Overview of Breast Cancer Management

1
Overview of Breast Cancer Management

• Edith A. Perez, MD
• Director, Clinical Investigations
• Director, Breast Cancer Program
• Division of Hematology/Oncology
• Mayo Clinic
• Jacksonville, Florida

2
Incidence of Breast Cancer Compared With Other
Sites (Women)
Uterine corpus Ovary Non-Hodgkins lymphoma
Breast Lung and bronchus Colon and rectum
160
140
120
100
80
Rate per 100,000 Females
60
40
20
0
1975
1980
1985
1990
1995
2000
Year of Diagnosis
Adapted from Jemal A et al. CA Cancer J Clin.
2004548-29 ACS. Breast Cancer Facts and
Figures. 2003.
3
Mortality Rate for Breast Cancer Compared With
Other Sites (Women)
Uterus Ovary Pancreas
Breast Lung and bronchus Colon and rectum
60
50
40
Rate per 100,000 Females
30
20
10
0
1975
1980
1985
1990
1995
2000
Year of Diagnosis
Adapted from Jemal A et al. CA Cancer J Clin.
2004548-29 ACS. Breast Cancer Facts and
Figures. 2003. .
4
Risk Factors for Breast Cancer

• Personal history of breast cancer or
  proliferative breast disease
• Genetic mutations in BRCA1, BRCA2, and others
• Positive family history of breast or ovarian
  cancer
• History of DES therapy (exposure to estrogen or
  progesterone compounds)
• Prior breast irradiation at young age

• Childbearing absent or delayed until after age
  30 years
• Early menarche/ late menopause
• Hormone replacement therapy
• High body mass index
• High alcohol intake

BRCA1 breast cancer 1 gene BRCA2 breast
cancer 2 gene DES diethylstilbestrol. Hollingsw
orth AB et al. Am J Surg. 2004187349-362.
5
Breast Cancer Risk Assessment Interactions
Between Risk Factors

• Modified Gail model used by the National Cancer
  Institute and National Surgical Adjuvant Breast
  and Bowel Project in the Breast Cancer Prevention
  Trial
• Assessment tool analyzes combinations of 7
  factors to calculate risk
• History of DCIS, LCIS
• Age (patients 35 years)
• First-degree relatives with breast cancer
• Prior breast biopsies and presence of atypical
  ductal hyperplasia
• Risk of developing breast cancer is indicated by
  the composite score of the relative risk for each
  factor

• Age at menarche
• Age at first live birth
• Ethnicity

DCIS ductal carcinoma in situ LCIS lobular
carcinoma in situ. Gail MH et al. J Natl Cancer
Inst. 1989811879-1886.
6
Factors That Influence Survival in Breast Cancer
Patients

• Age at diagnosis
• Tumor size at diagnosis
• Stage at diagnosis
• Biologic characteristics of the tumor
• Hormone receptor status (less significant)
• HER2

HER2 human epidermal growth factor receptor 2.
ACS. Breast Cancer Facts and Figures. 2003
Lohrisch C, Piccart M. Clin Breast Cancer.
20012129-135 Michaelson JS et al. Cancer.
200295713-723.
7
Overview of Stages of Breast Cancer
Stage I
Stage II
Stage III
Stage IV
Early disease Tumor confined to the
breast (node-negative)
Early disease Tumor gt2 cm in diameter or spread
to movableipsilateral axillarynode(s)
(node-positive)
Locally advanced diseaseTumor spread to
thesuperficial structures ofthe chest wall
involvementof ipsilateral internal mammary
lymph nodes
Advanced (or metastatic) disease Metastases
presentat distant sites such as bone, liver,
lungs, and brain, and including supraclavicular
lymph node involvement
Greene FL et al, eds. AJCC Cancer Staging
Handbook from the AJCC Cancer Staging Manual.
2003.
8
TNM Staging in Breast Cancer

• Provides information about
• Tumor size
• Node involvement
• Whether the cancer has spread to the lymph nodes
  of the breast (axilla, internal mammary,
  supraclavicular, intramammary)
• Metastasis
• Whether the tumor has spread to other parts of
  the body

Tis tumor in situ. Greene FL et al, eds. AJCC
Cancer Staging Handbook from the AJCC Cancer
Staging Manual. 2003.
9
Breast Cancer TreatmentTNM Stage 0
Objective To reduce the risk of invasive breast
cancer and achieve local control of carcinoma and
decrease risk of death
Surveillance(LCIS, DCIS)

