Breast

Managing Breast Abnormalities

BYPROF/ GOUDA ELLABBAN

Outline - 1

Clinical presentations of breast disease Nipple discharge Mastalgia Breast mass

diagnostic imaging who to biopsy how to biopsy

Outline – 2

Treatment of breast cancer Local-regional control of breast cancer

Surgery Modified Radical Mastectomy (MRM) Breast Conservation Therapy (BCT) Addressing nodal disease

Axillary Lymph Node Dissection (ALND) Sentinel Lymph Node Biopsy (SLNB)

Radiation therapy Postmastectomy Radiotherapy (PMRT) Whole breast irradiation versus Accelerated Partial Breast

Irradiation (APBI)

Outline - 3

Systemic adjuvant therapy Advances in chemotherapy

Taxanes Dose dense regimens

Evolving paradigms in hormonal manipulation Estrogen receptor inhibition Aromatase inhibitors

Outline - 4

Breast cancer screening Guidelines for screening Risk Factors for breast cancer

Family history Low relative risk High relative risk

BRCA genes Who should be tested

Breast cancer risk reduction Prophylatic surgery Chemoprevention

Clinical Presentation

3 most common breast complaints: Mastalgia NIPPLE DISCHARGE MASS

>50% of patients presenting to surgeon with a breast condition will have benign disease

Marchant, Surg Oncol Clinics of North America, 1998

Caution!

Applying the correct diagnostic and/or therapeutic algorithm is critical Treat patient thoughtfully –

Look for a mass Image area as appropriate

Ultrasound Mammogram

Balance the need for diagnostic workup and avoid unnecessary procedure(s)

Breast Pain (Mastalgia) Almost all women will have experienced varying

degree of breast pain in her lifetime ranging mild discomfort severe pain cyclical

estrogen overstimulation methylxanthines

Mastalgia

Mastalgia is a poor predictor for cancer risk <5% of breast cancer are associated with

pain >95% of patients with some breast pain Beware!

Though the association of breast pain and breast cancer is NOT strong, the fear is very REAL

Management of Mastalgia The most important questions:

Is there a dominant mass? Physical examination for dominant mass

Follow the workup of a breast mass Is there associated nipple discharge?

If there is bloody or serous discharge, follow nipple discharge workup

Does patient have recent breast imaging Mammogram Ultrasound If abnormal, follow workup of a breast mass

Management of Mastalgia If the breast examination and mammograms are

negative: Discontinue caffeinated products Discontinue nicotine use Nonsteroidal anti-inflammatory agents (NSAIDs) Hormonal manipulation

Danazol 6 month trial of 100 to 400mg daily Side effects

Tamoxifen Vitamins

A and E Repeat examination in 4 to 6 months

Nipple Discharge

Less than 5% chance of cancer

Leis, World J Surgery, 1999

Differentiate between high versus low risk by history

Higher risk Lower riskSpontaneous versus provoked

Unilateral versus bilateral

Bloody/serous versus cloudy and/or multicolored

Post- versus pre-menopasual

Nipple Discharge Physical examination

Is there a subareolar mass? Types of imaging

Mammogram Ultrasound

Duct ectasia Ductogram

Intraductal defect

Nipple Discharge

Determine the need for histologic diagnosis based on the following History Examination Imaging

Causes of nipple discharge Most common cause for spontaneous nipple discharge

is intraductal papiloma BUT intraductal (DCIS) and invasive ductal carcinoma

can cause nipple discharge (5%)

Management of a Breast Mass

Questions that need to be addressed Is it dominant? What is the age of patient? How long has it been? Has it change in size? Any associated symptoms?

discharge skin changes pain

What is the relative risk for cancer? previous biopsy family history

Management of a Breast Mass

Determine the type of imaging Diagnostic mammogram

Reserved for older than 30 years of age Pleomorphic microcalcification Architectural distortion

Ultrasound Diagnostic imaging Cystic versus solid NOT a screening test – nonspecific

MRI Dense breast tissue Post radiation therapy

PET scan In house protocol for recurrent disease

Management of a Breast Mass

Determine if histologic confirmation is necessary Cystic lesion

Simple versus complex Is there any intra-cystic defect? Does it need drainage?

