Transcript Breast_Cancer2

Introduction to the Management
of Breast Cancer
Statistics
• 192,370 new cases and 40,170 deaths
estimated for 2009 in the US
– 62,280 cases in situ breast cancer
• Lifetime risk of developing breast cancer is
12-13%, or ~1 in 8 women
– Highest incidence
• Lifetime risk of dying is approximately 3.0% (1
in 33 women)
– Second cancer mortality (after lung ca)
CA Cancer J Clin 2009; 59:225-249
Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United
States, 2009
From Jemal, A. et al.
CA Cancer J Clin 2009;59:225-249.
Copyright ©2009 American Cancer Society
Annual Age-adjusted Cancer Incidence Rates among Males and Females for Selected
Cancers, United States, 1975- 2005
Incidence decreasing 19992005, -2.2%
Death rates decreasing 19912005
Absolute change of -8.7%
From Jemal, A. et al.
CA Cancer J Clin 2009;59:225-249.
Copyright ©2009 American Cancer Society
Incidence and Mortality
• Incidence
– Increased screening (mammography)
– Environmental factors?
– 2003 7% decline in incidence (> in ER+)
• Decrease in use of hormone replacement therapy
• Mortality decreasing
– 2.3 percent per year from 1990 to 2002
– Early detection
– Better adjuvant therapy
Ravdin, SABCS 2006
Berry et al NEJM 2005 353:1784
Breast Cancer Risk Factors
• Age
• Prior breast biopsies with proliferative breast
disease
• Atypical hyperplasia
• Lobular carcinoma in-situ
• Family History
• Thoracic radiation
• Endogenous hormones
– Early menarche
– Late menopause
– Nulliparity or older age at birth of first child
• Exogenous hormones
• Mammographic density
• Lifestyle Factors (alcohol, obesity, diet, exercise)
Most Breast Cancer is NOT
Hereditary
15%20%
~10%
5%–10%
Breast Cancer
Ovarian Cancer
Sporadic
Family clusters
Hereditary
Comparing Breast Cancer Risk
Estimates in BRCA Mutation Carriers
100
BRCA1+ carriers
(BCLC)
80
Breast
cancer
risk (%)
BRCA1+ carriers
(Ashkenazi Jews)
60
40
20
General population
0
40
50
60
Easton DF et al. Am J Hum Genet 56:265, 1995
Struewing JP et al. N Engl J Med 336:1401, 1997
70
80
Age
ACS Screening Recommendations
Breast
Test or
Procedure
Frequency
Breast selfexamination
Monthly, starting at age 20
Clinical breast
examination
Every 3 years from ages 20-39
Annually, starting at age 40{a}
Mammography
Annually, starting at age 40
•20% of breast cancers not seen on mammo
•When do you stop screening
mammography?
