breast cancer kristi mcintyre m.d. resident’s lecture

Breast CancerBreast Cancer

Kristi McIntyre M.D.Kristi McIntyre M.D.

Resident’s lectureResident’s lecture

Breast cancerBreast cancer

Risk factorsHereditary breast cancerDetectionStagingSurgical interventionPrognostic factorsManagement of early stage breast cancer

Risk factorsHereditary breast cancerDetectionStagingSurgical interventionPrognostic factorsManagement of early stage breast cancer

Breast cancer risk Breast cancer risk factorsfactors

Age/raceAge/race Reproductive issues/Estrogen-Reproductive issues/Estrogen-

related factorsrelated factors Breast histologyBreast histology Life style factorsLife style factors Family history/Genetic factorsFamily history/Genetic factors

Breast Cancer Risk Breast Cancer Risk FactorsFactors

Breast Cancer Risk Breast Cancer Risk FactorsFactors

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Breast Cancer IncidenceBreast Cancer Incidence

image library - f094-01.jpg.url

Race/Ethnicity and Breast Race/Ethnicity and Breast Cancer RiskCancer Risk

Annual incidenceAnnual incidence

Caucasian 137

African Americans 120

Hispanic 82

Asian 93

American Indian 59

Caucasian 137

African Americans 120

Hispanic 82

Asian 93

American Indian 59

SEER results: age adjusted only

Jemal CA:Cancer J.Clin ;2003,53:5


““Adjusted Hazard Ratios”Adjusted Hazard Ratios”

1.00.80.6

0.4 1.2

Only African Americans had lower breast cancer risk (p=o.oo6) than Caucasians

Only African Americans had lower breast cancer risk (p=o.oo6) than Caucasians

African American

Hispanics

American Indian

Asian

.72

Cheblowski JNCI ;March 2005


Combined Grade III and ER negative by raceCombined Grade III and ER negative by race

0102030405060708090100

white AA Hispanic Asian

%



o Differences in breast cancer incidence Differences in breast cancer incidence rates between most ethnic groups can rates between most ethnic groups can largely be explained by control of risk largely be explained by control of risk factorsfactors

o African American women are at African American women are at significantly reduced risksignificantly reduced risk

o African American women have a African American women have a higher proportion of unfavorable higher proportion of unfavorable features suggesting cause for higher features suggesting cause for higher mortality ratesmortality rates


Reproductive Factors and Reproductive Factors and Breast CancerBreast Cancer

Reproductive Factors and Reproductive Factors and Breast CancerBreast Cancer

Menarche < 16Menarche < 16 Menopause >50Menopause >50

Menarche <16 OR 1.2Menopause >50 OR 1.5Null parity OR 2.0Breastfeeding 4.3% decrease risk/yrFirst live birth<20 OR 0.5First live birth >35 OR 1.5

WHI Trial of Estrogen plus WHI Trial of Estrogen plus ProgestinProgestin

E+P placebo E+P placebo p-value p-value Invasive Breast cancers 199 150

0.003

Abnormal Mammograms 716 395 0.0001

SEER high stage 25% 16% 0.041

More breast cancers diagnosed at more advanced stage and increased abnormal mammograms

More breast cancers diagnosed at more advanced stage and increased abnormal mammograms

Chlebowski JAMA 2003;289. 3243

Breast histology and breast Breast histology and breast cancer riskcancer risk

Benign breast disease RRBenign breast disease RR

Fibrocystic disease 0Atypical ductal hyperplasia 4.3Atypical ductal hyperplasia and 11.0 family history

Risk Factors for Breast Risk Factors for Breast CancerCancer

Family History RiskFamily History Risk

First Degree relative•Premenopausal diagnosis

3.0•Bilateral disease

5.0•Premenopausal diagnosis and bilateral disease 9.0•Postmenopausal diagnosis

1.5Second Degree relative•Premenopausal diagnosis

1.2•Postmenopausal diagnosis

0

Hereditary

Family history and breast Family history and breast cancer riskcancer risk

Most hereditary breast cancers arise Most hereditary breast cancers arise from mutations in BRCA1 and BRCA2from mutations in BRCA1 and BRCA2