Solid lesion Mammographic criteria

BiRads Suspicious ultrasound characteristics

Solid lesion with Low level internal echo Irregular margin Taller than in it is wide

Management of a Breast Mass

2 categories of biopsy Excisional

Removes the whole lesion Incisional

Removes part of the lesion

Excisional Biopsy

Often used for palpable lesion Nonpalpable, mammographically detected lesion

Needle localization Blue dye injection

Benefits Removes lesion completely Reduces risk for sampling error If tumor-free margin is achieved

Lumpectomy with curative intent

Incisional Biopsy

By definition, samples the lesion Fine needle aspiration (FNA)

Cytology Open wedge biopsy Tru-cut or core biopsy

Image guided or by palpation Mammogram

Stereotatic core biopsy (SCB) Mammotomy

Ultrasound

Treatment for Breast Cancer

Breast Cancer Outcome Incidence 211,240 Death 40,410 5 yr survival

1975 75%1986 78%2000 88%

Jemal, et al., CA Cancer J Clin 55(1);10, 2005

Improvement in breast cancer outcome Early detection Multimodal therapy

Locoregional control Systemic adjuvant therapy

Breast Cancer Therapy

Local-regional control Surgery Radiation therapy (XRT)

Systemic control Chemotherapy Hormonal manipulation

Surgical Therapy for Breast Cancer“The Gold Standard”

Modified Radical Mastectomy (MRM) Total mastectomy

Removal of all gross breast tissue including the nipple areolar complex

Level I and II axillary node dissection (ALND) Breast Conservation Therapy (BCT)

Excision of cancer with tumor-free margin lumpectomy

ALND XRT

Systemic Therapy Adjuvant therapy based weighing

Risk of recurrence Sequelae of therapy

Chemotherapy Node-positive patients Tumors >1 cm Age/Menopausal status Overall health of patient

Endocrine therapy Receptor status (ER and PR)

Anti-estrogen Aromatase inhibitors (AIs)

Modified Radical Mastectomy

Breast Conservation Therapy Removal of breast cancer

Lumpectomy Quadrantectomy Partial mastectomy Segmentectomy Must achieve tumor-free margins

Axillary node dissection Breast irradiation

4500 to 5000 cGy 5 to 6weeks Whole breast irradiation

What to do with the lymph nodes?

Management of Axillary Lymph Nodes

Infitrating ductal cell carcinoma (IDCA) Invasion of tumor cells beyond the basement

membrane Nodal basin needs evaluation

Gold Standard Complete ALND

Sentinel Node Biopsy (SLNB) Early breast cancer

Axillary Node Dissection

Staging: Single best predictor for risk of systemic

disease and cancer recurrence Therapeutic decisions

Systemic therapy Radiation therapy

May improve survival and cuure

Axilla Nodes-Level I, II and III

NSABP B-06 20 Year Update Randomized trial initiated in 1976

3 arms (all patients underwent ALND) Total mastectomy (MRM) Lumpectomy Lumpectomy and XRT (BCT)

Accrued 2,163 patients with tumors < 4 cm Included node- positive and negative patients

Establishes the efficacy and safety for BCT

Fisher, NEJM Oct., 2002

Breast Conservation Versus Mastectomy

For most women, breast conservation therapy is as good as mastectomy

Contraindications remain Multicentric disease Inability to obtain negative margins Breast lesion and breast size Contraindication to radiation therapy Patients’ preference Compliance

Evolving Treatment Paradigms:The Sentinel Node

Sentinel Lymph Node Biopsy (SLNB)

Definition “gate-keeper” or first echelon node to drain a tumor,

i.e. primary breast cancer

Focuses on Identify node-negative patients

avoid unnecessary node dissection Identify node-positive patients

Complete node dissection Systemic therapy XRT

Identifying the Sentinel Node

Injection material Technetium-99m sulfur colloid Isosulfan blue

Site of injection Intra-tumoral Intra-parenchymal Intra-dermal/peri-areolar

Embryological: axilla May miss internal mammary nodes

Blue Sentinel Node

Potential Benefits Risk reduction for lymphedema

Group 1: 117 patients SLNB and node dissection Group 2: 303 patients SLNB without node dissection Lymphedema 17.1% versus 3% (p<0.0001)

Sener, Cancer, 2001

Higher degree of scrutiny of SLN by pathologists Cursory examination of 10 to 25 nodes Extensive evaluation of a few nodes Application of molecular techniques

