Biology and Treatment of Breast Cancer Julie R. Gralow, M.D. Director, Breast Medical Oncology Jill Bennett Endowed Professor of Breast Cancer Professor, Global Health University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle Cancer Care Alliance

Breast Cancer Biology: Not all Breast Cancers are the Same!! Estrogen Receptor (ER) + 75% of Breast Cancer HER-2 + 20-25% of Breast Cancer Tumor ER and HER2 status are CRITICAL in selecting therapy in both early stage and metastatic breast cancer!

Breast Cancer Biology: Triple Negative Breast Cancer (TNBC) Breast cancer that does not express: Estrogen Receptor (ER) Progesterone Receptor (PR) HER-2 15 to 20 percent of breast cancers Virtually always high grade Common in BRCA1 mutation carriers (over 80%) Overrepresented in premenopausal and African women Poor prognosis Sensitive to chemotherapy

Determining ER and HER-2 Status Tissue Processing: Each Step Matters! Cold ischemia time: time from tissue removal to placement in fixative Fixation parameters: type of fixative and duration

Breast Cancer Treatment: A Multidisciplinary Team Approach Radiology Pathology Surgery Radiation Oncology Medical Oncology Fighting the Crab – Kiev, Ukraine

Breast Cancer Systemic Therapies Drug treatments that can attack cancer cells throughout the body Endocrine (hormonal) therapy Chemotherapy Targeted therapy

Estrogen Receptor as a Target for Therapy Aromatase inhibitors, ovarian suppression SERMS (tamoxifen), SERDS Cell Growth and Division Estrogen Estrogen Receptor Endocrine therapy is effective only in ER-positive breast cancer

WHO Model List of Essential Medicines 19th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Endocrine therapy: Tamoxifen Anastrozole (Arimidex) – aromatase inhibitor, postmenopausal only Leuprolide (Lupron) – ovarian suppression, premenopausal only http://www.who.int/medicines/publications/essentialmedicines/en/

WHO Model List of Essential Medicines 19th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Chemotherapy: Doxorubicin (Adriamycin) Cyclophosphamide (Cytoxan) Paclitaxel (Taxol) Docetaxel (Taxotere) Fluorouracil (5-FU) Methotrexate Carboplatin Gemcitabine (Gemzar) Capecitabine (Xeloda) Vinorelbine (Navelbine) http://www.who.int/medicines/publications/essentialmedicines/en/

HER-2 as a Target for Therapy Pertuzumab Anti-HER-2 Antibody HER-2 Trastuzumab Anti-HER-2 Antibody cancer cell nucleus Lapatinib Dual HER-1/HER-2 Tyrosine Kinase Inhibitor T-DM1 Ado-trastuzumab emtansine Antibody-Drug Conjugate cell division

WHO Model List of Essential Medicines 19th Edition (April 2015) Antineoplastic drugs relevant to breast cancer Targeted Therapy Trastuzumab (Herceptin) http://www.who.int/medicines/publications/essentialmedicines/en/

Targeting the Cancer Environment In Addition to Targeting the Cancer Cell, We Can Also Target the Cancer Environment Cancer cell Fibroblast Immune cell Blood vessels Osteoclast (bone cells)

Targeting the Cancer Environment: Bone Inhibition cancer cells osteoclasts osteoblasts, macrophages Drugs that block bone destruction: Bisphosphonates (zoledronic acid, pamidronate) RANK ligand inhibitor (denosumab)

Goals in the Treatment of Breast Cancer Vary by Stage

Non-Metastatic Breast Cancer Cancer confined to the breast and local lymph node areas

Treatment of Non-Metastatic Breast Cancer Goal: Cure Breast cancer is most curable when detected early Micrometastases (undetectable) can exist at time of diagnosis in many patients, leading to eventual recurrence Multidisciplinary care is critical for best outcomes Surgery Radiation therapy Adjuvant systemic (drug) therapy Reduces risk of recurrence and death Should be tailored to the patient and tumor

Metastatic Breast Cancer Cancer that has spread beyond the breast and local lymph node areas

Treatment of Metastatic Breast Cancer Goals: Control and regression of disease Prolongation of life Improvement in symptoms and quality of life Metastatic breast cancer is not currently usually curable, but is treatable

Quantity of Life Quality of Life Treatment of Metastatic Breast Cancer: A Balancing Act Balancing treatment efficacy and toxicity is a major objective Quantity of Life Quality of Life

Choices in the Treatment of Metastatic Breast Cancer Treatment is mainly with drug therapy that can attack cancer throughout the body Radiation can be important (ie for pain control) Surgery uncommon Choice of treatment is based on many factors: Patient age, menopausal status, general health and functional status Tumor ER status, HER-2 status Previous treatments Extent and sites of disease Available therapies in the patient’s country

Biology and Treatment of Breast Cancer: Challenges Despite important progress to date, cancer remains one of the world’s most serious health problems Disparities in cancer care and survival remain significant Worldwide, new cancer cases and deaths continue to rise

Biology and Treatment of Breast Cancer: The Future Cancer care is set to change dramatically in the next 10-20 years Advances in technology and a deeper understanding of cancer biology will transform cancer care Continued investments in cancer research required to translate scientific breakthroughs into new and affordable treatments

Biology and Treatment of Breast Cancer: Summary Main principles of modern oncology Multidisciplinary treatment Evidence-based medicine Individualized (tailored) therapy Primary goals of therapy Adjuvant: curative intent Metastatic: incurable but treatable Include psychosocial and supportive care and symptom-related interventions Include patient preferences and active participation Patients, families and caregivers should be invited to participate in decision-making