Lisa A. Carey, MD, Medical Oncology

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UNC Internal Medicine Resident Lecture January,
2010
Breast Cancer Contemporary Issues, Survivorship,
and the Primary Physician

• Lisa A. Carey, MD, Medical Oncology

Theres a guy at the door from the Parks
department. He wants to know if there are any
poor swimmers here in need of swimming lessons
Tell him no. We know how to swim.
No.
He seemed disappointed.
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Objectives

• Describe the biologic heterogeneity of breast
  cancer
• Discuss how this heterogeneity translates into
  the clinic

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Cancer Incidence Rates for Women, 1975-2003
Rate Per 100,000
250
200
Breast
150
100
Colon and rectum
Lung bronchus
50
Uterine Corpus
Ovary
Non-Hodgkin lymphoma
0
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
From SEER, NCI
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Cancer Death Rates, for Women, US,1930-2003
Rate Per 100,000
Lung bronchus
Uterus
Breast
Colon rectum
Stomach
Ovary
Pancreas
Age-adjusted to the 2000 US standard
population. Source US Mortality Public Use Data
Tapes 1960-2003, US Mortality Volumes
1930-1959, National Center for Health Statistics,
Centers for Disease Control and Prevention, 2006.
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Adjuvant Choices
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Prognostic relevance of LN
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AJCC TNM Staging

• T tumor size
• T1 lt 2cm
• T2 2-5
• T3 gt5 cm
• T4 chest wall or skin involvement.
• N - ipsilateral lymph nodes
• N1 1-3
• N2 4-9
• N3 10, infraclavicular, supraclavicular
• M distant metastases

• 0 Tis
• I T1N0
• IIA T0-1N1 T2N0
• IIB T2N1 T3N0
• IIIA T0-3 N2 T3N1
• IIIB any T4
• IIIC any N3
• IV M1

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Online Modeling Programs

• Several prognosticators available, most commonly
  used Adjuvantonline
• Lets you calculate recurrence risk and benefit of
  known interventions
• http//www.adjuvantonline.com
• Validated in large British Columbia registry
  (Olivotti et al, JCO 2005)
• Doesnt include trastuzumab (yet)
• Doesnt include HER2
• Doesnt include Oncotype Dx results

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www.Adjuvantonline.com
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• 50 year old otherwise healthy woman has surgery
  for a breast mass. She is found to have a 3cm,
  high grade, node-positive, hormone
  receptor-positive, HER2-negative breast cancer.

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How do I counsel her?
Risk of relapse untreated 80 With optimal
endocrine therapy 50 Endocrine and
chemotherapy 30
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A More Pessimistic View of My Counsel
Over- Treatment (50)
Under- Treatment (30)
Optimal Treatment (20)
Patients whowould have been fine with no
therapy or endocrine therapy only
Chemotherapy made the difference
Cancer recurred despite optimal treatment
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Issues in Adjuvant Therapy Side Effects of Long
Term Therapy

• Herceptin for HER2 (infusional x1 year)
• LVEF decline 10, symptomatic in lt5
• Unlike anthracyclines, probably partly reversible
• Implications later (aging, other cardiac RF)
  unknown
• Tamoxifen for ER (5 years)
• Hot flashes, uterine Ca (1/2000 overall, 0.5-1
  in selected pts), DVT/PE (4x baseline risk)
• BUT improved bone health
• Aromatase inhibitors for ER postmenopausal (5
  years)
• Myalgia/arthralgias (most common reason to
  discontinue)
• Osteoporosis acceleration
• Bisphosphonates on trial (for now) 3-5 years
• ONJ 0.7 maximum. May be ameliorated by oral Abx
  and washes.

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Issues in Adjuvant Therapy Long Term Effects of
Prior Therapy

• Anthracyclines
• Cardiotoxicity clinical 1. May increase long
  term risk of cardiomyopathy
• Leukemia 0.5. Onset usually 2-3 years after
  therapy.
• Alkylating agents (CMF-type)
• Leukemia 0.5. Onset usually 5 years after
  therapy.
• Taxanes
• Peripheral neuropathy 5 persistent
• Stocking/glove numbness/paresthesias
• Begins with therapy. Onset post Rx is something
  else.
• Herceptin ?