Potential Risks

Risk of not finding the sentinel node: 5% In clinical trials after training Higher in early part of learning curve

FALSE negative rate (FNS): 5 to 10% Technical error

Injection site Type of contrast used

Learning curve Alternate lymphatic drainage

Risks of False Negative SLN

Implications for the patients Leaving behind nodal disease

Local-regional recurrence Systemic implications

Understaging of disease will lead to under-treatment

Small tumor, node-negative disease Impacts choice of adjuvant

Chemo regimen Postoperative axillary XRT

False Negative SLN

To reduce the number of missed node-positive patients: Select patients with less likelihood of node-

positive disease Practical application based on 1,000 patients

FNR = 5% Applied to a 10% node-positive risk group

You will miss 5 node-positive patients Applied to a 40% node-positive risk group

You will miss 20 node-positive patients

Critical Issues with SLN Biopsy

Technical competence Learning curve Mapping accuracy

Blue dye plus Tc-sulfur colloid Maintain quality control

False negative rate must be 5% or less Validated by performing completion ALND in the initial

experience Surveillance of patients for cancer recurrence

Critical Issues with SLN Biopsy

NO SURVIVAL DATA NSABP trial ACOSOG Z00010 and Z00011

Await cancer cooperative groups results

Importance of Informed Consent

Is SLNB Safe?

Prospective, randomized trial in Milan Over 250 patients in each arm SLNB with completion ALND versus SLNB alone (if

SLNB is negative) In the SLNB followed by ALND

Accuracy = 96.9% False negative rate = 8.8%

SLNB alone group (median follow-up = 46 months) No overt axillary metastasis No difference in rate of cancer events

16.4 per 1,000 per year in ALND 10.1 per 1,000 per year in SLNB

Veronesi, et al., NEJM, 2003.

Take Home Message ALND remains the gold standard Quality control Careful patient selection for SLNB alone

T1 and small T2 lesion Unicentric lesion Avoid patients with excisional breast biopsy > 6 cm Avoid patients treated with neoadjuvant therapy Avoid patients with previous axilla surgery Avoid patients with gross nodal disease

Anderson, JNCCN, 2003.

Evolving Treatment Paradigms: Adjuvant Radiation Therapy

Accelerated Partial Breast Irradiation (APBI)

Postmastectomy radiotherapy (PMRT)

Postoperative XRT after BCT

External Beam Radiation Therapy (EBRT) Whole breast therapy Daily treatment for 5 to 6 weeks Total dosage: 5000 cGy

Compliance issue Non-compliance: 50% Local failure: 50%

Li, Ann Surg, 1999

Accelerated Partial Breast Irradiation (APBI)

Limit the volume of breast to be treated Within 2 cm border of lumpectomy

XRT completed in 4 to 5 days after lumpectomy

Multicatheter interstitial brachytherapy Balloon catheter brachytherapy (MammoSite) 3-D conformal external beam radiotherapy Intraoperative radiotherapy

Brachytherapy

IBRT

3D-Conformal EBRT

Summary of APBI Results

Multicatheter interstitial brachytherapy Longest follow-up (median FU 27 to 91 months) 5 yr local recurrence (LR) rate: 5% (0% to 37%)

Balloon catheter brachytherapy (MammoSite) LR rate: 0% (F/U11 to 29 months) Infection rate 16%

3-D conformal external beam radiotherapy LR rate: 0 to 25%

Arthur, et al., J Clin Oncol 23:1726, 2005.

Clinical Trial – NSABP B39

Partial breast irradiation trial Tumor size < 3 cm Unifocal tumor After lumpectomy, randomized to

External beam radiation (EBRT) Partial breast irradiation (PBI)

MammoSite Intracavitary catheters 3-D conformal EBRT

Take Home Message

The role of APBI is evolving This is NOT the standard of care Must be considered in the context of

Clinical trial Careful patient selection Informed consent

Radiotherapy After Mastectomy Pre-1997: NOT indicated except for

Positive margins High risk for local failure

Locally advance breast cancer Inflammatory breast cancer

Post-1997 Overgaard, et al., NEJM 337:949, 1997.

Danish Breast Cancer Cooperative Group Ragaz, et al., NEJM 337:956, 1997.

