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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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breast cancer recurrence
Breast Cancer Recurrence
  • Detection
  • Tools
  • Future directions
  • Questions
detection
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
staging
Staging
  • Local/regional
  • Systemic
    • Bone only
    • Visceral organs
      • Lung
      • Liver
      • Other sites
local regional recurrence
Local/Regional Recurrence
  • Breast (Same side)
  • Skin (after mastectomy)
  • Axilla (arm pit)
  • Over collar bone
management of local recurrence
Management of Local Recurrence
  • Surgery
  • Radiation
  • Chemotherapy
  • All of the above
regional therapy
Regional Therapy
  • Radio Frequency Ablation
  • Cryotherapy
  • Chemoembolization
  • Surgery
  • Radiation
surgery
Surgery
  • Palliative intent vs curative intent
  • Solitary brain metastasis
  • Skin recurrence
  • Other selected situations
radiation therapy
Radiation Therapy
  • External Beam
  • Gamma Knife/Novalis/Cyberknife/Tomotherapy
    • (for brain lesions)
normal breast cell
Normal Breast Cell

Estrogen

Receptor

Estrogen

Resting Breast Cell

Activated Breast Cell

breast cancer evolution
Breast Cancer Evolution

Estrogen

Receptor

Genetics

Breast Cancer Cell

Environment

Hormone

Sensitive

Hormone

Resistant

hormone therapy16
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?
chemotherapy for breast cancer
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
chemotherapy for breast cancer cont
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
combinations of chemo drugs
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
what are the targets in breast cancer
What are the Targets in Breast Cancer?

Her-2

(Herceptin)

PARP

Estrogen Receptor

EGFR/VEGF

(Avastin)

slide21
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

slide22

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

slide24

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

extracellularly herceptin binds to tumor cells and flags them for destruction by the immune system
Extracellularly, Herceptin binds to tumor cells and flags them for destruction by the immune system
intracellularly bound herceptin prevents her2 receptor activity by blocking her2 signaling
Intracellularly, bound Herceptin prevents HER2 receptor activity by blocking HER2 signaling
slide27
Based on pre-clinical studies, Herceptin enhanced the effects of chemotherapy, leading to cell stasis and death
herceptin therapy
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%
phase iii study to test if total her2 blockade improves clinical outcome
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

bevacizumab avastin
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
bevacizumab avastin summary
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
triple negative breast cancer
Triple Negative Breast Cancer
  • Estrogen Receptor Negative
  • Progesterone Receptor Negative
  • Her-2 negative
  • No targets?
parp inhibitor based therapy for tnbc
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
phase ii tnbc study treatment schema
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

progression free survival
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

overall survival
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

supportive therapy
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)
alternative complementary therapy
Alternative/Complementary Therapy
  • Herbal
  • Vitamin
  • Diet
  • Accupunture
  • Immune stimulants
  • Prayer
making the best choice
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?
choosing therapies
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
aggressive approach
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
balancing act
Balancing act
  • Single agents as good as combinations
  • Balance control of cancer with nurture of normal tissues
  • Recurrent breast cancer a chronic disease?
survival
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
when is chemo no longer useful
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
resources
Resources
  • WWW.breastcancer.org
  • WWW.komen.org
  • WWW.cancerconsultants.com
  • WWW.peoplelivingwithcancer.org
  • WWW.NCCN.ORG