Treatement of Metastatic Breast Cancer: A Long and Winding Road Slovenian Experience Simona Borštnar, MD, PhD Division of Medical Oncology Head of breast cancer multidisciplinary board President of Slovenian Senologic Society Skopje, 24.October 2017

Breast cancer statistic WORLD ~522,000 BC deaths annually 25.1% All cancers in women 14.7% Cancer deaths in women ~1.67m new BC cases annually Includes: 458,718 women in Europe (28.6%)2 232,714 women in the US (29.9%)2 Includes: 131,347 deaths in Europe (16.9%)2 43,909 deaths in the US (15.0%)2 SLOVENIA ~380-400 BC deaths annually 1200-1300 new BC cases annually 20.5%* All cancers in women 14.6%* Cancer deaths in women Data 2014: N=1288 Data 2014: N= 379

Age standardised incidence and mortality rates for breast cancer in Slovenia http://www.slora.si/

Incidence of early, primary and secondary metastatic Breast cancer in Slovenia All BC patients Incidence ≈1250 Prevalence ≈16000 Primary metastatic (6%) N ≈90 (per year) Secondary Metastatic BC (25%-30%) N ≈300

Adjuvant systemic therapy Why is adjuvant systemic treatment important? Adjuvant systemic therapy surgery , Fisher “demonstrated that the regional lymph nodes were not a barrier to the dissemination of tumor cells, as postulated earlier, but were routes traversed by tumor cells to gain access to the circulating bloodstream and lymphatic system. Out of this basic work on cancer metastasis came a new model for the management of breast cancer based on the premise that the disease is systemic from its inception. Adapted fromAdjuvant!online.com

Common Breast Cancer Metastasis Sites When cancer cells break away from a tumor, they can travel to other areas of the body through the bloodstream or the lymphatic system.

Facts About Metastatic Breast Cancer 20% to 30% of people initially diagnosed with early stage disease will develop metastatic breast cancer. Early detection does not guarantee a cure. Metastatic breast cancer can occur 5, 10 or 15 years after primary diagnosis and successful treatment checkups and annual mammograms.

Clinical Breast Cancer Subsets Defined by IHC in metastatic disease

Treatment options Chemotherapy Hormonal therapy Anti-HER2 therapy

The Goals of Treatment of Metastatic Breast Cancer Maximizing the quality of life Prevention and palliation of symptoms Prolongation of survival

Treatment of Breast Cancer Treatment for metastatic breast cancer is lifelong, characterized by remissions and relapses. ST 1 ST 5 ST 2 ST 3 ST 4 PT ST= systemic treatment , PT= palliative treatment

Hormonal therapy Most important treatment in HR positive BC Estrogen receptor positive breast cancer need hormones to grow Hormone therapies can work by either Stopping hormones being made Preventing the hormone reaching the cancer cell Estradiol Hormonal therapy is a treatment that adds, blocks, or removes hormones. For certain conditions (such as diabetes, hypothirosis or menopause), hormones are given to adjust low hormone levels. The principe of hormonal therapy in cancer is actualy opposite. Cancers that are hormone sensitive or hormone dependent need hormones to grow. So stopping the hormone reaching the cancer cells may either slow down or stop the growth of the cancer. Hormone therapies can work by either stopping hormones being made or preventing the hormone reaching the cancer cell. Hormone-sensitive breast cancer cells contain proteins known as hormone receptors that become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes, which can lead to the stimulation of cell growth. Gene transcription Estrogene receptor Proliferation

Types of hormonal therapies Drug Route of administration, dose Aromatase inhibitors Anastrozole (Arimidex) P.O.(1x1 mg) Letrozole (Femara) P.O.(1x 2,5 mg) Exemestane (Aromasin) P.O. (1x 25 mg) Antiestrogenes Tamoxifen (Nolvadex) P.O.(2 x 10 mg) Fulvestrant (Faslodex) 500 mg I.M. on Days 1 and 15 of Cycle 1 and Day 1 of each cycle thereafter) Gonadotropin-reeasing hormon agonist Goserelin (Zoladex) S.C.(3,6 mg every 4 weeks) Progestin Megestrol acetate (Megace) P.O.(1 x 160 mg)

HR+ HER2- mBC: Response to endocrine therapy Sequential endocrine therapy provides high-quality survival for many of HR+ HER2- mBC patients Eventually, tumors become endocrine-resistant R E S I T A N C 40-50% 30% 25% 15% Unfortunately, the majority of patients with HR+ advanced breast cancer will ultimately progress despite endocrine therapy thus, resistance is a major clinical problem. 1. line 2. line 3. line 4. line

Targeted treatments in HR+ mBC m-TOR INHIBITOR (everolimus) CDK 4/6 INHIBITORS (palbociclib, ribociclib, abemaciclib)

Chemotherapy Cytotoxic chemotherapy works primarily through the inhibition of cell division.   In addition to cancer cells, other rapidly dividing cells (e.g., hair, gastrointestinal epithelium, bone marrow) are affected by these drugs. 

Chemotherapy for metastatic breast cancer Mono- or poli-chemotherapy anthracylines docetaxel paclitaxel nab-paclitaxel capecitabine cyclophosphamide cisplatin carboplatin gemcitabine vinorelbine eribulin methotrexate 5-FU liposoma doxorubicine

Forms and routes of chemotherapy administration Peripheral vein Port-a-cath

HER2 positive breast cancer HER2 overexpression ~ 15- 20% of breast cancers normal ~ 25,000-50,000 HER2 receptors Overexpression of HER2 receptors (10-100x) do ~ 2,000,000 receptors HER2 Pegram MD, et al. Cancer Treat Res. 2000;103:57-75. Ross JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71. Slamon DJ, et al. Science. 1987;235:177-182. excessive cell division ad proliferation

Dr. Dennis Slamon

Anti-HER 2 Therapies trastuzumab pertuzumab T-DM1 lapatinib HER3 HER2

Availability of anti- HER2 drugs FDA EMA Slovenija Herceptin mBC September 1998 August 2000 2001 Herceptin eBC November 2006 May 2006 July 2005 Perjeta mBC June 2012 March 2013 October 2014 Kadcyla mBC February 2013 November 2013 May 2016 eBC=early breast cancer ; mBC=metastatic breast cancer

New Treatments (not registered yet) PARP INHIBITOR (olaparib) BRCA 1/2 MUTATION PRESENT CHECKPOINT INHIBITORS TNBC

Publications for Patients

Colaboration with patients associations

CONCLUSIONS Approximately 20% to 30% of woman initially diagnosed with early stage disease will develop metastatic breast cancer. The goals of treatment are: maximizing the quality of life, prevention and palliation of symptoms, and prolongation of survival. Treatment is lifelong, characterized by remissions and relapses. The trust and collaboration between oncologist and patient is crucial for successful treatment.

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