British Columbia Postmastectomy radiotherapy became relevant

Postmastectomy Radiotherapy (PMRT)

ASCO Expert Panel Reviewed data from 18 randomized clinical

trials (RCTs) Reduction in risk for local failure (LF)

By two thirds to three quarters, proportionally In practical terms:

Reduction of LF from 8 per 100 patients To 2-3 per 100 patients

Recht, et al., J Clin Oncol19(5):1539, 2001

Controversies with PMRT

Sparked debates regarding routine use of PMRT Complications of XRT include

Lymphedema Brachial plexopathy Radiation pneumonitis Rib fractures Cardiac toxicity Radiation-induced 2nd primaries

ASCO Expert Panel

Specific review of the British Columbia and Danish trials First to report improvement in DFS and OS

Relative reduction in risk for death Danish trial: 29%

British Columbia Trial: 26%

Controversies with PMRT

Limitations of the Danish and BC trials No other trials demonstrating similarly

significant benefits Benefits only apparent after 12 years

of follow-up Number of nodes recovered after

mastectomy were low

Take Home Message

ASCO Guidelines for PMRT Patients with 4 or more positive nodes Patients with T3 or Stage III Disease Insufficient data to PMRT:

Patients with 1 to 3 positive nodes All patients treated with neoadjuvant therapy and

mastectomy Other tumor characteristics

HER2, ER, vascular and lymphatic invasion, etc

Recht, et al., J Clin Oncol19(5):1539, 2001

Advances in Systemic Adjuvant Therapy: Chemotherapy and Endocrine Therapy

Adjuvant Chemotherapy

Treatment of patients at risk for disease dissemination prior to the diagnosis and initiation of therapy of the primary cancer

Goal: Reduce risk for recurrence and death

Only helps those who recur May harm those that do not

After 200+ RCTs - Combination therapy is superior to single

agents 4 to 6 months produced optimal results

Longer treatment with the same regimen did NOT provide incremental gains

Hormone receptor-positive patients benefit from sequential chemotherapy plus endocrine therapy Additive therapeutic effect

What have we learned?

Standard regimens are CMF and CAF Anthracycline (e.g. Adriamycin) containing

regimens are superior to those that lacks it High dose therapy did not improve overall

survival Increased morbidity and mortality

Hamilton, et al., J Clin Oncol 23:1760, 2005.

Taxanes

1st Trial CALGB 9344: AC + placlitaxel(T) 3,121 node-positive patients Median follow-up of 69 months

5 yr DFS: 70% v 65%, p=0.0023 5 yr OS: 80% v 77%, p=0.0064

Henderson, et al., J Clin Oncol 21:976, 2003

Supporting Data

NSABP B28 Trial 3,060 node-positive patients AC X4 + T X4 Relative risk for recurrence reduced by 13%

Mamounas, et al., Proc ASCO 22:4, 2003.

MDACC 94-002 524 patients T X4 + FAC X4 v FAC X8 Relative risk for recurrence reduced by 22%

Buzdar, et al., Clin Cancer Res 8:1073, 2002.

Docetaxel (Taxotere) Trial

BCIRG 001 Trial 1,491 node-positive patients TAC X6 v FAC X6 5 yr outcome

DFS: 75% v 68% OS: 87% v 81%

Increased morbidity Febrile neutropenia 10X control arm Neurotoxicity

Nabholz, et al., Proc ASCO 21:36, 2002

Dose-dense Regimen

Theoretical premise:“Full doses of drug, given at the highest possible frequency, will

produce the highest degree of cell kill”

CALGB 9741 2,005 node-positive patients 2 X 2 factorial design

A T C every 3 weeks A T C every 2 weeks + G-CSF AC T every 3 weeks AC T every 2 weeks + G-CSF

CALGB 9741

Median follow-up of 36 months Dose dense regimen

4 yr DFS: 82% v 75% Significant OS in favor of dose-dense arm Low rate of neutropenic fever and cardiac

toxicity Increased rate of anemia

Citron, et al., J Clin Oncol 21:1431,2003.

Neoadjuvant Chemotherapy

NSABP B-18 pre- versus post-operative adjuvant therapy 1,523 women

operable breast cancer AC X 4 pre v post

No survival benefit

Advantages

Higher rate of breast conservation Convert some “inoperable” breast cancer to potentially

curative surgical candidates Response in real time

Lack of response – change regimen Prognosis can be refined by degree of residual

disease Pathologic clinical response had much higher DFS and

OSWolmark, et al., JNCI 30:96, 2001.

