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When Breast Cancer Recurs

When Breast Cancer Recurs. Kevin Olson. Breast Cancer Recurrence. Detection Tools Future directions Questions. Recurrence vs Second Primary. Detection. Symptoms Tumor markers CA 27 -29 CA 15 -3 Other blood tests CTC (Circulating Tumor Cells) X-rays/CAT scan/Bone Scan PET scan.

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When Breast Cancer Recurs

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  1. When Breast Cancer Recurs Kevin Olson

  2. Breast Cancer Recurrence • Detection • Tools • Future directions • Questions

  3. Recurrence vs Second Primary

  4. Detection • Symptoms • Tumor markers • CA 27 -29 • CA 15 -3 • Other blood tests • CTC (Circulating Tumor Cells) • X-rays/CAT scan/Bone Scan • PET scan

  5. Staging • Local/regional • Systemic • Bone only • Visceral organs • Lung • Liver • Other sites

  6. Local/Regional Recurrence • Breast (Same side) • Skin (after mastectomy) • Axilla (arm pit) • Over collar bone

  7. Management of Local Recurrence • Surgery • Radiation • Chemotherapy • All of the above

  8. Management of Systemic Disease

  9. Regional Therapy • Radio Frequency Ablation • Cryotherapy • Chemoembolization • Surgery • Radiation

  10. Surgery • Palliative intent vs curative intent • Solitary brain metastasis • Skin recurrence • Other selected situations

  11. Radiation Therapy • External Beam • Gamma Knife/Novalis/Cyberknife/Tomotherapy • (for brain lesions)

  12. Systemic Treatments for Systemic Disease

  13. Hormone Therapy

  14. Normal Breast Cell Estrogen Receptor Estrogen Resting Breast Cell Activated Breast Cell

  15. Breast Cancer Evolution Estrogen Receptor Genetics Breast Cancer Cell Environment Hormone Sensitive Hormone Resistant

  16. Hormone therapy • Turn off Estrogen (pre-menopausal) • Removal of ovaries • Turn off ovaries (Lupron, Zoladex) • Block Estrogen Receptors • Tamoxifen/Toremifine/Raloxifene and Faslodex • Aromatase Inhibitors • Arimidex/Femara/Aromasin • Other options • Megace, Aminoglutethamide?

  17. Chemotherapy for Breast Cancer • Taxanes: • Taxol/Taxotere/Abraxane • Major side effect is nerve injury • Anthracyclines: • Adriamycin/Doxil/Epirubicin/Mitoxantrone • Major side effect is weakening of heart • Microtubule inhibitors: • Navelbine/Vincristine • Major side effect is low blood counts

  18. Chemotherapy for Breast Cancer (cont.) • Antimetabolites: • 5FU/Xeloda/Gemcitabine/Methotrexate • Major side effects vary • Ixempra (ixabepilone) • Major side effect is fatigue • Carboplatinum/Cytoxan/Cisplatinum • Major side effect low blood counts

  19. Combinations of chemo drugs • Alphabet soup • AC FAC FEC AT TAC EC CMF GT TC • What we know about combinations: • They are more toxic • They may work faster • They do not result in better long term control • Combinations of chemo and Targeted Therapy is a different story

  20. What are the Targets in Breast Cancer? Her-2 (Herceptin) PARP Estrogen Receptor EGFR/VEGF (Avastin)

  21. Some of the most aggressive breast cancers are driven by a transmembrane receptor protein known as “HER2” Roughly 20,000 HER2 receptors are typically expressed on the surface of healthy breast cells

  22. In approximately 25% of primary breast cancers, the HER2 protein is overexpressed, resulting in tumor cells with as many as 2 million receptors present

  23. Herceptin is a monoclonal antibody specifically designed to target the HER2 receptor

  24. Based on pre-clinical studies, Herceptin delivers continuous inhibition of HER2 activity by working on both the extracellular and intracellular domains of the receptor

  25. Extracellularly, Herceptin binds to tumor cells and flags them for destruction by the immune system

  26. Intracellularly, bound Herceptin prevents HER2 receptor activity by blocking HER2 signaling

  27. Based on pre-clinical studies, Herceptin enhanced the effects of chemotherapy, leading to cell stasis and death

  28. Herceptin therapy • Her-2 neu oncogene abnormal in 20% of breast cancers • 18-20% response rate when used alone in Her-2 positive tumors • When combined with chemo response rate = 60-70%

