1

Diagnosis and Management of Breast

Cancer

Harry D. Bear, MD, PhDDivision of Surgical Oncology

VCU School of Medicine

1

Signs and Symptoms of Breast Cancer

• Mass or “Thickening”• Skin dimpling• Nipple retraction or scaling• Skin erythema or peau d’orange• Focal breast pain – 10%• Spontaneous nipple discharge• Occult mass or calcifications

2

Diagnosis of Breast DiseasesPhysical Examination

• Start with palpation of supraclavicular fossa and then axillary nodes– Initial patient “contact”– Hold arm and elbow while rolling axillary

contents against chest wall• Inspection

– Skin discoloration or edema– Skin dimpling– Nipple retraction

3

Palpation of Axillary Nodes

4

Examination of Axillary Nodes

5

Inspection for Skin Changes and Nipple Retraction

6

2

Skin Dimpling

7

Nipple Retraction

8

Peau D’Orange

9

Palpation of the Breast

• Patient supine with ipsilateral hand behind head

• Use 2 hands• Use “pads” of fingers, not fingertips• Systematically examine all breast

tissue

10

11 12

3

Breast Palpation

13

Breast Palpation

14

Diagnosis of Breast Complaints

• Physical Examination• Mammography

– Characteristics of the mass– Other masses– CANNOT RULE OUT CANCER –

• 10% false negative rate

15

Mammograms of a Woman with a Palpable Right Breast Mass

16

Mammography - Multiple Cancers

17

Diagnosis of Breast Complaints

• Physical Examination• Mammography

– Characteristics of the mass– Other masses– CANNOT RULE OUT CANCER –

• 10% false negative rate

• Ultrasound - Selectively

18

4

Role of Breast Ultrasound

• Can determine whether a mass (occult or palpable) is solid or cystic

• To clarify indeterminate exam or mammogram findings

• Image-guided biopsy/aspiration• NOT as a screening test

19

Occult Mass on Mammogram

20

Breast Ultrasound – Simple Cyst

21

Sonogram of Mass - Complex Cyst

22

Ultrasound Guided Aspiration of Breast Cyst

23

Ultrasound - Breast Cancer

24

5

Breast Ultrasound - Small Cancer

25

Sestamibi Breast Scan

26

MRI Detection of Breast Cancer

27

Breast Biopsy Choices

28

Fine Needle Aspiration Biopsy

29

Fine Needle Aspiration Biopsy Smear

30

6

Triple Negative Test

• Non-suspicious physical exam (weak link; cannot be a definite mass)

• Negative imaging (mammogram +/- US)• Benign FNA cytology• Nearly 100% accurate – must follow-up

31

Missed Breast CancersTriad of Error

• Young age• Self-discovered mass• Negative mammogram

32

Screening Mammography

• Annually after Age 40• Earlier for strong family history at

young ages– Start 5 years earlier than youngest prior cancer

• NOT just for high risk patients• Emerging role for selective use of

MR Mammography

33

Mammographic Signs of Cancer

• Mass• Calcifications• Dilated duct• Skin changes• Architectural distortion• Asymmetry• Enlarged axillary nodes

34

Mammograms - SpiculatedDensity

35

Mammography - PleomorphicCalcifications

36

7

Mammography - Calcifications

37

Stereotactic Breast Biopsy

38

Stereotactic Breast Biopsy

39

Breast Diagnosis -Mammographic Localization

40

Breast Diagnosis -Mammographic Localization

41

Breast Diagnosis -Mammographic Localization

42

8

Carcinomas in SituDuctal and Lobular

43

Duct Carcinoma In Situ

44

Breast Pathology is Treacherous

Atypical Ductal Hyperplasia

45

Defining Risk for Breast Cancer

Gail Model• Age• Age at menses• Age at first live birth• Number of first degree relatives with BC• Number of prior breast biopsies• Biopsies with ADH

46

Breast Cancer Risk Assessment

47

Breast Cancer Risk Assessment

48

9

Options for Mutation-Positive or Other High Risk Women

• Intensive screening • Chemoprevention• Prophylactic mastectomies +/-

oophorectomies

49

Clues to Effective Chemoprevention

• Estrogen has a role in breast cancer etiology

• Anti-estrogen therapy can cause regression of breast cancers that express hormone receptors

• Tamoxifen, used to decrease recurrence of ER+ breast cancer also decreased incidence of contralateralbreast cancers by almost half