Take Home Message Node-positive breast cancer patients with high

likelihood of a long life span should be offered taxane systemic therapy in addition to anthracycline-based chemotherapy

Dose-dense regimen may play a more significant role in chemotherapy administration in the near future

Neoadjuvant therapy should be considered for late stage disease and/or for larger lesions in women who are to be considered for BCT

Endocrine Therapy

Gold Standard: Tamoxifen (Nolvadex) Anti-estrogen receptor 5 years treatment of ER+/PR+ breast cancer Relative risk reduction of 25%

Node-positive: 10% improvement in 10-yr survival Node-negative: 5% improvement in 10-yr survival

Lower toxicity profile compared to chemotherapy

Aromatase Inhibitors (AIs) Conversion of androgenic substrates to estradiol

Enzyme complex - aromatase Highly expressed in ovarian follicles in premenopausal women

AIs blocks aromatase activity Postmenopausal women:

Residual estrogen production by peripheral conversion Subcutaneous fat, liver, muscle

AIs suppress circulating estrogen by 98+%

AIs and Breast Cancer

Estrogen and receptor positive breast carcinoma Tamoxifen binds estrogen receptors and exerts anti-estrogenic

effect AIs block peripheral estrogen conversion in postmenopausal

women Reduction in estrogen results in cancer growth inhibition

AIs have minimal effect on breast cancer in premenopausal women in clinical trials

Aromasin

Arimidex Femara

AIs in the Adjuvant Setting ATAC Trial

Arimidex, Tamoxifen, Alone or in Combination 9,366 postmenopausal patients After median follow-up of 47 months:

Risk for recurrence Hazard Ratio of patients on AI = 0.86 that of Tamoxifen (p=0.03)

Risk for 2nd primary in contralateral breast Hazard Ratio of patients on AI = 0.56 that of Tamoxifen (p=0.04)

Combination of Arimidex and Tamoxifen did not appear to be superior

No overall survival difference to date

Adverse Effects: AIs v Tamoxifen

Lower incidence Hot flashes Vaginal bleeding and discharge Venous thromboembolism Endometrial cancer

Higher risk for Musculoskeletal symptoms Fractures associated with osteoporosis

ATAC Trialists’ Group Lancet 359:2313, 2002.

Baum, et al., Cancer 98:1802, 2003.

Use of AIs Beyond Year 5

ER+ patients treated with tamoxifen fail between 5 to 15 years after surgery

Tamoxifen therapy beyond 5 yrs NOT useful

Question: Does adding AI to beast cancer patients after 5

years of Tamoxifen therapy help?

MA.17 Trial

5,187 women after 4.5 to 6 yrs of Tamoxifen Randomized to placebo v letrozole (Femera) Median follow-up of 2.4 yrs

Trial terminated DFS: 93% v 87%, p<0.001 HR for recurrence 0.57 (p=0.00008)

Extending endocrine therapy beyond 5 yrs with an AI offers significant DFS benefit

Goss, et al., NEJM 349:1793, 2003.

Clinical Trial – ACoSOG Z1031 Stage II and III breast cancer patients Neoadjuvant hormonal manipulation trial

comparing the 3 aromatase inhibitors Anastrozole Letrozole Exemestane

Estrogen receptor positive Postmenopausal women Endpoints

Response Toxicity profile

Take Home Message In postmenopausal women, AIs appears to be

superior to Tamoxifen Reducing/delaying cancer recurrence Lowering contralateral second primary cancer Slightly better adverse effects profile except for

osteoporosis Should be considered for women having

difficulties with Tamoxifen Should be considered in addition to 5 years of

Tamoxifen

Breast Cancer Screening

Breast Cancer Screening General population guideline

Age 50 and above Breast examination

Annually by healthcare professional Monthly breast self examination

Annual mammogram Age 40 to 49

Guidelines based on risk assessment More controversial

More false positives More procedures Higher risk for interval cancer

Cancer Screening in Young Women

Controversies High false positive rates

3 of 10 women will have a “positive” mammogram Unnecessary procedures and anxiety

