Jo Anne Zujewski MD June 2019 Thimphu Bhutan Define the breast cancer Is the cancer operable Stage 1 systemic therapy after surgery and radiation if breast conservation Stage 2 systemic therapy before or after therapy ID: 1045908
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1. Systemic Therapy of Breast CancerJo Anne Zujewski, M.D.June 2019Thimphu, Bhutan
2. Define the breast cancerIs the cancer operable?Stage 1: systemic therapy after surgery (and radiation if breast conservation)Stage 2: systemic therapy before or after therapyStage 3 (locally advanced and inflammatory): systemic therapy BEFORE surgery Is the cancer metastatic? Role of surgery is limited What are the chances of curative therapy?Prognostic factorsStage, pathologic features, some biomarkersResponse to therapyWhat therapies are likely to be effective? Estrogen Receptor (Progesterone Receptor)HER-2 overexpression
3. Breast Cancer Therapy: Local and SystemicLocal therapy primarily surgery and radiationSystemic therapy: chemotherapy and targeted therapy
4. Early stage breast cancerCancer is confined to the breast and axillary lymph nodesTreatment: Surgery and Radiation May give systemic therapy before or after surgery; if inoperable, must give systemic therapy (chemotherapy +/- targeted therapy) before surgeryAdjuvant- Systemic therapy after surgeryNeoadjuvant- systemic therapy before surgery
5. Early Stage Breast Cancer Prognostic factorsAxillary nodes containing cancer cells, and particularly if many nodes are involvedLarge tumor size high-grade TumorHER2+ tumorER negative, PR negative, and Her-2 negative breast cancerTreatmentChemotherapy +/- targeted therapy
6. Adjuvant Chemotherapy:Benefits versus RisksDecrease relative risk of death by 20-40%Long-term risks Secondary leukemia Cardiomyopathy Early menopause Cognitive impairmentShort-term side effects Hair Loss Nausea/Vomiting Febrile Neutropenia Inability to workCombination chemotherapy: anthracycline and taxane
7. EstrogenCell Growth and DivisionEstrogen ReceptorSERMS, SERDSAromatase inhibitors, ovarian suppression, oophorectomyHormonal (endocrine therapy):ER and/or PR positive
8. HER-2 directed therapy if HER-2 positive Loibl, S and Gianni L Lancet 2017; 389: 2415–29 NEJM 353:16 (2005)Trastuzumab in Early Stage Breast Cancer
9. Metastatic Breast Cancer: Treatment GoalsMetastatic breast cancer is not curable, but is treatableGoals:Control and regression of diseaseProlongation of lifeImprovement in symptoms and quality of lifeBalancing treatment efficacy and side effects is a major objective
10. De Novo Metastatic Breast CancerMariotto A, et al. Cancer Epidemiology Biomarkers Prev, 2017In young patients initially diagnosed with metastatic breast cancer 5-year survival has doubled in the USA since 1992
11. Choices in the Treatment of Metastatic Breast CancerChoice of treatment is based on many factors:Patient age, menopausal status, general health and functional statusTumor ER status, HER-2 statusPrevious treatmentsExtent and sites of diseaseAvailable therapies in the patient’s countryPatient preferences
12. Treatment of Metastatic Breast Cancer: Local therapySurgeryMastectomy for open or painful breast lesionsSurgery for brain metastasesOrthopedic surgery for fracture, cord compression, impending fractureRadiationBone Pain or impending fractureBrain metastasisSpinal cord compression
13. Treatment of Metastatic Breast CancerSystemic TherapyEndocrine therapyChemotherapyHER2-targeted therapyOther targeted agentsOsteoclast-targeted therapy
14. Endocrine Therapy for Metastatic Breast CancerASCO Guideline Rugo H et al, J Clin Oncol 2016Sequential endocrine therapy is preferred choice for ER+ metastatic breast cancerLess side effects than chemotherapyExceptions:Concern or proof of endocrine resistanceNeed for fast response (location, symptoms)Targeted therapy in addition to hormonal therapy improves outcomecdk4/6 inhibitor (inhibits cell cycle progression)Drugs approved in USA: palbocicib, ribociclib, abemaciclib
15. European School of Oncology Guideline: Chemotherapy for Metastatic Breast CancerCardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009Sequential single agent chemotherapy is generally the preferred choiceLess toxicity than combination chemoNo data to support optimal sequenceCombination chemotherapy is reserved for patients with: Rapid clinical progressionLife-threatening visceral metastasesNeed for rapid symptom/disease controlChosen regimen should be evidence-based, with proven efficacy and acceptable toxicity
16. Chemotherapy for Advanced Breast CancerASCO guideline Partridge A et al, J Clin Oncol 2014Endocrine therapy preferable to chemo as 1st-line treatment for ER+ metastatic breast cancer unless immediately life-threatening diseaseSingle agent preferable to combination chemotherapyNo single optimal 1st-line or subsequent line chemoChoice of treatment will be determined by multiple factors:Prior therapyToxicityPerformance statusComorbid conditionsPatient preference