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Breast cancers can look like this
....or like this
High grade, aggressive appearing
Low grade, more benign appearing
Courtesy A. Harden, L. Dressler
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Looks Can Be Deceiving
Bono International humanitarian
Bernie Madoff Estate planner and philanthropist
Like people, we cant tell how cancers will
behave based upon appearance
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Traditional Progressive Model of Cancer
Development
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The Biologic Model
Calvinist model Biologic predeterminism
Behavioral heterogeneity
Cancer subtypes
Initial differences Biologic variability

• Arguments in favor
• Screening doesnt work that well
• Demonstrated, e.g. intrinsic subtypes of breast
  cancer

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Understanding BiologyGene Expression Microarray
Approach
Green
Red
Spot 1
Normal Cells
Tumor Cells
Spot 2
Spot 3
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Thank god for computers
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Gene Expression Patterns
Before the computer gets to it
and after
Genome-wide picture of what genes are up, what
are down, and how they relate
Courtesy Chuck Perou
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Breast Cancer Molecular Subtypes
Normal breast-like
Luminal B2
Luminal B
Luminal A
HER2/ER-
Basal-like
Breast cancer is not one disease. But a group of
biologically distinct diseases. What does this
mean?
It means that it does not make sense to ask
what causes breast cancer? It also means that
individualized medicine is not just desirable, it
is crucial.
Courtesy Chuck Perou
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Subtype Example Basal-like Breast Cancer

• Low HER2 cluster expression
• High basal cluster
• EGFR
• basal cytokeratins
• others
• Low ER (and related genes) cluster expression
  
• Very proliferative
• High degree of genomic instability

HER2
Basal
Luminal
Proliferation
Insensitive to conventional targeted therapies
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Subtypes and Prognosis
Sorlie T et al, PNAS 2001
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Clinical Characteristics of Breast Cancer
Subtypes Carolina Breast Cancer Study (CBCS)
Courtesy of R. Millikan
Population-based case-control study of breast
cancer risk. Phase I 1993-96, 40
African-American, 50 lt 50yo
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Carolina Breast Cancer Study Subtype Incidence
Expression Subtype Immunohistochemical Surrogate No ()
Basal-like ER/PR/HER2-negative CK5/6 or HER1 100 (20)
HER2 (ER-negative) HER2 ER and PR-negative 33 (7)
Luminal A ER or PR HER2-negative 255 (51)
Luminal B ER or PR HER2 77 (16)
Unclassified All markers negative 31 (6)
Total 496
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Basal-like Breast Cancer Clinicopathologic
Characteristics
P-value
Luminal B (n77)
Luminal A (n255)
HER2/ER- (n33)
Basal-like (n100)
AA Premenopausal Postmenopausal White
Premenop. Postmenopausal
39 14 16 16
9 7 6 6
36 59 51 58
9 16 18 16
lt0.001
Stage I II III-IV
44 47 9
0.06
39 54 6
28 53 19
24 62 13
0.04
47
34
56
41
Lymph node
79 7 12 1
70 12 9 3
94 0 6 0
84 0 6 10
Invasive ductal Invasive lobular Mixed Poor
histologies
lt0.001
31
31
75
84
Grade III
lt 0.001
lt 0.001
P53 mutated
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43
15
23
Carey LA et al, JAMA 2006
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Risk Factors by Subtype May Differ,Potentially
Modifiable
Adjusted OR cases v. controls
Luminal A N796 Basal-like N225
Menarche lt 13 1.1 (0.9-1.3) 1.4 (1.1-1.9)
gt 3 children 0.7 (0.5-0.9) 1.9 (1.1-3.3)
Waisthip gt 0.84 1.5 (1.1-1.9) 2.3 (1.4-3.6)
First birth lt 26 0.7 (0.5-0.9) 1.9 (1.2-3.2)
Breastfeeding gt 4m 0.9 (0.7-1.1) 0.7 (0.4-0.9)
BMI gt 30 0.8 (0.6-1.0) 0.8 (0.6-1.2)
N1424, population-based
Varying magnitude of effect
Varying direction of effect
Millikan et al, Breast Cancer Res Treat, 2008
If confirmed 68 of basal-like in young
African-American women could be prevented by
weight control and breast feeding!
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New drugs for breast cancer

• 2000s
• Anastrozole
• Letrozole
• Exemestane
• Fulvestrant
• Docetaxel
• Paclitaxel
• Epirubicin
• N-ab paclitaxel
• Ixabepilone
• Trastuzumab
• Lapatinib
• Bevacizumab

• 1980s
• Mitoxantrone

• 1990s
• AIs (metastatic)
• Zoladex
• Zoledronate
• Taxanes (metastatic)
• Epirubicin
• Vinorelbine
• Gemcitabine
• Liposomal doxorubicin
• Capecitabine
• Dexrazoxane (cardiac toxicity)