ACS guidelines for Breast MRI
CA Cancer J Clin 2007; 57; 75-89
Diagnosis of Breast Cancer
• Fine needle aspiration
– Cytologic diagnosis, cannot distinguish DCIS from invasive
disease
– Negative aspiration does not rule out cancer
• Core-needle biopsy
– Preferred method for diagnosis; preserves architecture
• Excisional biopsy
– Useful to determine tumor size
– Precludes primary chemotherapy
• Needle localization
– Nonpalpable lesions, multiple lesions
• Stereotactic biopsy
– Image-guided FNA or core biopsy
Breast Cancer Pathology
• Invasive carcinoma
– Infiltrating ductal (75% of breast cancers)
– Infiltrating lobular (5-10% of breast cancers)
• “Indian file” histology, less distinct mass
• More often metastasizes to: pleura, peritoneum, meninges
– Medullary (5-7%)
• Lymphocytic and plasma cell infiltrate, well circumscribed
– Good prognosis
• Mucinous/Colloid (3%,)
• Papillary (1-2%)
• Tubular (5 %)
Breast Cancer Pathology
• Non-invasive tumors
– Ductal carcinoma in situ (DCIS)
• Comedo (poorly differentiated)
• Noncomedo (well differentiated, low-grade)
– Papillary, micropapillary, cribiform, solid
– Lobular carcinoma in situ (LCIS)
• Uncommon tumors
– Inflammatory carcinoma
– Paget’s disease
– Phyllodes tumor (cystosarcoma phyllodes)
Breast Cancer Classification
• Staging (TNM)
• Histologic evaluation
– Tumor grade
– Hormone receptors
– HER2 expression
– Molecular subtypes
Prognostic Factors
•
•
•
•
•
Patient age (menopausal status)
Tumor size
# of Lymph nodes
Histologic tumor type
Tumor grade (% tubule formation, nuclear
pleomorphism, mitotic count)
• Hormone receptor status
• Her2/neu status
• Oncotype DX score/ Recurrence score
Natural History
Fig 1. (A) Relapse free survival (RFS) based on size for entire cohort 1 (0.1 to 1.0
cm, top); entire cohort 2 (1.1 to 2.0 cm, middle); and entire cohort 3 (2.1 to 5.0
cm, bottom)
82%
75%
66%
Chia, S. K. et al. J Clin Oncol; 22:1630-1637 2004
Copyright © American Society of Clinical Oncology
Risks of Mortality by Tumor
Type in Women aged 50-79 yrs
SEER 1974-1998 (164,958 pts)
Histology
Ductal
Lobular
Mucinous
Medullary
Tubular
Papillary
Survival (%)
58.7
67
65.3
55.2
81.5
62.8
HR 995% CI)
1.00 (reference)
0.89 (0.86-0.91)
0.80 (0.76-0.85)
0.82 (0.78-0.87)
0.66 (0.60-0.73)
0.81 (0.73-0.90)
Li, et al Arch Int Med 163:2149-53, 2003
Tumor Grading
• Tumor grade is a system used to classify
cancer cells in terms of how abnormal they
look under a microscope and how quickly the
tumor is likely to grow and spread
Hormone receptor status
• Estrogen and progesterone receptors
are nuclear transcription factors
• Determined by immunohistochemistry
• Scored as a percentage of cells staining
• 1% or greater is considered positive
Her2/neu status
• Membrane-associated tyrosine kinase
receptor (aka erbB2)
– Expressed in breast cancers, DCIS, and some
other tissues such as heart
• Worse prognosis with HER2 gene
amplification
– Prognosis changing with use of trastuzumab
Her2/neu status
• Measured by immunohistochemistry (IHC)
and/or FISH
• FISH more accurate
• IHC: Graded 0, 1+, 2+, or 3+
– Based on characteristics of staining
– 0-1 = negative
– 2 = in determinant, should be followed with
FISH (fluorescent in situ hybridization) to
determine status (amplified/not amplified)
– 3 = positive
Prognosis: Tumors  1 cm, HER2 gene
amplification, Node-negative
Press, M et al. J Clin Oncol 15:2894-904, 1997
The HER Family of Receptors
•Lapatinib
HER1
EGFR
HER2
HER3
HER4
Tumor Cell
•Trastuzumab (Herceptin)
•Pertuzumab (Omnitarg)
Her2 therapy
• Trastuzumab (Herceptin)
– Monoclonal antibody directed towards
Her2/neu receptor
– cardotoxicty
• Lapatinib (Tykerb)
– Small molecule tyrosine kinase inhibitor
blocking HER2 and EGFR1 (HER1)
– Diarrhea, rash
– Cardiotoxicity?
