2012
Navigating Hormonal Therapy
Paula D. Ryan, MD, PhD
Associate Professor, Medical Oncology
April 29, 2012
Questions to Ask your Doctor
Who will be on my medical team?
What type of breast cancer do I have?
How many tumors do I have?
What are my treatment options?
How often will we review my progress?
Are there any clinical trials for which I
might qualify?
• Will I still be able to ____?
2012
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Breast Cancer Team
2012
• Breast cancer expert: medical, surgical, radiation
oncology
• Psychological well being
• Oncology Nurse and/or Nurse Practitioner
• Genetic Counselors
• Pain and Supportive Care Team
• Registered dietitians
• Oncology social workers
• Increased knowledge of the biology of
cancer
• New molecular understanding that breast
cancer is a family of diseases
• Endocrine therapy with tamoxifen,
aromatase inhibitors, fulvestrant
• Targeted therapies: mTOR inhibitors and
beyond
2012
Navigating Hormonal Therapies:
Today
Hanahan and Weinberg, 2000
2012
Acquired Capabilities of Cancer
Genomics to the Clinic
• Molecular classification of breast cancer
into clinically relevant subtypes
2012
• New insights into various cancer
pathways and the process of
metastastic progression
DNA Chip or Microarray
Technology
ER neg
Breast
Cancer
is not a
Single
Entity…
It is a
Family of
Diseases
Her-2 +
ER pos
Sorlie, et al.
PNAS 2001
Breast Cancer—Not just one
disease
2012
• Hormone Receptor positive: Estrogen
Receptor (ER) and/or Progesterone
Receptor (PR) positive
• HER2 positive: ~20%
• ER, PR and HER2 negative, “triple
negative”: ~15-20%
Antagonizing Estrogen Dependent
Growth in Breast Cancer
Premenopausal
Postmenopausal
Peripheral Sites: adrenal
gland, liver, muscle, fat
Ovaries
Ovarian
Suppression
GnRH inhibitors or
Ovarian removal
ER
ER
Tamoxifen
Estrogen
X
Cancer Cell
Aromatase
Inhibitors
Tamoxifen
Fulvestrant
Hormonal Therapies
• There are three different types of hormonal therapy
medicines:
• Aromatase inhibitors:
– Arimidex (chemical name: anastrozole)
– Aromasin (chemical name: exemestane)
– Femara (chemical name: letrozole)
• SERMs (Selective Estrogen Receptor Modulators):
– Tamoxifen
– Fareston (chemical name: toremifene)
• ERDs (Estrogen Receptor Downregulators):
2012
– Faslodex (chemical name: fulvestrant)
2012
Tamoxifen
Tamoxifen
2012
• Premenopausal women with or without
ovarian suppression
• Postmenopausal women
• Pill taken once per day
• Side effects: hot flashes, vaginal
symptoms, rare uterine cancer and
clotting risks
Aromatase Inhibitors
2012
• Postmenopausal
women
• Lowers estrogen levels
• Pill taken once per day
• Side effects: hot
flashes, muscle or bone
aches or pains, bone
density loss
Fulvestrant
2012
• Postmenopausal
women
• Blocks the estrogen
receptor
• Administered
intramuscularly once
per month
• Side effects: hot
flashes, headache,
back pain, GI, all
generally mild
Strategies to Restore Hormone
Responsiveness
IGF-1R, EGFR
ER
RAS
PI3K
E
AKT
ER
RAF
TSC2 TSC1
MEK
mTOR
ERK
E
ER
Cell Proliferation
Reprinted from J Steroid Biochem Mol Biol. 106/1-5, Yue W et al, Mechanisms of acquired resistance to endocrine therapy
in hormone-dependent breast cancer cells, Pages102-110, “Copyright 2007 with permission from Elsevier .
