Neoadjuvant Endocrine Therapy in Breast Cancer

1
Neoadjuvant Endocrine Therapy in Breast Cancer

• Priya Gopalan
• 10/27/06

2
Overview

• Estrogen production
• Estrogen pathways
• Endocrine therapy in the neoadjuvant setting
• Initial studies
• Phase III studies
• Effect of Her-2 status

3
Case

• 60 yo woman palpated a mass in her right breast
• Biopsy showed invasive carcinoma with lobular
  features
• ER, PR-, Her-2/neu amplified by FISH (3.25)
• Referred by surgeon for neoadjuvant therapy
  because of a concern for positive margins with
  immediate mastectomy

4
Case

• On initial exam, mass 10 x 8 cm, with peau
  dorange of overlying skin (no signs of
  erythema/inflammation)
• Also had palpable 1 cm R axillary lymph node
• Stage T4bN1M0 (IIIB)
• Breast MRI showed 8.5 cm mass, 3 axillary lymph
  nodes
• CT negative for metastases

5

• What should we do now?

6
Overview

• Estrogen production
• Estrogen pathways
• Endocrine therapy in the neoadjuvant setting
• Initial studies
• Phase III studies
• Effect of Her-2 status

7
Estrogen Metabolism
From Up-to-Date
From Up-to-Date
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Placenta Bones
From Bulun SE et al. 2005. Pharm Rev
57359-383.
9
Aromatase gene
From Bulun SE et al. 2005. Pharm Rev
57359-383.
10
From Bulun SE et al. 2005. Pharm Rev
57359-383.
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Breast cancer

• Estradiol stimulates growth and prevents
  apoptosis in ER breast cancer

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Blocking effect of estrogen

• Block estrogen production
• e.g. Aromatase inhibitors
• Selectively modulate estrogen effect
• e.g. SERMs (tamoxifen)
• Bind and downregulate estrogen receptors
• e.g. fulvestrant

13
Overview

• Estrogen production
• Estrogen pathways
• Endocrine therapy in the neoadjuvant setting
• Initial studies
• Phase III studies
• Effect of Her-2 status

14
Estrogen pathways

• Direct gene transactivation
• Nuclear-Initiated Steroid Signaling (NISS)
• Indirect activation via activation of signaling
  pathways at the cell membrane
• Membrane-Initiated Steroid Signaling (MISS)

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Nuclear-Initiated Steroid Signaling (NISS)

• Estrogen binds estrogen receptor a and b in the
  nucleus
• ERa - important in breast cancer
• ERb - role in breast cancer is controversial
• May antagonize ERa activity
• ERa then undergoes conformational change
• Receptor then dimerizes

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Nuclear-Initiated Steroid Signaling (NISS)

• ER interacts with estrogen response element in
  the promoter region of estrogen-sensitive genes,
  leading to transactivation of specific genes
• e.g. IGFR, cyclin D1, Bcl-2, VEGF
• Coactivator/corepressor molecules modulate
  activity
• ER also binds to nuclear transcription factors -
  leads to transactivation
• Acts as a coactivator

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Tamoxifen

• Selective Estrogen Receptor Modulator (SERM)
• Binds ER with high affinity
• ER then undergoes a conformational change that is
  different from the change after estrogen binding
• Changes the way ER interacts with coactivators
  and corepressors
• Binds DNA, but get altered gene transcription
• Tissue-specific pattern of interaction with
  coactivators and corepressors
• Promotes bone mineralization, endometrial
  proliferation (acts as agonist)
• Inhibits growth in the breast (acts as antagonist)

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Membrane-Initiated Steroid Signaling (MISS)

• Also have rapid estrogen-mediated activation of
  signaling pathways at the plasma membrane
• ER is probably localized near plama membrane
• ER forms a complex with many proteins
• CSK is a kinase that interacts with ER
• Model Estrogen-bound ER activates CSK, which
  phosphorylates IGF1R
• Activates signaling molecules
• This form of signaling by estrogen is not always
  inhibited by SERMs (tamoxifen resistance)