Molecular Portrait of Breast Cancers
Basal-like
HER-2
“Normal”
Luminal B
Luminal A
Sorlie T et al, PNAS 2001
Slide courtesy of L. Carey
Proxies for Gene Signature
“Subtypes”
Triple
Negative
ER/PR+
HER2+
ER/PR-
Basal-like
75%
9%
0%
Luminal
12%
76%
14%
“HER2”
9%
5%
85%
Courtesy of L Carey
Subtypes and Prognosis
Sorlie T et al, PNAS 2001
2003 AJCC: Primary Tumor (T)
• T1:  2 cm
– T1mic
microinvasion
 0.1 cm
– T1a >0.1 - 0.5 cm
– T1b 0.6 – 1 cm
– T1c 1.1 – 2 cm
• T2: 2.1- 5 cm
• T3: > 5 cm
• T4a: Extension to chest
wall, not including
pectoralis
• T4b: Edema, ulceration,
satellite skin nodules
• T4c: both T4a and T4b
• T4d: inflammatory ca
AJCC 2003: Stage Grouping
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage IIA
T0
N1
M0
T1
N1
M0
T2
N0
M0
T2
N1
M0
T3
N0
M0
T0-3
N2
M0
T3
N1
M0
Stage IIIB
T4
N0-2
M0
Stage IIIC
Any T
N3
M0
Stage IV
Any T
Any N
M1
Stage IIB
Stage IIIA
Staging Classification of Breast
Tumour
Therapy of Breast Cancer
• Local:
– Surgery
• Mastectomy
• Breast Conserving Therapy
• SLND/ALND
– Radiation therapy
• Systemic:
– Endocrine/hormonal therapy
– Chemotherapy
– Biologic therapy
Breast Cancer Local Treatment
• Modified radical mastectomy with axillary
lymph node dissection
• Breast-conserving therapy – lumpectomy with
axillary lymph node dissection followed by
radiation
• Equivalence established by NSABP B-06
• Original report (Fisher, et al., NEJM 1985)
• 12 year follow up (Fisher, et al., NEJM 1995)
• NCI audit (Christian, et al., NEJM 1995)
Surgical Treatment for early stage
localized breast cancer
• Lumpectomy (partial mastectomy/
breast conserving therapy)
• Mastectomy
– Total (simple)
– Subcutaneous
– Modified Radical
– Radical
Contraindications to BCT
•
•
•
•
Pregnancy
Previous breast or mantle RT
Diffuse malignant microcalcifications
Collagen vascular disease (SLE,
scleroderma)
• Multicentric disease
Indications for Post-Mastectomy
Radiation
• 4 or more positive axillary lymph nodes
• Tumor 5 cm or greater
• Tumor invading the skin or adjacent
musculature
• Positive surgical margins
• Note: Role in patients with 1 – 3 positive
nodes is controversial (balanced discussion)
• ASCO guidelines for postmastectomy XRT
• Recht, et al., JCO 19:1539, 2001.
Adjuvant systemic therapy
• Can eliminate hidden, microscopic
metastases
•Decreases local recurrence in patients
treated with breast conservation
•Includes:
• Hormone therapy
• Chemotherapy
• Target therapy (ie Herceptin)
Who should receive adjuvant
therapy?
• Consensus statements:
– Early Breast Cancer Trialists’ Collaborative
Group (EBCTCG, aka Oxford Overview)
last published 2005
– 7th International Conference on Adjuvant
Therapy of Primary Breast Cancer (St.
Gallen, 2009)
– NCI Consensus Conference (Nov 2000)
– NCCN guidelines
Indications for Adjuvant
Chemotherapy
•
•
•
•
All lymph node-positive
Her2/neu positive tumors
Triple negative tumors
Invasive, lymph node-negative
- invasive ductal/lobular, > 1 cm (NIH)
- invasive ductal/lobular, > 2 cm (St. Gallen’s)
- invasive, favorable histology, > 3 cm
Case#1
• 68 y.o. postmenopausal female noted to
have abnormality in left breast on
screening mammogram
– approx 1 cm abnormality noted in upper
outer quadrant
• No sig PMH or FH
• Negative ROS
• Left core biopsy-infiltrating ductal
carcinoma, grade 1, ER 90%, PR 95%,
Her2/neu negative
• Left lumpectomy and SLNB-1.1cm IDC,
0/2LN+
• What adjuvant therapy should she
receive?