Autosomal dominant , tumor suppressor gene

BRCA mutations and lifetime BRCA mutations and lifetime cancer riskcancer risk

50-85% breast cancer50-85% breast cancer

15-45% ovarian cancer risk

50% Second breast cancers

Other malignancies:prostratepancreaticmale breast cancer

Founder mutations and Founder mutations and Breast cancerBreast cancer

• Ethnic background should be considered in risk assessment for breast cancerEthnic background should be considered in risk assessment for breast cancer• “ “ Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent • 50-90 % have gene susceptibility with positive family history50-90 % have gene susceptibility with positive family history• Founder mutations have been found in populations of Iceland,Finland, France, Founder mutations have been found in populations of Iceland,Finland, France,

Holland , Russia,and SwedenHolland , Russia,and Sweden

• Ethnic background should be considered in risk assessment for breast cancerEthnic background should be considered in risk assessment for breast cancer• “ “ Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent Founder” gene mutations discovered in individuals of Ashkenazi Jewish descent • 50-90 % have gene susceptibility with positive family history50-90 % have gene susceptibility with positive family history• Founder mutations have been found in populations of Iceland,Finland, France, Founder mutations have been found in populations of Iceland,Finland, France,

Holland , Russia,and SwedenHolland , Russia,and Sweden

Models for risk Models for risk assessmentassessmentGail modelGail model

AgeAge first live birthAge first mensesFH-maternal only; no age# prior breast biopsies/ADHrace

Claus model

Family historyAge at diagnosis

Both models inadequate : not useful for mutation carriers or individual risk Both models inadequate : not useful for mutation carriers or individual risk

www3.utsouthwestern.edu/cancergene/

http://bcra.nci.nih.gov/brc

Lifestyle factors and breast Lifestyle factors and breast cancer riskcancer risk

• Body mass index: postmenopausal women >30% excess BMI increased riskBody mass index: postmenopausal women >30% excess BMI increased risk• Dietary fat intake: increased riskDietary fat intake: increased risk• NSAID use: decreases risk NSAID use: decreases risk • Physical activity: 1.25 to 2.5/hrs week brisk walking had 18 % decrease riskPhysical activity: 1.25 to 2.5/hrs week brisk walking had 18 % decrease risk• Smoking : increased riskSmoking : increased risk• Alcohol use: increased (dose dependent)Alcohol use: increased (dose dependent)

Risk Reduction StrategiesRisk Reduction Strategies

Early childbirthEarly childbirth ExerciseExercise Maintain normal Maintain normal

weightweight Avoid smoking/alcoholAvoid smoking/alcohol Avoid prolonged HRTAvoid prolonged HRT

Average RiskAverage Risk

Moderate Risk

•Chemoprevention

Most breast Most breast cancers are non cancers are non palpable masses palpable masses

discovered only on discovered only on screening screening

mammogramsmammogramsMalignant breast densitieshave irregular borders, are stellate anddistort surrounding architecture

Breast Cancer DetectionBreast Cancer Detection

United States Preventive Services Task ForceUnited States Preventive Services Task Force

•Mammogram every 1-2 years for female age 40-49(average risk)•Age > 50 annual mammography and clinical exam•Age > 70 debatable

Mammography detects only 85% of biopsy Mammography detects only 85% of biopsy proven breast cancer hence not a proven breast cancer hence not a substitute for tissue sampling of palpable substitute for tissue sampling of palpable massmass

Mammography detects only 85% of biopsy Mammography detects only 85% of biopsy proven breast cancer hence not a proven breast cancer hence not a substitute for tissue sampling of palpable substitute for tissue sampling of palpable massmass

Breast Cancer ScreeningBreast Cancer Screening

There is almost universal There is almost universal agreement that randomized agreement that randomized controlled trials of screening controlled trials of screening have demonstrated death have demonstrated death rate from breast cancer can rate from breast cancer can be reduced by periodic be reduced by periodic screening with screening with mammographymammography

There is almost universal There is almost universal agreement that randomized agreement that randomized controlled trials of screening controlled trials of screening have demonstrated death have demonstrated death rate from breast cancer can rate from breast cancer can be reduced by periodic be reduced by periodic screening with screening with mammographymammography

