When Breast Cancer Recurs

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When Breast Cancer Recurs

• Kevin Olson

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Breast Cancer Recurrence

• Detection
• Tools
• Future directions
• Questions

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Recurrence vs Second Primary
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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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Staging

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

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Local/Regional Recurrence

• Breast (Same side)
• Skin (after mastectomy)
• Axilla (arm pit)
• Over collar bone

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Management of Local Recurrence

• Surgery
• Radiation
• Chemotherapy
• All of the above

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Management of Systemic Disease
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Regional Therapy

• Radio Frequency Ablation
• Cryotherapy
• Chemoembolization
• Surgery
• Radiation

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Surgery

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

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Radiation Therapy

• External Beam
• Gamma Knife/Novalis/Cyberknife/Tomotherapy
• (for brain lesions)

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Systemic Treatments for Systemic Disease
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Hormone Therapy
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Normal Breast Cell
Estrogen Receptor
Estrogen
Resting Breast Cell
Activated Breast Cell
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Breast Cancer Evolution
Estrogen Receptor
Genetics
Breast Cancer Cell
Environment
Hormone Sensitive
Hormone Resistant
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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?

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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

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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

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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

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What are the Targets in Breast Cancer?
Her-2 (Herceptin)
PARP
Estrogen Receptor
EGFR/VEGF (Avastin)
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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
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In approximately 25 of primary breast cancers,
the HER2 protein is overexpressed, resulting in
tumor cells with as many as 2 million receptors
present
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Herceptin is a monoclonal antibody specifically
designed to target the HER2 receptor
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Based on pre-clinical studies, Herceptin delivers
continuous inhibition of HER2 activity by working
on both the extracellular and intracellular
domains of the receptor
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Extracellularly, Herceptin binds to tumor cells
and flags them for destruction by the immune
system
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Intracellularly, bound Herceptin prevents HER2
receptor activity by blocking HER2 signaling
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Based on pre-clinical studies, Herceptin enhanced
the effects of chemotherapy, leading to cell
stasis and death
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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

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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 N148
Crossover if PD after 4wk therapy (N73)
Lapatinib 1000 mg/day PO Trastuzumab 4 2
mg/kg IV qw N148

• Stratification Factors
• Visceral Disease
• Hormone Receptor

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Angiogenesis development of new blood vessels
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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

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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

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Triple Negative Breast Cancer

• Estrogen Receptor Negative
• Progesterone Receptor Negative
• Her-2 negative
• No targets?

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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

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Phase II TNBC Study Treatment Schema
RANDOMIZE
Metastatic TNBC N 120
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
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Progression-Free Survival
BSI-201 Gem/Carbo (n 57) Median PFS 6.9
months Gem/Carbo (n 59) Median PFS 3.3
months P lt 0.0001 HR 0.342 (95 CI,
0.200-0.584)
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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)
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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)

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Alternative/Complementary Therapy

• Herbal
• Vitamin
• Diet
• Accupunture
• Immune stimulants
• Prayer

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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?

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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

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Differing Philosophies
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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

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Balancing act

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

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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

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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

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Resources

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

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Questions