• Hormonal treatment first choice
• Could consider chemotherapy
– Oncotype DX
Indications for Adjuvant Hormonal
Therapy
• Indicated for almost all patients with ER
or PR expression > 1%
• Sequential preferred over concurrent
chemo-hormonal therapy
• Tamoxifen and/or AI
– No AI in premenopausal women
Albain, K. St Gallen Conf 2003
Hormonal (Endocrine) Therapies:
Mechanisms of Action
• Decrease ligand
• Aromatase inhibitors
• Oophorectomy
• Goserelin, Leuprolide
• Block receptor
• SERM (selective
estrogen receptor
modulators)
• SERD (selective
estrogen receptor
downregulator)
Diff hormonal agents
• Tamoxifen
– Blood clots, uterine cancer, increased
LFTs, cataracts, hot flashes
– Improves BMD in postmenopausal,
improves lipid profile
• Aromatase Inhibitors (anastrozole, letrozole,
exemestane)
– Myalgias/arthralgias, decrease in BMD
– Elevate BP, elevate lipids, CV risk?
Adjuvant Therapy
Guiding Principles: Hormones
EBCTCG Lancet. 365(9472):1687-717 2005
EBCTCG tamoxifen in subgroups
Tamoxifen benefits all
groups:
Older and younger
Chemo or not
Lymph node + or not
EBCTCG Lancet 2005 365: 1687 - 1717
Trials of AIs in the adjuvant setting
TAMOXIFEN x 5
ATAC
ANASTROZOLE x 5
TAM + ANAST x 5
TAMOXIFEN x 5
BIG I-98
LETROZOLE x 5
TAM x 2
LET x 3
LET x 2
TAM x 3
IES
TAM x 2-3
ABCSG 8
ARNO 95
ITA
TAM x 2-3
MA-17
TAM x 2-3
EXEMESTANE x 2-3
TAM x 2-3
Anastozole x 2-3
TAMOXIFEN x 5
LETROZOLE x 5
PLACEBO x 5
Summary of Results from Large
Adjuvant Aromatase Inhibitor Trials
IES
0.76 (0.66, 0.88)
MA.17
0.58 (0.45, 0.76)
ATAC
0.83 (0.73, 0.94)
ABSCG/
ARNO
0.60 (0.44, 0.81)
0.81 (0.70, 0.93)
BIG I-98
0.4
0.6
0.8
1.0
1.2
Length of Hormonal Tx
• Atleast 5 years
• Up to 10 years
• Maybe more?
Endocrine Rx:
What you need to know
• Use in anyone with ER+ and/or PR+
– Sequence after chemotherapy
• Tamoxifen reduces the risk of recurrence and
improves overall survival across the board
• AIs reduce risk of recurrence compared with
tamoxifen. NO increased OS yet.
– Try to use AIs in all postmenopausal women
• SERM and AI side effect profiles differ, keep in mind
when assessing individual patients
• Ovarian suppression is an option for
premenopausal women (added benefit with
hormonal tx?)
Case #2
• 48 y.o. perimenopausal female notes a
1.5 cm mass in her right breast on self
exam
• Mammogram shows no abnormalities
• Biopsy-IDC, grade 3, ER 30%, PR 10%,
Her2/neu negative
• Lumpectomy and SLNB-2cm IDC,
grade 3, 1/2 LN+
• What should she receive as adjuvant
therapy?
Lymph Node Positive Breast Cancer
• ER negative
– chemotherapy
(pre-menopausal or post-menopausal)
• ER positive
– premenopausal: chemotherapy + tamoxifen**
– postmenopausal: tamoxifen/AI +
chemotherapy
- age > 70: tamoxifen (+ chemotherapy?)