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Overview

• Estrogen production
• Estrogen pathways
• Endocrine therapy in the neoadjuvant setting
• Initial studies
• Phase III studies
• Effect of Her-2 status

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Neoadjuvant therapy

• Used to shrink locally advanced or unresectable
  tumors to render them operable
• Used for tumor shrinkage of large tumors to
  permit breast-conserving surgery
• Used to allow less extensive resections in
  breast-conserving surgery to produce better
  cosmetic results

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Neoadjuvant endocrine therapy

• Early trials
• Initially did not treat patients on basis of
  ER/PR status
• Anastrozole
• 1mg and 10mg in 24 postmenopausal pts. with ER
  locally advanced or large operable breast cancer
  - compared tumor volume after 3 months
• 75.5 median reduction by ultrasound for both
  doses grouped together
• Dixon et al. 2000. Clin Cancer Res 62229-35

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Neoadjuvant endocrine therapy

• Letrozole
• 2.5mg and 10mg in 24 postmenopausal pts. with ER
  locally advanced or large operable breast cancer-
  compared tumor volume after 3 months
• 88 reduction clinically for both doses grouped
  together
• Dixon et al. 2001. Breast Cancer Res Treat
  66191-99
• Exemestane
• 25mg in 13 postmenopausal pts. with ER locally
  advanced or large operable breast cancer-
  compared tumor volume after 3 months
• 85 reduction clinically
• Dixon et al. 2001. Proc Am Soc Clin Oncol 20ab
  1908

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Phase III trials comparing Aromatase Inhibitors
to Tamoxifen

• 3 main trials
• IMPACT
• PROACT
• P024

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IMPACT Trial

• Smith et al. JCO 235108-16.
• IMPACT (Immediate Preoperative Anastrozole,
  Tamoxifen or Combined with Tamoxifen) trial
• Phase III randomized, double-blind,
  placebo-controlled multicenter trial
• 330 postmenopausal women with ER and/or PR,
  operable or locally advanced potentially operable
  breast cancer
• Randomized to
• tamoxifen (20 mg qd) anastrozole placebo
• anastrozole (1 mg qd) tamoxifen placebo
• tamoxifen (20 mg qd) anastrozole (1 mg qd)
• 3 month treatment then 5 years as adjuvant
  therapy
• Endpoint - tumor objective response (caliper and
  ultrasound measurement)

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IMPACT Trial
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PROACT Trial

• Cataliotti et al. 2006. Cancer 1062095-103
• Pre-Operative Arimidex Compared to Tamoxifen
  (PROACT)
• Phase III, randomized, multicenter trial
• 451 postmenopausal women with ER and/or PR,
  with large operable or potentially operable
  disease
• Randomized to
• tamoxifen (20 mg qd) anastrozole placebo
• anastrozole (1 mg qd) tamoxifen placebo
• Concomitant neoadjuvant chemotherapy permitted
• Treated for 12 weeks, f/u for 5 years
• Endpoint Tumor objective response (caliper and
  U/S measurements)

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PROACT Trial
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P024 Trial

• Eiermann et al. 2001. Ann Onc 121527-32
• Phase III randomized, double-blinded, multicenter
  trial
• 337 postmenopausal women, ER and/or PR
• Ineligible for breast-conserving surgery (BCS)
• 14 were considered inoperable
• Randomized to letrozole (2.5mg) vs. tamoxifen
  (20mg) for 4 months
• Endpoint - Clinical response (2 response by
  U/S and mammogram, number of pts qualified for
  BCS)

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P024 Trial
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Letrozole vs Tamoxifen

• Ellis et al. 2001. JCO 19 3808-16.
• Extension of P024 trial
• Prospective study of activity of tamoxifen and
  letrozole with respect to EGFR and Her-2
  expression
• Both thought to be involved in endocrine
  resistance

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Effect of EGFR/Her-2 status
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Why is letrozole better than tamoxifen in
EGFR/Her-2 , ER patients? (Ellis et al. JCO
2001)