50

Tamoxifen for Chemoprevention - P1

Women at High Riskfor Breast Cancer

Tamoxifen for 5 Years Placebo for 5 Years

Randomize

or

51

Average Annual Rates of Invasive Breast Cancers in P-1

Trial

0

2

4

6

8

10

12

14

All Women LCIS Atypical Hyperplasia

PlaceboTamoxifen

Rat

e pe

r 10

00

Fisher, et al. JNCI, 1998 52

Tamoxifen for Chemoprevention - STAR

Post-Menopausal Women at High Risk

for Breast Cancer

Tamoxifen for 5 Years Raloxifene for 5 Years

Randomize

or

53 54

10

William Steward Halsted

55

Halsted’s Radical Mastectomy

56

57

Mastectomy to Breast Conservation

• 1891-1970’s: Halsted radical mastectomy

• 1970’s-1980’s: “Modified” radical mastectomy

• 1980’s-Present: Breast conserving therapy

58

NSABP Protocol B-06

Breast Cancers < 4 cm

Segmental Mastx+ ALND

Segmental Mastx+ ALND

+ Breast Radiation

Total Mastx+ ALND

Randomized

59

NSABP B-06 - 20 Year Results

NEJM, 200260

11

Breast Conservation is Under-Utilized

61

Changes in Breast Cancer Surgery Over Time

62

Possible Advantages of BCT• Psychological• Cosmetic• Reduced fear of “mutilation” may

encourage earlier diagnosis

63

True Contraindications to BCT

• Multicentric disease– Diffuse calcifications– Two or more foci in separate quadrants

• Prior breast irradiation• Inability to achieve negative margins• Radiation therapy inaccessible• Patient choice

64

Non-Contraindications to Breast Conserving Therapy

• Extensive intraductal component• High grade histology• Positive nodes• Breast size (too large or too small)• Patient age (too young or too old)• Multi-focal disease• Central location/nipple involved

65

Contraindications to BCT?

• First or second trimester of pregnancy– Can be overcome by delaying RT

• Tumor too large – Can be overcome with primary chemotherapy

66

12

Clinical Response to Primary Chemotherapy, Protocol B-18

After AC X 4No palpable tumor

Before Treatment

Primary tumor

67

NSABP B-18: Overall SurvivalNine Year Update

405060708090

100

0 1 2 3 4 5 6 7 8 9

Years from study entry

% S

urvi

val

Postop Preop68

NSABP B-18: Surgery Performed

60

40

68

32

020406080

100

Postop Preop

MastectomyLumpectomy

%

p < .01

69

NSABP B-18: Overall Survival According to Primary Tumor

Response

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9Years from study entry

% S

urvi

ving

pCR pINV cPR cNR

p = 0.000870

Cosmetic Results After BCS and Radiation

71

Cosmetic Results After BCS, Radiation and Contralateral

Ptosis Correction

72

13

BCT - Long-Term Results

73

Breast Conservation SurgeryCentral Location is NOT a

Contraindication

74

Brachytherapy Delivery of Radiation

75

Spherical 4 to 5 cm (35 - 70 cc)

• Simplified, reproducible approach

• Placement by– Surgeon – Radiation Oncologist

• Timing– At time of lumpectomy– Post-lumpectomy

• ultrasound guidance• CT guidance

• Treatment distance - 1cm• FDA approval in May 2002

MammoSiteRadiation Therapy System

Proxima Therapeutics

Balloon IntracavitaryBrachytherapy

76

Mammosite Balloon Catheter

77 78

14

Approaches to Reconstruction After Mastectomy

• Immediate versus delayed• Prosthetic implant versus autologous

tissue transfer• “Skin-sparing” approach• Possibility of contralateral prophylactic

mastectomy

79

Prosthetic Breast Implants for Reconstruction

80

Reconstruction with Implant and Contralateral Reduction

Mammoplasty

81

Transverse Rectus AbdominisMyocutaneous (TRAM) Flap

82

Bilateral Mastectomies and TRAM Reconstruction: Late

Results

83 84

15

Axillary Lymph Node DissectionPurposes• Regional control• Staging:

– Prognosis– Need for systemic therapy

85

Purposes of Axillary Node Dissection

Staging• Most important predictor of

prognosis and need for chemotherapy & regional RT (??)