Non-invasive cancer (DCIS) No statistically significant difference in breast

cancer mortality 0-10 lives in 10,000 screened from 40 - 49

Canadian National Breast Cancer Screening Study, Can Med Assoc J, 1992

Reserved for high risk women

NIH Consensus Panel

Risk reduction in cancer death by breast cancer screening women over 50

33% risk reduction in death in the screened populationNIH Consensus Statement, 1977

women between 40 and 49 17% risk reduction in death in the screened population

NIH Consensus Statement, 1997

Defining “High Risk” Patients What exactly is the relative risk when there is a

family history of breast cancer? One family member with postmenopausal breast

cancer 2-3 fold relative risk elevation

“high risk” family Multiple 1st degree relatives Pre-menopausal breast cancer Bilateral breast cancer Male breast cancer Ovarian cancer

The BReast CAncer (BRCA) Genes

5 to 10% of breast cancer are hereditary BRCA1 BRCA2

50% to 80% lifetime risk Tumor suppressor genes

Involved in cell cycle control In addition to breast cancer

BRCA1 mutation is associated with 50% risk for ovarian cancer BRCA2 mutation is associated with increased risk for male

breast CA

BRCA Genes

Who should be considered for BRCA testing? 2 first degree relatives One first degree relative

Premenopausal Bilateral

Ovarian cancer Multiple breast cancer, including male breast cancer

Offered with complete genetic/social counseling

Other Risk Factors Personal history of breast cancer

10 to 15% lifetime risk for contralateral breast cancer Previous biopsy with the diagnosis of in situ carcinoma

Lobular Carcinoma In Situ (LCIS) Ductal Carcinoma In Situ (DCIS)

Proliferative breast disease Without atypia With atypia

Estrogen Unopposed stimulation versus prolonged exposure Replacement therapy

Prophylatic Surgery for Breast Cancer

Bilateral mastectomies 639 patients with family history of breast cancer 90% risk reduction

Hartman, NEJM, 1999 Women with BRCA1 or BRCA2 mutations

76 underwent prophylatic mastectomies 63 surveillance only At 3 years follow-up

0 patients with breast cancer in 76 treated with prophylatic mastectomies

8 patients with breast cancer in the surveillance groupMeijers-Heiboer, NEJM, 2001

Prophylatic Surgery for Breast Cancer

Prospective trial of 131 BRCA carriers 69 underwent prophylatic bilateral

oophorectomies 3 developed breast cancer subsequently

62 patients were in the surveillance group 8 developed breast cancer

Median follow-up of 2 years

Kauff, NEJM, 2002

Chemoprevention NSABP BPCT-1

13,388 women randomized to receive tamoxifen versus placebo

At median follow-up of 54 months 49% reduction of invasive breast cancer 50% reduction of non-invasive breast cancer

Caveats No reduction in ER negative carcinomas Overall survival was not a measured outcome

We Don’t Know If The Breast Cancer Reduction Translates into Cancer Death Reduction

Increased risk for endometrial cancer (RR = 4 in age>50) DVT (RR = 1.7) PE (RR=3.0)

Fisher, JNCI, 1999

Summary - 1

Management of the 3 most common clinical presentations for breast disease Nipple discharge Mastalgia Breast mass

diagnostic imaging who to biopsy how to biopsy

Summary – 2

Treatment of breast cancer Local-regional control

Surgery Modified Radical Mastectomy (MRM) versus Breast

Conservation Therapy (BCT) Addressing nodal disease

Axillary Lymph Node Dissection (ALND) Sentinel Lymph Node Biopsy (SLNB)

Radiation therapy Whole breast irradiation versus Accelerated Partial Breast

Irradiation (APBI) Postmastectomy Radiotherapy (PMRT)

Summary - 3

Systemic adjuvant therapy Advances in chemotherapy

Anthracycline-based therapy Taxanes Dose dense regimens

Evolving paradigms in hormonal manipulation Estrogen receptor inhibition

Tamoxifen Aromatase inhibitors

Femara, Aromasin, Arimidex

Outline - 4

Breast cancer screening Guidelines for screening

NIH consensus statement: women over 40 Breast examination

Risk Factors for breast cancer Family history BRCA genes

Who should be tested Breast cancer risk reduction

Surgical prophylaxis Tamoxifen

Questions ????