• Physical examination
• Mammogram MRI in some cases
• Lumpectomy
• If DCIS in 1 area
• Mastectomy
• If DCIS in ?2 areas
• If multifocal or large
• Usually (not always) accompanies lumpectomy
• In selected ER-positive cases for 5 years to
  lower cancer risk

Surgery(DCIS)
Radiotherapy(DCIS)
Hormonal therapy(DCIS)
LCIS lobular carcinoma in situ DCIS ductal
carcinoma in situ MRI magnetic resonance
imaging ER estrogen receptor. ACS. Available
at www.cancer.org/docroot/CRI/content/CRI_2_4_4X
_Breast_Cancer_Treatment_by_ stage_5.asp. 2003.
10
Breast Cancer TreatmentTNM Stages I and II
Objective To eradicate local disease by direct
localized action on the breast and axillary lymph
nodes (when appropriate)
Breast conservation surgery

• Lumpectomy or quadrantectomy
• Axillary dissection
• Affected breast, chest wall
• Combination chemotherapy
• 3-6 months
• Premenopausal
• Tamoxifen if ER-positive
• Postmenopausal
• Tamoxifen and/or aromatase inhibitor

Radiotherapy
Adjuvant chemotherapy
Adjuvant hormonal therapy
ACS. Available at www.cancer.org/docroot/CRI/cont
ent/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.
asp. 2003. .
11
Breast Cancer Treatment TNM Stage III
Objective To achieve local control, prevent
metastases, and extend overall survival through
aggressive treatment
Surgery

• Mastectomy or lumpectomy
• Chest wall, regional nodes
• Combination chemotherapy
• 4-6 months
• Benefit if tumor ER-positive and/or PR-positive

Radiotherapy
Adjuvant/neoadjuvant chemotherapy
Hormonal therapy
ER estrogen receptor PR progesterone
receptor. ACS. Available at www.cancer.org/docroo
t/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_b
y_Stage_5.asp. 2003.
12
Breast Cancer TreatmentTNM Stage IV
Objective To improve symptoms, prolong survival,
and enhance quality of life

• Used in selected cases to relieve symptoms
• Used in selected cases to relieve symptoms and
  control local disease
• Primary therapy single-agent or combination
  chemotherapy
• HER2-positive
• ER-positive and/or PR-positive

Surgery
Radiotherapy
Chemotherapy
Monoclonal antibody
Hormonal therapy
ACS. Available at www.cancer.org/docroot/CRI/cont
ent/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.
asp. 2003.
13
Local Therapy Major Surgical Treatment Options
for Breast Cancer

• Local therapy provides adequate control of
  locoregional disease
• Includes surgery and radiation therapy
• Surgery
• Mastectomy
• Modified radical with sentinel lymph node
  evaluation
• Radical or total mastectomy with sentinel lymph
  node evaluation
• May include breast reconstruction
• Breast-conserving surgery
• Wide local excision
• Quadrantectomy
• Lumpectomy
• Includes axillary dissection if disease is
  invasive

ACS. Available at www.cancer.org/docroot/CRI/cont
ent/CRI_2_4_4X_Surgery_5.asp. 2003.
14
Complications Following Breast Cancer Surgery

• Lymphedema
• May occur in 10 to 30 of women undergoing
  axillary dissection
• Reduced to 3 in patients undergoing sentinel
  node biopsy alone
• Numbness
• Reduced shoulder mobility
• Psychosocial impact of mastectomy
• Phantom breast sensations

ACS. Available at www.cancer.org/docroot/NWS/cont
ent/NWS_3_1x_New_Procedure_Reduces_Risk_of_
Lymphedema_After_Breast_Cancer_Surgery.asp, 2001
Rowland JH et al. J Natl Cancer Inst.
2000921422-1429 Staps T et al. Cancer.
1985562898-2901.
15
Local Therapy Radiotherapy in Breast Cancer

• Adjuvant radiotherapy in ESBC
• Reduces risk of recurrence
• May improve survival
• Radiotherapy in MBC
• Relieves symptoms such as pain, for example in
  patients with bone and brain metastases, while
  not effecting a cure

