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Mdi Medical Management of Breast Cancer Morbidity and Mortality Aug 13, 2009 Irina Kovatch, PGY3

Introduction Metastatic disease is the principal cause of death from breast cancer Metastatic events often occur prior to initial clinical evaluation Systemic approach is needed in concert with local treatment Benefit from chemo and/or hormonal therapy is due to metastasis being prevented, cured, or delayed

Molecular Markers ER PR HER-2 (erb-b2/neu protein) has 3 binding partners: HER-1 (EGFR), HER-3, and HER-4 Triple negative cancers (basal-like like cancers) Oncotype DX (21 gene RT-PCR Assay) genomic test which quantifies expression of specific mrna for 16 cancer genes and 5 reference genes in breast cancer biopsy py tissue, combining the expression results into a single Recurrence Score (0-100) which predicts a chance of the breast cancer recurrence within 10 years. Risk categories: low <=18, intermediate 19-31, high >31

Steroid Hormone Receptors If >10% of tumor cells stain positive for the nuclear receptor, response to hormonal treatment is likely 60% of breast tumors contain either ER or PR Male breast cancer is almost always ER-positive Clinically the most important protein induced by ER is the receptor for progesterone PR may serve as an indicator for the presence of a functional ER (PR-positive breast cancers display intermediate responsiveness to hormonal treatments, even if measured value of ER is very low or zero)

Distribution of Steroid Receptors

Response Based on Steroid Receptors Presence of ER predicts clinical response to all types of endocrine therapy, both additive and ablative Presence of PR correlates with response to endocrine therapy Presence of both receptors is associated with 80% chance of favorably responding to hormone addition or blockade

Relationship Between Steroid Receptor Status and Objective Response to Endocrine Therapy

Hormonal Therapy Effect of steroid hormones and inhibitors on sensitive tissues is the basis for effective treatment of breast cancer Surgically induced menopause (bilateral oophorectomy) produced a beneficial regression in 25-40% of pre- menopausal patients Endocrine organ ablation has been replaced by antiestrogen therapy in most patients Tamoxifen (estrogen agonist-antagonist) antagonist) is currently the first-line treatment of estrogen-sensitive sensitive ii breast cancer

Hormonal Agents

Selective Estrogen Receptor Modulators Estrogen receptor agonists/antagonists (e.g. tamoxifen, raloxifene, toremifene) Tamoxifen acts as a competitive i antagonists of estrogen in breast Can replace oophorectomy in premenopausal p women with ER-positive metastatic cancer Considered the drug of first choice in both premenopausal and postmenopausal patients with ER- positive breast cancer Ideal SERM blocks ER in breast cancer tissue, is neutral or inhibitory in the endometrium, lacks procoagulant activity, and acts like estrogen in skeletal, cardiovascular, and central nervous system

Selective Aromatase Inhibitors SAI inhibit the last enzymatic step in the formation of estrone SAI include nonsteroidal compounds (reversible inhibitors e.g anastrozole, letrozole) and steroid-based compounds (irreversible inhibitors e.g. exemestane) SAI used in postmenopausal women to completely suppress production of estrogen from extragonadal sites (adipose tissue) In premenopausal p women SAI cause reflex pituitary release of gonadotropins, development of polycystic ovaries, and excessive androgen production [may be used di in combination with ithl luteinizing i i hormone-releasing releasing hormone agonists (LHRH)]

Luteinizing Hormone-Releasing Hormone Agonists LHRH-As are superagonists that cause early, massive release of pituitary gonadotropins, followed by paralysis of pituitary and resistance to normal LHRH LHRH-As are peptide analogs of normal releasing hormone which are 50-100 times more potent Two are in clinical use for treatment of breast cancer (goserelin and leuprolide)

Adjuvant Tamoxifen Trials Scottish trial 1978 randomized women after surgery for breast cancer regardless of ER status Results in tamoxifen treated arm: Reduction in recurrence from 38 to 24% Increase in survival rates from 18 to 23% Twenty more trials combined into large meta-analysis analysis confirmed the above results Later trials showed that all benefit from endocrine treatment t t was in women with ither ER-positive disease and PR-positive but ER-poor tumors

Meta-Analysis of Adjuvant Tamoxifen for Breast Cancer More than 60 randomized dt trials Compared 1 to 2 years or 5 years with no treatment (control) in women with ER-positive breast cancer Result: 5 years of treatment was better than 1 to 2 years Proportional reductions unaffected db by age, menopausal status, nodal status or concomitant treatment 5 years of tamoxifen halved recurrence rate and reduced breast cancer mortality by a third

Results of Meta-Analysis

Tamoxifen vs. Anastrozole ATAC trial large, g, multinational,,p prospective, p double blinded (9366 women) Compared 5 years of tamoxifen with 5 years of anastozole and combination of the two Results at 4 years favor use of anastrozole as a single agent with a 14% reduction in the risk for recurrence and absolute benefit of f24% 2.4% Benefits are in women with ER-positive breast cancer (no difference in ER-negative) Drugs in SAI group are not appropriate as single agents in premenopausal women

Trastuzumab Trastuzumab (Herceptin) humanized murine monoclonal antibody raised against erb-b2/her B2/HER-2 surface receptor Recent studies evaluated addition of trastuzumab to conventional chemotherapy in women with operable breast cancer (surgical adjuvant) and women with metastatic disease that is HER-2 positive Outcomes: 50% reduction in either recurrence (for adjuvant treatment) or time to progression (for metastatic disease)

Meta-analysis analysis of Adjuvant Chemotherapy Adjuvant chemotherapy administration of cytotoxic drugs after surgery 33,000 women participated i in >100 clinical i l trial worldwide Trials opened before 1995 and randomized d before 2000 Results published on a 5-year cycle, last summarized in 2005 Substantial improvements in recurrence and survival for invasive cancer

Strategies Tested No chemotherapy (control) Single agent chemotherapy Polychemotherapy Polychemotherapy containing an anthracycline (doxorubicin or epirubicin) More recent studies include use of taxanes (docetaxel, paclitaxel) mitotic inhibitors, radiosensitizing agents use of trastuzumab for patients with HER-2

Results Anthracycline-based chemotherapy combination reduces estimated breast cancer death rate by 38% in women <50, and 31% in women 50-69 years of age Seen in virtually all subtypes of breast cancer based on node status, ER status, and characteristics of the tumor

Adjuvant Chemotherapy

NCCN Clinical Practice Guidelines

Adjuvant Endocrine Therapy

NCCN Clinical Practice Guidelines

Summary Adjuvant chemotherapy, endocrine therapy, or both, likely l to benefit nearly all patients with invasive i breast cancer Adjuvant hormonal therapies benefit only breast cancer patients with ER-positive cancers Risk-benefit ratio of adjuvant therapy must be estimated for each patient Patients with very favorable tumors (e.g. <1cm in size or tumors with good histology up to 2-3cm) are candidates for no treatment besides local surgery plus irradiation

References Willett WC, Rockhill B, Hankinson SE, et al: Nongenetic factors in the causation of breast cancer.. In: Harris JR, Lippman ME, Morrow M, Osborne CK, ed. Diseases of the Breast,, 3 rd ed. Philadelphia: Lippincott Williams Wilkins; 2004:223-276. 276. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005; 365:1687-1717. 1717. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as post-operative operative adjuvant treatment of node- positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21:1431-1439. 1439. Goldhirsch A, Glick JH, Gelber RD, et al: Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16:1569-1583. 1583. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Breast Cancer. V.1.2009