** ovarian ablation/GnRH analog may be considered
Adjuvant!
• Computer program to determine breast
cancer prognosis by adjuvant therapy
– http://www.adjuvantonline.com
• Recurrence rates based on Oxford
Overview data
• Overall survival based on SEER data
Adjuvant Online
Adjuvant Online Printout
Genomic Health 21 Gene Panel
Predicts Benefit from Chemotherapy
- Results from NSABP B-14 and B-20
Soonmyung Paik1, Steven Shak2, Gong Tang1, Chungyeul Kim1, Joffre
Baker2, Maureen Cronin2, Rick Baehner2, Drew Watson2, John Bryant1,
Joseph Costantino1, William Hiller1, and Norman Wolmark1
From
1. Division of Pathology, Operation Center, and Biostatistics Center,
NSABP, Pittsburgh, PA
2. Genomic Health, Inc., Redwood City, CA
Oncotype DX 21 Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
INVASION
Stromolysin 3
Cathepsin L2
HER2
GRB7
HER2
ESTROGEN RS = + 0.47 x HER2 Group Score
- 0.34 x ER Group Score
ER
+ 1.04 x Proliferation Group Score
PR
+ 0.10 x Invasion Group Score
Bcl2
+ 0.05 x CD68
SCUBE2
- 0.08 x GSTM1
- 0.07 x BAG1
GSTM1 BAG1
CD68
Category
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
RS (0 – 100)
Low risk
RS < 18
Int risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
Validation Study of Oncotype DX
Tamoxifen treated patients from NSABP B-14
(N=668)
Performance exceeded standard measures of patient age,
100%tumor size
40%
Intermediate
Risk Group
Low Risk Group
Distant Recurrence at 10 Years
90%
80%
DRFS
70%
60%
50%
40%
30%
20%
Low Risk (RS <18)
Intermediate Risk (RS 18 - 30)
High Risk (RS  31)
10%
0%
35%
High Risk Group
30%
25%
20%
15%
10%
5%
338 pts
149 pts
181 pts
0%
0
5
10
15
20
25
30
Recurrence Score
0
2
4
6
8
Years
10
12
14
16
35
40
45
50
OncotypeDX Results
Oncotype Dx: Chemotherapy benefit
RS < 18
RS ≥ 31
RS 18-30
1.0
1.0
0.9
0.8
0.9
0.8
0.7
0.8
0.7
0.6
0.7
0.6
0.5
0.6
0.4
DRFS
0.9
DRFS
DRFS
1.0
0.5
0.5
0.4
0.3
0.4
0.3
0.2
0.3
0.2
0.2
0.1
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0.1
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
0.1
0.0
0
2
4
6
Years
8
10
12
0.0
0
0.0
0
2
High Risk Patients (RS  31)
Tam + Chemo
Tam
4
6
8
10
12
2
4
6
8
10
Years
Years
• Patients with tumors that have high Recurrence Scores
have a large absolute benefit of chemotherapy (similar
results with CMF and MF)
• Patients with tumors that have low Recurrence Scores
derive minimal, if any, benefit from chemotherapy
Paik et al, J Clin Oncol. 2006;Epub May 23.