Baselga J et al N Eng J Med 2012;366:520-529
2012
Overcoming endocrine resistance
Navigating Hormonal Therapy
For postmenopausal women:
– Tamoxifen, toremifine
– Nonsteroidal aromatase
inhibitors (anastrozole,
letrozole)
– Steroidal aromatase inibitor
(exemestane)
– Pure anti-estrogens
(fulvestrant)
– Progestin (megestrol
acetate)
– High-dose estrogen (ethinyl
estradiol)
•
For premenopausal women:
– LHRH agonists (goserelin
and luprolide)
– Surgical oophorectomy
– Tamoxifen
2012
•
Role of Ovarian Suppression in
Premenopausal Women
Klijn JGM et al JNCI 2000;92:903-911
2012
• Ovarian suppression is an integral part of the
treatment for women who are premenopausal
who have ER-positive breast cancer
• In a small randomized clinical trial, there was
a small advantage for incorporating both
ovarian suppression and tamoxifen
simultaneously in the initial treatment of
premenopausal patients
Preferred First-Line Hormonal
Therapy for Postmenopausal
Women
2012
• Aromatase Inhibitors
• Tamoxifen or fulvestrant also options in
the setting of postmenopausal women
who have not received prior endocrine
therapy within the previous year
Sequential Use of Endocrine
Therapies
• Women with breast cancer showing a clinical
benefit from an endocrine therapy (shrinkage
of tumor or long-term disease stabilization)
should receive additional endocrine therapy
at the time of disease progression
Chia S et al J Clin Oncol 2008;26:1664-1670
2012
• EFECT trial: Exemestane or fulvestrant equal
benefit after anastrozole or letrozole
Anti-HER2 Therapy Combined with Endocrine
Therapy for Hormone Receptor Positive and
HER2 Positive Breast Cancer
• The TanDEM trial showed trastuzumab plus
anastrozole led to a longer interval before
disease progressed compared to anastrozole
alone (although side effects greater with the
combination)
Mackey JR et al Breast Cancer Res Treat 2006, 100(Suppl 1)
Johnston S J Clin Oncol 2009;27:5538-46
2012
• Letrozole plus lapatinib led to improved
clinical benefit compared to letrozole alone
• Aromatase inhibitors: hot flashes, bone
density loss, increased rate of bone fracture,
joint and muscle aches
• Tamoxifen: hot flashes, increased risk of
uterine cancer, increased risk of deep venous
thrombosis
• LHRH agonist therapy and fulvestrant:
injection site reactions
• Estrogen: increased risk of clots
2012
Potential Side Effects of
Endocrine Agents
Bone Modifying Agents in
Breast Cancer
2012
Mechanism of Action
• Reduces and
delays bone
complications due
to bone
metastases
• Treats
hypercalcemia of
malignancy
2012
Bone Modifying Therapy:
zoledronic acid
Denosumab
Reduces Skeletal Events
• Fully humanized monoclonal
antibody targeting RANKL
– RANKL activates bone
digesting osteoclast cells
Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.
27
2012
• FDA-approved in 2010 for
prevention of skeletal related
events in patients with bone
metastases from solid
tumors
Should Metastatic Disease Be
Confirmed by Biopsy?
2012
• Biopsy of metastatic disease is recommended
• Tumor marker testing (ER/PR and HER2)
– For women with an initial breast cancer
diagnosis, tumor markers must be
determined
– Are tumor markers stable with disease
progression?
Karolinska Cohort:
Intra-individual ER Status at Relapse
Lindstrom L, et al. SABCS 2010. Abstract S3-5.
2012
• Aim
– Determine if hormone receptor and HER2 status
change between primary breast cancer and relapse
• Methods
– N = 1051 breast cancer patients relapsing between
1997-2007 at single center in Stockholm, Sweden
– Hormone receptor and HER2 status gathered from
original patient records
Karolinska Cohort:
Intra-individual ER Status at Relapse
ER Status*
Relapse Sites
Positive
Positive
33.7
Negative
Negative
37.6
Positive
Negative
10.9
Negative
Positive
11.9
Heterogeneous
5.9
Heterogeneous
Lindstrom L, et al. SABCS 2010. Abstract S3-5.
2012
Primary tumor
Patients, %
Navigating Hormonal Therapy:
Tomorrow
2012
• We will use our rapidly increasing knowledge of
cancer genomics and cell biology to develop more
effective and less toxic treatments
• We will continue to probe the mechanisms of
endocrine resistance to develop better strategies to
overcome this problem
• We will continue to improve our knowledge of
metastatic progression and develop improved
technologies to identify cancer at its earliest stages