Navigating Hormonal Therapy Paula D. Ryan, MD, PhD

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 ____?

Breast Cancer Team 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

Navigating Hormonal Therapies: Today 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

Hanahan and Weinberg, 2000 Acquired Capabilities of Cancer

Genomics to the Clinic Molecular classification of breast cancer into clinically relevant subtypes New insights into various cancer pathways and the process of metastastic progression

DNA Chip or Microarray Technology

Sorlie, et al. PNAS 2001 ER neg ER pos Her-2 + Breast Cancer is not a Single Entity… It is a Family of Diseases

Breast Cancer—Not just one disease 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 Estrogen Ovaries Peripheral Sites: adrenal gland, liver, muscle, fat Aromatase Inhibitors Tamoxifen X Postmenopausal Ovarian Suppression GnRH inhibitors or Ovarian removal Premenopausal Cancer Cell Fulvestrant Tamoxifen

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): Faslodex (chemical name: fulvestrant)

Tamoxifen

Tamoxifen 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 Postmenopausal women Lowers estrogen levels Pill taken once per day Side effects: hot flashes, muscle or bone aches or pains, bone density loss

Fulvestrant 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 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 . RAS RAF MEK ERK ER ER AKT PI3K E E mTOR TSC1 TSC2 IGF-1R, EGFR Cell Proliferation

Overcoming endocrine resistance Baselga J et al N Eng J Med 2012;366:520-529

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

Role of Ovarian Suppression in Premenopausal Women 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 Klijn JGM et al JNCI 2000;92:903-911

Preferred First-Line Hormonal Therapy for Postmenopausal Women 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 EFECT trial: Exemestane or fulvestrant equal benefit after anastrozole or letrozole Chia S et al J Clin Oncol 2008;26:1664-1670

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) Letrozole plus lapatinib led to improved clinical benefit compared to letrozole alone Mackey JR et al Breast Cancer Res Treat 2006, 100(Suppl 1) Johnston S J Clin Oncol 2009;27:5538-46

Potential Side Effects of Endocrine Agents 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

Bone Modifying Agents in Breast Cancer Mechanism of Action

Bone Modifying Therapy: zoledronic acid Reduces and delays bone complications due to bone metastases Treats hypercalcemia of malignancy

Denosumab Reduces Skeletal Events Fully humanized monoclonal antibody targeting RANKL RANKL activates bone digesting osteoclast cells FDA-approved in 2010 for prevention of skeletal related events in patients with bone metastases from solid tumors 27 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

Should Metastatic Disease Be Confirmed by Biopsy? 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 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 Lindstrom L, et al. SABCS 2010. Abstract S3-5.

Karolinska Cohort: Intra-individual ER Status at Relapse Lindstrom L, et al. SABCS 2010. Abstract S3-5.

Navigating Hormonal Therapy: Tomorrow 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