  29. Phase III Study to Test if Total HER2 Blockade Improves Clinical Outcome RANDOMIZATION • Key Inclusion • HER2+(FISH+/ IHC3+) MBC • Progression on • Anthracycline • Taxane • Trastuzumab • Progression on most recent trastuzumab regimen Lapatinib 1500 mg/day PO N=148 Crossover if PD after 4wk therapy (N=73) • Stratification Factors • Visceral Disease • Hormone Receptor Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV qw N=148

  30. Angiogenesis: development of new blood vessels

  31. Bevacizumab (Avastin) • an intravenous antibody • binds to VEGF  inhibits new blood vessel formation • another target to interrupt tumor growth • FDA approved for: breast, lung, colorectal, kidney, brain tumors

  32. Bevacizumab (Avastin) Summary • Alone, response rate is low • When combined with chemotherapy responses are more frequent and delay progression of disease • In combination with Paclitaxel (Taxol) progression delayed by four months, twice as many responses • Similar results in 1st line setting with Taxotere • Simlar results in 2nd line setting with a number of drugs • no overall survival benefit to date • consider: disease burden, overall treatment sequencing plan, cost, side effects

  33. Triple Negative Breast Cancer • Estrogen Receptor Negative • Progesterone Receptor Negative • Her-2 negative • No targets?

  34. PARP Inhibitor-Based Therapy for TNBC • PARP1 • DNA repair Enzyme (helps cells overcome injury from chemo) • Upregulated in majority of triple negative human breast cancers1 • BSI-201 • Small molecule PARP inhibitor • Potentiates effects of chemotherapy-induced DNA damage • No dose-limiting toxicities in Phase I studies of BSI-201 alone or in combination with chemotherapy • Marked and prolonged PARP inhibition

  35. Phase II TNBC Study: Treatment Schema Metastatic TNBC N = 120 RANDOMIZE BSI-201 (5.6 mg/kg, IV, d 1, 4, 8, 11) Gemcitabine (1000 mg/m2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) Gemcitabine (1000 mg/m2, IV, d 1, 8) Carboplatin (AUC 2, IV, d 1, 8) 21-Day Cycle RESTAGING Every 2 Cycles 38

  36. Progression-Free Survival BSI-201 + Gem/Carbo (n = 57) Median PFS = 6.9 months Gem/Carbo (n = 59) Median PFS = 3.3 months P < 0.0001 HR = 0.342 (95% CI, 0.200-0.584) 39

  37. Overall Survival BSI-201 + Gem/Carbo (n = 57) Median OS = 9.2 months 8 Gem/Carbo (n = 59) Median OS = 5.7 months P = 0.0005 HR = 0.348 (95% CI, 0.189-0.649) 40

  38. Supportive therapy • Bisphosphonates to protect bones • Aredia (Pamidronate) • Zoledronate (Zometa) • Clodronate • Growth Factors to repair blood cell injury from chemo • Procrit/Aranesp (red blood cells) • Neupogen/Neulasta (white blood cells)

  39. Alternative/Complementary Therapy • Herbal • Vitamin • Diet • Accupunture • Immune stimulants • Prayer

  40. Making the Best Choice • No single drug treatment rises above all others • Some drugs or combinations will work better in one patient and not in another • New tools becoming available to predict how an individual cancer will respond • DNA “fingerprint”-Oncotype Dx • Research trial? When is the best time?

  41. Choosing Therapies • Age of patient • Social situation • Location and behavior of disease • Extent of disease • Symptoms of disease • Targets on this particular cancer • Philosophy of patient • Philosophy of physician

  42. Differing Philosophies

  43. Aggressive approach • Combinations better than single agents • Dose intensity (more milligrams per month) matters • Short term toxicity in return for long term control • More important with aggressive or imminently life threatening disease

  44. Balancing act • Single agents as good as combinations • Balance control of cancer with nurture of normal tissues • Recurrent breast cancer a chronic disease?

  45. Survival • Depends on a number of variables: • Extent of disease/location of disease • Behavior of disease (growing fast or slow) • Susceptibility of the cancer to our therapy • Overall health of the patient (can she take the treatments that are available) • Luck • Spirit of the patient • Support available for the patient

  46. When is Chemo no longer useful? • As women progress through treatments, cancer becomes more resistant to treatment and the body becomes more fragile • At some point, even mild forms of chemo may do more harm than good (getting out of balance) • There is no “bright line” to determine when it is better to focus on purely comfort oriented care • Need to balance desire to remain hopeful with need to think and plan for the time when chemo no longer makes sense

  47. Resources • WWW.breastcancer.org • WWW.komen.org • WWW.cancerconsultants.com • WWW.peoplelivingwithcancer.org • WWW.NCCN.ORG

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