12
EBCTCG: Chemotherapy
reduces risk of recurrence
<50 years
50- 69 years
EBCTCG Lancet. 365(9472):1687-717 2005
Progress in Adjuvant Chemotherapy
of Breast Cancer
1970s
1980s
1990s
2000s
Before Anthracyclines
• CMF, CMFVP
With Anthracyclines
• Combination: AC, FAC, FEC, CEF
• Sequence and Alternating
• Dose intensity, dose density, HDCT
Taxanes (Paclitaxel/Docetaxel)
• Sequential: A → T → C or AC → T
• Combination: TA, TAC
Biologic Modifiers
Vogel CL, ASCO 2003
Adjuvant Chemotherapy
Regimens
• Low risk/lymph node negative
– ACx4
– CMFx6
– CAFx6
– TCx4
• High risk/lymph node positive
– dd ACx4paclitaxel x4 (q2 week)
– TACx6
– FEC-100 or CAFx6 if taxane not tolerated
– TC 4-6 cycles if anthracycline not tolerated
• Her2+
– Herceptin based regimen
Neoadjuvant Therapy
• Indications
– Inoperable tumors
– Inflammatory breast cancer
– May consider to increase chance for BCS
– In operable breast cancer where chemotherapy is
recommended, neoadjuvant therapy can be considered
• No difference in DFS or OS between neoadjuvant and adjuvant
Rx
• Patients with pCR after neoadjuvant Rx have > 90% OS
(reported rates range of pCR 4-65%)
• The optimal approach to staging the axilla in patients getting
neoadjuvant Rx is not known
– This impacts surgery and radiation therapy
Surveillance
• History and physical every 4-6 months for 5
years, then annually
• Mammogram annually (and at 6 months after
treatment with XRT and breast conserving
surgery)
• Pelvic exam annually for women with intact
uterus on tamoxifen
• Other imaging only as indicated by history
and physical exam
Case #3
• 56 y.o. female with newly diagnosed
stage III right breast cancer (IDC, gr 2,
ER+, PR-, Her2/neu-)
• On staging studies found to have
multiple bony lesions on bone scan and
suspicious liver lesions on CT
• Liver bx-consistent with metastatic
breast cancer
• What do you do?
Disease Recurrence
Biopsy
ER, PR, HER2/neu status
ER+
Hormonal
therapy
2nd
line/3rd
line
hormonal
therapy
Chemotherapy
HER2/neu+
ER+
Hormonal
Therapy +/Trastuzumab
Chemotherapy +
Trastuzumab
ER-
ERChemotherapy +
Trastuzumab
Chemotherapy
Metastatic disease:
General principles
• Hormonal therapy for indolent disease
• Trastuzumab-based therapy for HER2/neu
positive disease
• Single agent chemotherapy for
aggressive/symptomatic disease or disease not
responsive to hormonal therapy
• Consider tx with bevacizumab
• Polyagent chemotherapy for visceral crisis or
disease requiring rapid response
History of Drug Approvals for
Breast Cancer
• General approvals
• Hormonal
– Methotrexate
Dec 1953
– Cyclophosphamide Nov 1959
– Doxorubicin
Aug 1974
• 1st Breast Cancer Approval
–
–
–
–
–
–
–
–
Paclitaxel
Docetaxel
Capecitabine
Pamidronate
Trastuzumab
Epirubicin
Abraxane
Bevacizumab
Apr 1994
July 1994
Mar 1998
Sept 1998
Sept 1998
Sept 1999
Jan 2005
Feb 2008
–
–
–
–
–
–
–
Tamoxifen
Anastrozole
Goserelin
Toremifene
Letrozole
Exemestane
Fulvestrant
Dec 1977
Dec 1995
Dec 1995
May 1997
July 1997
Oct 1999
Apr 2002
Metastatic Breast Cancer
• Not curable
• 1st recurrence should be biopsied!!
• 1st goal is to maintain good QOL –
consider it a chronic disease
• Bisphosphonates for bone metastases
Metastatic disease
• Tumor markers not shown to be helpful in
making clinical decisions
• Restaging studies every 3 to 6 months to
determine progression, sooner if
symptomatic, clinically warranted
• Clinical trials!
High Dose Chemotherapy with
Stem Cell Rescue
• Toxicities are substantial, including a 5-8%
mortality in past, 1-2% at present
• Overall survival benefit has not been
demonstrated; relapse-free benefit is
controversial in high risk patients
• No proven benefit in metastatic disease
• Should be done only on clinical trials
Conclusions
• Many effective treatment regimens
• Efforts now focused on defining subtypes to
individualize treatment and avoid
overtreatment
• Questions???