ESBC early-stage breast cancer MBC
metastatic breast cancer. Cairncross JG et al.
Ann Neurol. 19807529-541 Coia LR. Int J Radiat
Oncol Biol Phys. 199223229-238 Early Breast
Cancer Trialists Collaborative Group. N Engl J
Med. 19953331444-1455 Harris S. Int J Clin
Pract. 200155609-612.
16
Radiotherapy for Breast Cancer Methods of
Delivery

• External beam radiation
• Most common method
• Typically, radiation is delivered to entire
  breast
• Partial-breast irradiation, including
  brachytherapy
• Radioactive seeds or pellets placed internally
  near the site of the tumor for local effect
• Can deliver high dose-rate radiation, allowing
  for a shorter treatment regimen compared to
  traditional radiotherapy

Gordils-Perez J et al. Clin J Oncol Nurs.
20037629-636.
17
Partial-Breast Irradiation for Early-Stage
Breast Cancer

• Recent trial compared partial-breast to
  whole-breast irradiation
• 199 patients with ESBC
• Breast-conserving surgery
• Median follow-up of 65 months
• Compared to matched controls, recurrence rate
  was similar (1 vs 1 P .65)
• Partial-breast irradiation has 5-year local
  control rates comparable to those for
  whole-breast radiation therapy while sparing
  normal tissues

Vicini FA et al. J Natl Cancer Inst.
2003951205-1210.
18
Currently Available Systemic Therapies for Breast
Cancer

• Hormonal
• Chemotherapy
• Targeted
• Clinical trials provide support for optimal
  implementation of the above therapies in
  patients with breast cancer

19
Hormone Therapy Options for Breast Cancer
Options
Mechanism

• Antiestrogens
• Tamoxifen
• Toremifene
• Surgery
• Radiation (infrequently used)
• LHRH analogs
• Goserelin
• Aromatase inhibitors
• Anastrozole
• Exemestane
• Letrozole
• Estrogen receptor antagonist
• Fulvestrant

Estrogen receptor blockade
Hormonal ablation
Estrogen synthesis suppression
Estrogen receptor downregulation
LHRH luteinizing hormone-releasing hormone.
Hayes DR, Robertson JFR. In Robertson JFR et
al, eds. Endocrine Therapy of Breast Cancer.
2002. Leake R. Endocrine-Related Cancer.
19974289-296 NCI. Available at
www.cancer.gov/clinicaltrials/results/fulvestrant0
802.
20
Hormonal Environment of the Breast
Ovarian ablation
Gonadotropins(FSHLH)
Anti-estrogens
Premenopausal
Ovary
LHRHanalogs
Prolactin
Growth hormone
Pituitary gland
Corticosteroids
Aromataseinhibitors
LHRH (hypothalamus)
Adrenalglands
Pre-/post-menopausal
Androgens
ACTH
Progesterone
Peripheral conversion
FSH follicle-stimulating hormone LHRH
luteinizing hormone-releasing hormone ACTH
adrenocorticotropic hormone.
Osborne CK. N Engl J Med. 19983391609-1618
Masamura S et al. Breast Cancer Res Treat.
19953319-26.
21
Evolution of Systemic Adjuvant Chemotherapy for
Early-Stage Breast Cancer
Mastectomy alone
Adjuvant CMF
Progressive improvement in disease-free and
overall survival
Addition of tamoxifen, aromatase inhibitors
Adjuvant CAF, CEF
Adjuvant AC, EC, FEC
Adjuvant AC T
Dose-dense AC T
TAC
Bonadonna G et al. N Engl J Med.
1995332901-906 Citron ML et al. J Clin Oncol.
2003211431-1439 Early Breast Cancer
Trialists' Collaborative Group. Lancet.
19983511451-1467 Early Breast Cancer
Trialists' Collaborative Group. Lancet.
1998352930-942 Henderson IC et al. J Clin
Oncol. 20036976-983 Nabholtz JM et al. ASCO
2002 Orlando, Fla. Presentation.
22
Preferred Chemotherapy Regimens for Management of
Metastatic Breast Cancer

• Single-agent options for women with recurrent or
  metastatic breast cancer
• Anthracyclines (doxorubicin or epirubicin)
• Taxanes (paclitaxel or docetaxel)
• Capecitabine
• Others not approved by regulatory agencies
• Vinorelbine ? Irinotecan
• Combination options for women with recurrent or
  metastatic breast cancer
• CAF/FAC ? AT ? Docetaxel/capecitabine
• FEC ? CMF ? Paclitaxel/gemcitabine
• AC, EC ? Paclitaxel (or
  docetaxel)/ carboplatin with trastuzumab

