10.2 13.2 0.8 2.8 4.5 29.4 7.7 5.1 3.4
lt0.0001 lt0.0001 lt0.0001 0.02 0.03 0.0004 lt0.0001 lt
0.0001 lt0.0001 0.12
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Should we just start with AI?

• Most likely

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What order is best? Should we give tamoxifen at
all?
BIG 1-98 trial
Thurlimann, B, Letrozole as adjuvant endocrine
therapy for postmenopausal women with
receptor-positive breast cancer. Conference at
St. Gallens, 2005.
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Demographics
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DFS at median follow-up of 35.5 months
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OS at median follow-up of 35.5 months
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Toxicities
Letrozole 1st
Tamoxifen 1st
P value
Hot flashes Vaginal bleeding Fracture Endometrial
Ca Thromboembolism Hypercholesterolemia Nausea Ni
ght sweats Cardiac events
33.6 3.3 5.8 0.2 1.0 43.6 8.8 14.0 3.6
38.1 6.6 4.1 0.4 2.4 19.2 9.5 16.2 2.5
0.0006 0.078
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What order is best? Should we give tamoxifen at
all?

• We dont know yet but it appears that upfront
  letrozole is also more efficacious than
  tamoxifen.
• Will the cardiac and fracture events persist and
  have an adverse effect on survival?
• Will these adverse events be specific to
  letrozole?
• Will improved DFS ultimately improve OS?

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Summary of adjuvant AI trials
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ASCO guidelines for adjuvant therapy in HR
post-menopausal women

• Optimal adjuvant therapy should include an AI as
  initial therapy or after treatment with tamoxifen
  in order to lower the risk of tumor recurrence
• AIs are appropriate as initial treatment for
  women with contraindications to tamoxifen
• For all other postmenopausal women, treatment
  options include 5 years of AI treatment or
  sequential therapy consisting of tamoxifen (for
  either 2-3 years or 5 years) followed by AIs for
  2-3, to 5 years
• Women with breast cancer and their physicians
  must weigh the risks and benefits of all
  therapeutic options

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Conclusions

• AI have moved to the forefront of therapy for
  hormone receptor positive breast cancer at all
  stages
• Judgement should be exercised with regards to
  increased risk of fracture, endometrial cancer
  and MI for each patient and monitoring/preventing
  these events.