• Not indicated for DCIS• May not be needed for DCIS with

microinvasion• May not be needed for elderly

86

Axillary Lymph Node Dissection

Who benefits from ALND?• Only patients with positive nodes!• The 60 - 70% of patients with clinically

negative nodes who also have histologically negative nodes derive NO benefit and all the morbidity

87

Axillary Node Dissection for Breast Cancer - Disadvantages

• General anesthesia• Costs; medical and time lost from work• Complications

– Seromas– Drains– Dysesthesias, pain & numbness– Shoulder dysfunction– LYMPHEDEMA (10-20%)

88

89

Sentinel Lymph Node Mappingfor Breast Cancer

• With radionuclide + visible dye:– 90 - 95% success rate– 10% found by isotope OR dye only

• SLN biopsy is >95% accurate• False negative rates are 0 - 11%• If SLN is negative by H&E and IHC,

<3% of patients will have other positive nodes

90

16

Sentinel Node Mapping for Breast Cancer

91

Lymphoscintigraphy of SLN for Breast Cancer

Primary site

2 AxillarySLN

92

Sentinel Node Mapping for Breast Cancer

93

NAVIGATOR*

94

Sentinel Node Mapping for Breast Cancer

95

Blue Stained Sentinel Lymph Nodes

96

17

IHC Staining for Cytokeratin-Positive Cells in SLN

Clusters of CK+ cells

97

Staging Work-Up for Breast Cancer

“Routine”• Mammograms• CXR (?)• Metabolic panel (?)• CBC (?)

98

Staging Work-Up for Breast Cancer

• For Stage III– Bone scans

• NOT normally indicated:– Bone scans– CT scans– Liver scans– Liver US

99

Adjuvant Systemic Therapy

• Cause of deaths from breast cancer is distant metastases, not local tumor

• To impact metastatic disease, systemic adjuvant treatment is needed– Hormonal therapy– Chemotherapy

100

Adjuvant Therapy & Risk Reduction

Secondary treatment added to primary treatment to reduce the risk of recurrence and death

101

Adjuvant Systemic Therapy -Hormonal

• Not useful for ER-/PR- tumors• Should be offered to most HR+

patients, regardless of age• Ovarian ablation/suppression is an

alternative in pre-menopausal women; adding anti-estrogen may still be beneficial

102

18

Benefit of Adjuvant Tamoxifen

103

Androstenedione

Testosterone Estradiol Estrogenreceptor

(ER)

ER-mediated

effects

SteroidalAromatase

Inhibitor

SelectiveEstrogenReceptorModulator

Aromatase 17b-HSD

r

DNACell

proliferation

exemestanetamoxifen

Estrone

r

Mechanisms of Anti-EstrogenDrugs for Breast Cancer

104

Anti-Estrogen TherapyAromatase Inhibitors

105

Switching from Adjuvant Tamoxifen to Exemestane

Diagnosis of breast cancer & treatment for primary disease

RANDOMIZEN=4742

2-3 yearstamoxifen

N=2362

2-3 yearsexemestane

N=2380

years from startof tamoxifen

0

2

3

5

years fromrandomization

0

2-3

2 to 3 years tamoxifen

Patients followed up

106

IES Disease-Free Survival graph

Women surviving event-free (%)

Years from randomization0 1 2 3 4

0

25

50

75

100

No. events/at risk

Hazard ratio=0.68 (95% CI: 0.56-0.82)Log-rank test: p=0.00005

Exemestane

Tamoxifen

0 / 2362 52 / 2168 60 / 1696 44 / 757 20+6† / 2010 / 2380 78 / 2173 90 / 1682 76 / 730 18+4† / 185Tamoxifen

Exemestane

† events occurring more than 4 years after randomization

Coombes et al, N Engl J Med. 2004;350:1081-1092 107

Adjuvant Systemic Therapy -Chemotherapy

• Chemotherapy is indicated for most women with tumors > 1 cm or with positive nodes• Less benefit for older patients, esp. HR+

108

19

Benefit of Adjuvant Combination Chemotherapy for Breast

Cancer

Women < 50 years old Women 50-69 years old

109

Adjuvant Therapy & Risk Reduction

• Secondary treatment added to primary treatment to reduce the risk of recurrence and death

• Absolute risk reduction:– 40% vs. 30% dead = 10% ARR

• Relative risk reduction– 40% vs. 30% dead = 25% RRR

110

111

Breast Cancer TherapyNew Directions

• Increased dose intensity and density• Altered sequencing (e.g., neoadjuvant)• “Targeted” therapies (e.g., Herceptin)• New prognostic/predictive factors

112

Immunohistochemical Staining for HER-2/neu

113

HER-2 Amplification by FISH

114

20

115

Spotted Microarray Process

CTRL

TEST

116

Prognostic Value of Molecular Signatures

NEJM, 2003 117

Gene Expression MicroarrayPrediction of Response to

Docetaxel

Chang et al, Lancet 2003

118