• MCF-7 breast cancer cells transfected with Her-2
  grow in presence of tamoxifen (Benz et al. 1993,
  Breast Cancer Res Treat 2485-95)
• MEKK1, a downstream component of the
  EGFR-mediated signaling pathway, has been shown
  to activate ERa and stimulate the agonist effect
  of tamoxifen (Lee et al. 2000, Mol Endocrinol
  141882-96)
• Letrozole eliminates estrogen - ER becomes
  monomeric and may be unable to bind DNA

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Neoadjuvant endocrine therapy in Her-2 patients

• Ellis et al. 2003. Cancer Res 636523-31
• Ki67, a proliferation marker, was measured pre-
  and post-treatment
• Reduction in Ki67 significantly greater after
  letrozole (87) than tamoxifen (75) treatment
• Reduction in subset of pts. Her1/2- 86 (L) vs.
  79 (T)
• Reduction in subset of pts. Her1/2 88 (L) vs.
  45 (T)
• Thus, Her1/2 patients showed some resistance to
  tamoxifen therapy, and much less resistance to
  letrozole treatment

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What happens to gene transcription?

• PR and TFF1(trefoil factor 1) are genes directly
  regulated by ER through ERE
• Significant decrease in PR and TFF1 expression
  after letrozole treatment
• However, no significant change in PR or TTR1
  expression after tamoxifen treatment
• Thus, ER-regulated transcription of PR and TFF1
  is not inhibited by tamoxifen

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Letrozole
Tamoxifen
Ellis, M. J. et al. Cancer Res 2003636523-6531
36

• Thus, letrozole is effective in EGFR and/or Her-2
  positive and negative patients
• Superior to tamoxifen in EGFR and/or Her-2
  positive patients
• Significant reduction in Ki67 and PG/TFF1
  expression

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Her-2- positive breast cancer

• Ellis et al. 2006. JCO 243019-25
• P024 population
• Her-2 status confirmed by FISH

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Response to Letrozole Therapy
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Ki67 expression after letrozole
Her-2
Her-2 -
Ellis, M. J. et al. J Clin Oncol 243019-3025
2006
40

• Suggests that although clinical response is
  observed, proliferation is ongoing - may see
  eventual therapeutic resistance

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Conclusions

• Estrogen production is enhanced in the breast of
  breast cancer patients
• Estrogen acts through both direct DNA
  transcription and membrane-initiated pathways
• Neoadjuvant endocrine therapy with both tamoxifen
  and aromatase inhibitors help decrease tumor
  volume and increase breast-conserving surgery

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Conclusions

• Aromatase inhibitors are superior to tamoxifen in
  the neoadjuvant setting
• Particularly in patients with EGFR and/or Her-2
  expression
• Current trial addressing which aromatase
  inhibitor is superior in neoadjuvant setting
  (letrozole vs. anastrozole vs. exemestane)
• Still see proliferation, even though there is a
  marked clinical response, in patients with Her-2
  expression, after letrozole therapy

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Back to the Case

• Patient given letrozole 2.5 mg daily for 16 weeks
  on trial
• At 16 weeks
• Breast mass was 5.8 x 3.2 cm on clinical exam
  (initially 10 x 8 cm)
• Overlying skin changes no longer appreciated (by
  12 weeks)
• No palpable right axillary lymph node (by 4
  weeks)
• Breast MRI mass seen as a faint residual patchy
  enhancement without a discrete focus (initially
  8.5 cm)

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Case (continued)

• Right modified radical mastectomy
• Dense fibrosis with scattered areas of residual
  carcinoma measuring 0.1 to 0.2 cm in diameter
• No evidence of dermal involvement
• 5 out of 17 sampled lymph nodes positive
• F/U
• adjuvant CMF and radiation
• restarted letrozole and began trastuzumab
• disease-free after 17 months

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Thank you
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Estrogen Receptor-a
N
C
Hormone-independent activation function (AF-1)
Hormone-dependent activation function (AF-2)
Hormone-binding domain
DNA-binding domain/dimerization
Nuclear localization sequences