Mostly chemotherapy Mostly stage IV
Adjuvant (early) treatment Chemo, endocrine,
targeted Rx
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More Drugs, Smarter Drugs
Fewer effects on the normal tissues of the body
More specific effects upon the Achilles heel
of the tumor
Synergistic drugs ABC
The law of unintended consequences unexpected
toxicities (for example trastuzumab (Herceptin)
cardiotoxicity)
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What About Smarter Doctors?
Volume 3512817-2826 December 30, 2004 Number 27
A Multigene Assay to Predict Recurrence of
Tamoxifen-Treated, Node-Negative Breast
Cancer Soonmyung Paik, M.D., Steven Shak, M.D.,
Gong Tang, Ph.D., Chungyeul Kim, M.D., Joffre
Baker, Ph.D., Maureen Cronin, Ph.D., Frederick L.
Baehner, M.D., Michael G. Walker, Ph.D., Drew
Watson, Ph.D., Taesung Park, Ph.D., William
Hiller, H.T., Edwin R. Fisher, M.D., D. Lawrence
Wickerham, M.D., John Bryant, Ph.D., and Norman
Wolmark, M.D.
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Genes Selected to Predict Behavior In Spite of
Anti-Hormone Treatment
PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2
HER2 GRB7 HER2
ESTROGEN ER PGR Bcl2 SCUBE2
GSTM1
CD68
INVASION Stromolysin 3 Cathepsin L2
BAG1
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Breast Cancer U.S. Numbers
Despite similar incidence (150-200k/yr) gt 30
decrease in mortality (35 k/yr)
½ from improved screening ½ from improved
treatment
An increasing proportion of breast cancer
patients (by far the majority) are cured
Berry DA et al, NEJM 2005
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Relapse after Anti-Hormone Therapy (Tamoxifen)
According to Genetic Profile
No further treatment (lt7 risk of relapse)
DRFS for the Three RS Groups
Needs chemotherapy in addition to
antihormone (gt30 risk, most of benefit)
These assays allow us to only give chemotherapy
to those that need it
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Commercial Prognostic Profiles
Sotiriou and Pusztai, NEJM 2009
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Molecular Profiles Are Concordant
Subtype N Recurrence Score 70-gene Wound healing 2-gene
Basal-like 53 100 100 94 79
HER2/ER- 35 100 91 100 80
Luminal B 55 91 84 93 45
Luminal A 123 29 29 63 36
Adding them together doesnt prognosticate any
better than each alone they are not measuring
independent processes
Fan C et al. NEJM 2006
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Genomic Profile-Driven Decision-making and False
Dichotomies

• Numbers the tests provide are misleading.
• High Recurence Score risk by tumor size
• lt 1cm 20
• 1-4 cm 30
• 4 cm 65
• Risk assessment must take into account biology
  and anatomy

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Tailored TherapyTamoxifen and CYP2D6
Tamoxifen as prodrug
TTP
RFS
OS
DFS
Goetz BCRT 06
Shorter time to recurrence, worse DFS in 2D6
poor metabolizers Can 2D6 help choose tamoxifen
versus aromatase inhibitors?
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LCCC 0801 Genotype-Driven Tamoxifen DosingW.
Irvin
Extensive metabolizers (EM)
Same tam dose
Tamoxifen treated patients
Double tam dose
Intermediate metabolizers (IM)
Poor metabolizers (PM)
Double tam dose
2D6 genotyping Endoxifen levels
Repeat endoxifen levels

• Hypotheses
• Endoxifen will increase in IM
• Endoxifen change IM gt PM
• Treatment is tolerable

• Can we use 2D6 to choose not only use of
  tamoxifen but dose of tamoxifen e.g. compensate
  for inherited variability in metabolism by dose?

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Genotype-Driven Tamoxifen Dose Study Pilot
Intermediate metabolizers (only)
20mg
40mg

• In spite of impaired tamoxifen metabolism,
  endoxifen levels were significantly increased.

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Projected supply of and demand for oncologist
visits
Ganz, P. A. et al. J Clin Oncol 26759-767 2008
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What Happens Next?Survivorship Issues in Breast
Cancer
period following first diagnosis and treatment
before recurrence or death
Well, on no Rx
YOU / ME (when?)
200,000 New dx/yr
Active Rx 6m-1.5y

• Well, on Rx
• Endocrine (5-10y)
• Bisphosphonates

ME

• Relapsed
• 40,000 / year
• 75 within 5 y

ME
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Survivorship Issues

• Screening relapse and new cancer
• Hot flashes
• Bone Issues
• Osteoporosis
• Arthralgias/myalgias
• Lymphedema (10 AND)
• Cardiotoxicity
• 1 after anthracycline
• VTE

• Peripheral neuropathy
• Taxanes (5 any degree)
• Platinum agents
• Weight gain
• Fatigue / Depression
• Sexual Health / Infertility
• Second cancers
• MDS/AML 0.2-1 after standard adjuvant therapy
• Endometrial Cancer 0.5-1 women on tam for 5
  years