17. WHO Model List of Essential Medicines 20th Edition (2017)Chemotherapy:Doxorubicin (Adriamycin)Cyclophosphamide (Cytoxan)Paclitaxel (Taxol)Docetaxel (Taxotere)Fluorouracil (5-FU)MethotrexateChemotherapy (cont):CarboplatinGemcitabine (Gemzar)Capecitabine (Xeloda)Vinorelbine (Navelbine)Growth factorfilgrastimAntineoplastic drugs relevant to breast cancerhttp://www.who.int/medicines/publications/essentialmedicines/en/
18. HER2 Targeted Therapy 5 FDA-Approved Drugs with HER2 as a Targetcell divisionHER-2nucleuscancer cellTrastuzumab Anti-HER-2 AntibodyLapatinib HER-1/HER-2 Tyrosine Kinase InhibitorPertuzumab Anti-HER-2 AntibodyT-DM1Ado-trastuzumab emtansineAntibody-Drug ConjugateNeratinibHER-1/HER-2/HER-4Tyrosine Kinase Inhibitor
19. HER2 Targeted Therapy for Metastatic Breast CancerAnti-HER2 therapy should be offered early to all HER2+ metastatic breast cancer patients unless contraindicated (or unavailable)Requires availability of reliable and accurate tumor HER-2 testingOptimal duration of anti-HER2 therapy for metastatic breast cancer (when to stop) unknownMultiple anti-HER-2 therapies are availableStudies have shown that trastuzumab in combination with pertuzumab and docetaxel has improved survival in first line treatment of metastatic breast cancer
20. 515253545Months0.200.40.60.81.0Trastuzumab + Chemo (n=235)RR=0.80P=0.046Proportion alive20.3 mo (median) 25.1 mo (median)Chemo (n=234)Overall Survival Improved When Trastuzumab is added to Chemotherapy in Metastatic Breast CancerSlamon D et al, N Eng J Med 2001
21. WHO Model List of Essential Medicines 20th Edition (2017)Targeted TherapyTrastuzumab (Herceptin)Antineoplastic drugs relevant to breast cancerhttp://www.who.int/medicines/publications/essentialmedicines/en/
22. PARP Inhibitors in Metastatic Breast CancerConsider genetic testing for metastatic patients:Patients who meet guidelines for genetic testing based on age and family historyAll triple negativeER+ when thinking of switching to chemo?Additional studies of PARP inhibitors ongoing:Early stage BRCA1/2+ breast cancerPatients with mutations in other DNA repair genesTNBC with “BRCAness” features
23. Phase III OlympiAD Trial: Olaparib versus Physician’s Choice Chemotherapy in Metastatic BRCA-mutated Breast CancerRobson M et al, NEJM 377: 523-533, 2017N=302 patientsMetastatic breast cancerGermline BRCA mutation +HER2 negativePrior treatment with anthracycline and taxanePhysician’s Choice of Chemo(Capecitabine, Vinorelbine, Eribulin)Olaparib 300 mg BIDOlaparibChemoPFS 7.0 mo4.2 moHR 0.58, p < 0.001Response60%29%OS (interim)19.3 mo19.6 mo2:1
24. Complications of Breast Cancer: Bone MetastasesPainPathologic fractureSpinal cord compressionHypercalcemiaSkeletal complications account for 63% of hospital costs in advanced breast cancer patients (Coleman, Cancer 80:1588-1594, 1997)
25. Treating Bone Metastases in Breast CancerBone modifying agents should be routinely used in combination with other systemic therapy in patients with bone metastasesBisphosphonates (pamidronate, zoledronic acid)RANK ligand inhibitor (denosumab)Agents should be started early, if possible before onset of bone symptomsThese agents reduce fractures, the need for radiation or surgery, and other complicationsShould be continued even in presence of disease progression
26. Case #136 pre-menopausal woman presents with 3 month history of back and abdominal painPhysical exam: breast mass, point tenderness in the thoracic spine, and large liverBiopsy: poorly differentiated adenocarcinoma that is HER-2 negative; ER negative, PR negative CT scan: multiple liver lesions and lytic lesions in thoracic and lumbar spine
27. Take home points: early breast cancerEarly breast cancer is curableER positive: hormonal therapyER positive at high risk of recurrence: hormonal therapy plus chemotherapyER negative and Her-2 negative: chemotherapyHER-2 positive breast cancer: chemotherapy plus trastuzumabExtended adjuvant therapy, ovarian function suppression, and combined HER-2 targeted therapy adds marginal benefits at increased toxicity and costs
28. Take home points: Metastatic Breast CancerTreatment choices guided by breast cancer type, location and extent of metastasis, previous treatments and other factors Like early stage breast cancer, there are different types of metastatic breast cancer Every patient and their disease is uniqueTreatment for metastatic breast cancer is lifelong and focuses on control of disease, symptoms and quality of lifeMetastatic breast cancer is not an automatic death sentenceAlthough most will ultimately die of their disease, some will live for many years