NCCN. Breast Cancer Clinical Practice Guidelines
in Oncology. V.1.2004. Available at www.nccn.org.
23
Single-Agent vs Combination Chemotherapy in
Metastatic Breast Cancer

• Optimal treatment for metastatic breast cancer
  remains controversial
• Combination therapy is a good option for patients
  with symptomatic, metastatic breast cancer
• Recent trials show that newer drug combinations
  improve outcomes with manageable safety profiles
• Sequential therapy may be appropriate for
  patients with indolent disease or nonvisceral
  metastatic breast cancer

Biganzoli L et al. Curr Opin Obstet Gynecol.
20041637-41 Miles D et al. Oncologist.
20027(suppl 6)13-19.
24
Adjuvant Chemotherapy for Early-Stage Breast
Cancer Improves Outcomes
The Milan Study Relapse-Free and Overall
Survival With CMF 20-year follow-up (N 386)
Optimal Dose ()
³85 (n 42) 65-84 (n 94)
?65 (n 71) Control (n 179)
100
100
80
80
60
60
Probability of Relapse-Free Survival ()
Probability of Overall Survival ()
40
40
20
20
0
0
0
5
10
15
20
5
10
15
20
0
Years After Mastectomy
Adapted from Bonadonna G et al. N Engl J Med.
1995332901-906.
25
Reduced Dose Intensity in Early-Stage Breast
Cancer Chemotherapy
120
Reduction ? 15
Delay ? 7 days
RDI lt85
ARDIlt85
100
98
98
97
90
80
75
72
70
68
60
Percent ()
65
64
58
56
40
37
34
30
30
31
28
31
29
27
20
25
15
14
0
AC21
CAF21
CAF28
CMF21
CMF28
Overall
N 6849 2794 1244 5172
3839 19,898
Relative dose intensity (RDI) adjusted to a
standard doxorubicin/cyclophosphamide (AC)
regimen. Lyman GH et al. J Clin Oncol.
2003214524-4531 Lyman GH et al. ASCO 2004 New
Orleans, La. Abstract 776.
26
Dose-Dense or Frequent Chemotherapy for Breast
Cancer Reduces Time Between Cycles
Standard dose
Dose-dense
1012 1010 108 106 104 102 100
1012 1010 108 106 104 102 100
Cell Number
0 8 16 24
0 8 16 24
Time (weeks)
Norton L. Semin Oncol. 199724(4 suppl
10)S10-3S10-10.
27
Summary of Research on Adjuvant Chemotherapy for
Early-Stage Breast Cancer

• Adjuvant chemotherapy improves survival in ESBC
• Improved survival outcomes demonstrated with an
  RDI gt85 in 1 retrospective analysis with CMF
• Regimens containing an anthracycline and/or a
  taxane show improved outcomes
• Strong data in node-positive breast cancer
• A study of a dose-dense approach (chemotherapy
  Q2W with prophylactic G-CSF support) has also
  demonstrated benefit in disease-free and overall
  survival

RDI relative dose intensity ESBC early-stage
breast cancer CMF cyclophosphamide/methotrexate
/fluorouracil G-CSF granulocyte
colony-stimulating factor.
28
Targeted Therapy Options for Breast Cancer

• Investigational agents. HER2 human epidermal
  growth factor receptor 2.
• Goldman B. J Natl Cancer Inst. 2003951744-1746
  Gefitinib package insert. 2003 NCCN. Breast
  Cancer. Clinical Practice Guidelines in Oncology.
  V.1.2004. Available at www.nccn.org Normanno N
  et al. Endocrine-Related Cancer. 2003101-21 US
  FDA. Available at www.fda.gov/bbs/topics/NEWS/200
  4/NEW01027.html Perez E. ASCO 2004 New Orleans,
  La. Presentation.

29
Conclusions

• Although the incidence of breast cancer is
  increasing, mortality has decreased over the past
  2 decades
• Advances in conventional therapies include less
  radical surgical techniques and reduced radiation
  fields
• Cytotoxic chemotherapy advances include improved
  types, dosing, and scheduling
• Improvements have also been made in hormonal
  therapy
• Newer targeted therapies are further advancing
  the care of patients with breast cancer
• Treatment regimens are becoming more
  individualized