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Overview of Breast Cancer Management Edith A. Perez, MD Director, Clinical Investigations Director, Breast Cancer Program Division of Hematology/Oncology Mayo Clinic Jacksonville, Florida Incidence of Breast Cancer Compared With Other Sites (Women) Breast Lung and bronchus

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Overview of Breast Cancer Management

Edith A. Perez, MD

Director, Clinical Investigations

Director, Breast Cancer Program

Division of Hematology/Oncology

Mayo Clinic

Jacksonville, Florida


Incidence of Breast Cancer Compared With Other Sites (Women)

Breast

Lung and bronchus

Colon and rectum

Uterine corpus

Ovary

Non-Hodgkin’s lymphoma

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. 2004;54:8-29; ACS. Breast Cancer Facts and Figures. 2003.


Mortality Rate for Breast Cancer Compared With Other Sites (Women)

Breast

Lung and bronchus

Colon and rectum

Uterus

Ovary

Pancreas

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. 2004;54:8-29; ACS. Breast Cancer Facts and Figures. 2003.

.


Childbearing absent or delayed until after age 30 years

Early menarche/ late menopause

Hormone replacement therapy

High body mass index

High alcohol intake

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

BRCA1 = breast cancer 1 gene; BRCA2 = breast cancer 2 gene; DES = diethylstilbestrol.

Hollingsworth AB et al. Am J Surg. 2004;187:349-362.


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. 1989;81:1879-1886.


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. 2001;2:129-135;Michaelson JS et al. Cancer. 2002;95:713-723.


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 >2 cm in diameter or spread to movableipsilateral axillarynode(s) (node-positive)

Locally advanced disease:Tumor 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.


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.


Breast Cancer Treatment:TNM Stage 0

Objective: To reduce the risk of invasive breast cancer and achieve local control of carcinoma and decrease risk of death

  • 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

Surveillance(LCIS, DCIS)

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.


Breast Cancer Treatment:TNM Stages I and II

Objective: To eradicate local disease by direct localized action on the breast and axillary lymph nodes (when appropriate)

  • 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

Breast conservation surgery

Radiotherapy

Adjuvant chemotherapy

Adjuvant hormonal therapy

ACS. Available at: www.cancer.org/docroot/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.asp. 2003.

.


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/docroot/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.asp. 2003.


Breast Cancer Treatment:TNM 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/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.asp. 2003.


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/content/CRI_2_4_4X_Surgery_5.asp. 2003.


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/content/NWS_3_1x_New_Procedure_Reduces_Risk_of_ Lymphedema_After_Breast_Cancer_Surgery.asp, 2001; Rowland JH et al. J Natl Cancer Inst. 2000;92:1422-1429; Staps T et al. Cancer. 1985;56:2898-2901.


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. 1980;7:529-541; Coia LR. Int J Radiat Oncol Biol Phys. 1992;23:229-238; Early Breast Cancer Trialists’ Collaborative Group. N Engl J Med. 1995;333:1444-1455; Harris S. Int J Clin Pract. 2001;55:609-612.


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. 2003;7:629-636.


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. 2003;95:1205-1210.


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


Hormone Therapy Options for Breast Cancer

Mechanism

Options

  • 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. 1997;4:289-296; NCI. Available at: www.cancer.gov/clinicaltrials/results/fulvestrant0802.


Hormonal Environment of the Breast

Ovarian ablation

Gonadotropins(FSH+LH)

Anti-estrogens

Premenopausal

Ovary

LHRHanalogs

Prolactin

Growth hormone

Pituitary gland

Corticosteroids

Aromataseinhibitors

LHRH (hypothalamus)

Pre-/post-menopausal

Adrenalglands

Androgens

ACTH

Progesterone

Peripheral conversion

FSH = follicle-stimulating hormone; LHRH = luteinizing hormone-releasing hormone; ACTH = adrenocorticotropic hormone.

Osborne CK. N Engl J Med. 1998;339:1609-1618; Masamura S et al. Breast Cancer Res Treat. 1995;33:19-26.


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. 1995;332:901-906; Citron ML et al. J Clin Oncol. 2003;21:1431-1439; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351:1451-1467; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;352:930-942; Henderson IC et al. J Clin Oncol. 2003;6:976-983; Nabholtz JM et al. ASCO 2002; Orlando, Fla. Presentation.


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.


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. 2004;16:37-41; Miles D et al. Oncologist. 2002;7(suppl 6):13-19.


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

0

5

10

15

20

5

10

15

20

Years After Mastectomy

Adapted from: Bonadonna G et al. N Engl J Med. 1995;332:901-906.


Reduced Dose Intensity* in Early-Stage Breast Cancer Chemotherapy

120

Reduction  15%

Delay  7 days

RDI <85%

ARDI<85%*

100

98

98

97

90

80

75

72

70

68

60

Percent (%)

65

64

58

56

40

37

34

30

30

31

31

28

29

20

27

25

15

14

0

AC21

CAF21

CAF28

CMF21

CMF28

Overall

N = 68492794 1244 5172 3839 19,898

*Relative dose intensity (RDI) adjusted to a standard doxorubicin/cyclophosphamide (AC) regimen.

Lyman GH et al. J Clin Oncol. 2003;21:4524-4531; Lyman GH et al. ASCO 2004; New Orleans, La. Abstract 776.


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. 1997;24(4 suppl 10):S10-3–S10-10.


Summary of Research on Adjuvant Chemotherapy for Early-Stage Breast Cancer

  • Adjuvant chemotherapy improves survival in ESBC

  • Improved survival outcomes demonstrated with an RDI >85% 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.


Targeted Therapy Options for Breast Cancer

*Investigational agents. HER2 = human epidermal growth factor receptor 2.

Goldman B. J Natl Cancer Inst. 2003;95:1744-1746; 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. 2003;10:1-21; US FDA. Available at: www.fda.gov/bbs/topics/NEWS/2004/NEW01027.html; Perez E. ASCO 2004; New Orleans, La. Presentation.


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


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