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ExampleBone loss at 12 mos in Lumbar Spine
?
1) Warming et al Osteoporosis Int 13105-12,
2002 2) Eastell et al J Bone Min Res 211215-23,
2006 3) Shapiro et al J Clin Oncol 143306-11,
2001 4) Fogelman et al Osteoporosis Int
141001-6, 2003
Shapiro CL, et al. ASCO 2008
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Fractures with Aromatase Inhibitors
Trial N F/U (mo) F/U (mo) Treatment Clinical Fracture Rate ()
AI vs. Tamoxifen AI vs. Tamoxifen AI vs. Tamoxifen AI vs. Tamoxifen AI vs. Tamoxifen AI vs. Tamoxifen
ATAC 9366 100 ANA vs. TAM ANA vs. TAM 11.0 vs. 7.7 plt0.001
BIG 1-98 4922 51 LET vs. TAM LET vs. TAM 8.6 vs. 5.8 plt0.01
AI after 2-3 years of Tamoxifen AI after 2-3 years of Tamoxifen AI after 2-3 years of Tamoxifen AI after 2-3 years of Tamoxifen AI after 2-3 years of Tamoxifen AI after 2-3 years of Tamoxifen
IES 4724 58 EXE vs. TAM EXE vs. TAM 7.0 vs. 5.0 p0.003
ABCSG8/ ARNO 3224 28 ANA vs. TAM ANA vs. TAM 2.0 vs. 1.0 p0.015
AI after 5 years of Tamoxifen AI after 5 years of Tamoxifen AI after 5 years of Tamoxifen AI after 5 years of Tamoxifen AI after 5 years of Tamoxifen AI after 5 years of Tamoxifen
MA-17 5187 30 LET vs. Placebo LET vs. Placebo 5.3 vs. 4.6 p0.25
Courtesy of Charles Shapiro, MD
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Treatment of Bone Loss in Breast Cancer Survivors

• Assess and Modify Risk Factors
• Increase Physical Activity
• 30 min 3x/week also helps fatigue and weight gain
• Calcium (1500 mg) and Vitamin D (800-1000 IU)
• Stop smoking reduce alcohol
• DEXA screening every 2 years
• Bisphosphonate treatment if indicated by T-score
• lt-2.5 or lt-2.0 with risk factors

Risk Factors smoking alcohol sedentary family
history chronic corticosteroids being on AI
ovarian suppression
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Zolendronic Acid and Therapy-induced Bone Loss

• Zoledronic acid reduced bone loss
• Premenopausal popn
• All ovarian suppressed
• Fractures were rare
• (but premenopausal)
• ONJ not seen
• 35 decrease in breast cancer relapse
• If confirmed, we oncologists will be putting it
  in the water

Zoledronic acid
- Zoledronic acid
Zoledronic acid
- Zoledronic acid
Gnant M et al. J Clin Oncol 2007
Gnant, M. F.X. et al. J Clin Oncol 25820-828
2007
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The Future Might Include More Bisphosphonates
2 large trials (AZURE, B-34) to be reported SWOG
S0307 (randomized b/w 3 different
bisphosphonates) ongoing
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ASCO Guidelines Breast Cancer Surveillance
After Active Rx

• Relapse surveillance
• Local relapse mammogram, ?MRI
• Systemic relapse HP
• NO role for routine labs or screening xrays
• Coordination of care
• BMD for pts on aromatase inhibitor (q1-2y)
• Gyn evaluation for tamoxifen pts (qyr)
• Cardiology referral prn
• Genetics for FH
• Physiotherapy for lymphedema
• CBT / psychologist
• ? Survivorship plans?
• Interpretable treatment summaries

Q 3-6m x 3y
Q 6m x 2y
Q 12m to 10y
To PMD
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This Means That Effective Communication is Key
Oncologic issues
Other medical issues
Time

• Oncologists are usually bad internists
• Keeping up with oncology changes in practice and
  the fallout from same is challenging

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Key Elements of the Treatment Summary and Care
Plan

• Provider information
• Surgical Procedures and dates
• Pathology
• Chemotherapy treatment and dates and doses
• Endocrine therapy and dates
• Other therapies
• Radiation
• Potential Long-term and Late Effects of Therapy
• Recommended Post-treatment surveillance
• Work in progress!

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This Is a Nice Problem To Have

• Like Hodgkins Disease, we must focus not only on
  life, but quality of life
• Choosing chemotherapy rationally
• Monitoring the rest of the body during/after
  therapy
• Cardiac toxicity
• Neurologic toxicity
• Bone health
• Gynecologic health
• Even Stage IV patients are living longer

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Modern breast cancer research is a partnership
Clinical oncology staff
Other medical colleagues
Research staff
Our patients