MRI BreastMRI Breast

Implant evaluationImplant evaluation Axillary adenopathy ?occult primaryAxillary adenopathy ?occult primary Breast cancer patients (extent of Breast cancer patients (extent of

disease, response to neoadjuvant disease, response to neoadjuvant therapy)therapy)

Screening evaluation for high risk Screening evaluation for high risk patientpatient

Further evaluation of Further evaluation of mammographic abnormalitymammographic abnormality

Implant evaluationImplant evaluation Axillary adenopathy ?occult primaryAxillary adenopathy ?occult primary Breast cancer patients (extent of Breast cancer patients (extent of

disease, response to neoadjuvant disease, response to neoadjuvant therapy)therapy)

Screening evaluation for high risk Screening evaluation for high risk patientpatient

Further evaluation of Further evaluation of mammographic abnormalitymammographic abnormality

Staging of breast cancerStaging of breast cancer

Estimate extent Estimate extent of diseaseof disease

Guide Guide theratherapypy

Determine Determine prognosisprognosis

Staging of breast cancerStaging of breast cancer

Stage 0 (DCIS)Stage 0 (DCIS) Stage I Stage I node negativenode negative

Stage II Stage II node positivenode positive

Stage III Stage III advanced nodeadvanced node

Stage IV Stage IV distant distant metastasismetastasis

Stage 0 (DCIS)Stage 0 (DCIS) Stage I Stage I node negativenode negative

Stage II Stage II node positivenode positive

Stage III Stage III advanced nodeadvanced node

Stage IV Stage IV distant distant metastasismetastasis

2003 AJCC staging change

•Distinction between micrometastasis and isolated tumor cells•Identifiers for sentinel nodes•#number of positive LN

Burstein, H. J. et al. N Engl J Med 2004;350:1430-1441

Pathobiologic Events Associated with Ductal Carcinoma in Situ

Management of Early stage breast Management of Early stage breast cancercancer

1950 Halsted 1950 Halsted “radical mastectomy”“radical mastectomy”

“breast cancer spreads in an orderly fashion”

12%12%10 year 10 year survivalsurvival

20-30% node negative breast cancer 20-30% node negative breast cancer patients will develop metastatic patients will develop metastatic diseasedisease

Micrometastatic disease paradigmMicrometastatic disease paradigm

Management of Early stage breast Management of Early stage breast cancercancer

MORE LESSMORE LESS

Radical Mastectomy

Whole breast radiation

Axillary dissection

Lumpectomy

Partial breast radiation

Sentinel node biopsy

Surgical intervention for Surgical intervention for Breast CancerBreast Cancer

NSABP B-04NSABP B-04

Total Mastectomy+

Axillary dissection

Lumpectomy +Breast radiation

Lumpectomy alone

No difference in Overall Survival or Disease Free Survival

No difference in Overall Survival or Disease Free Survival

Fisher et al.NEJM2002;347:1456-61(20 year follow-up)

Surgical Intervention of Breast Surgical Intervention of Breast CancerCancer

NSABP B-04NSABP B-04 Cumulative Cumulative

incidence of incidence of ipsilateral breast ipsilateral breast cancercancer

Standard of care: Standard of care: lumpectomy+ Xrtlumpectomy+ Xrt

39%

14%

Surgical intervention for Surgical intervention for Breast CancerBreast CancerNSABP B-04NSABP B-04

Fisher,et al.NEJM(2002):347;1454-61

Surgical Staging of AxillaSurgical Staging of Axilla

Axillary dissection= removal of Axillary dissection= removal of level I and Level II lymph nodeslevel I and Level II lymph nodes

Morbidity : wound infection motion restriction arm stiffness pain lymphedema

Sentinel node mappingSentinel node mapping

Chemotherapy for early stage Chemotherapy for early stage breast cancerbreast cancer

Prognostic factors in Breast Prognostic factors in Breast cancercancer

Recognized Factors Potential factorsRecognized Factors Potential factors

Nodal statusNodal statusTumor sizeTumor sizeHistologic typeHistologic typeER/PRER/PR

Proliferative Proliferative indexindexTumor gradeTumor gradeVascular Vascular invasioninvasionHer- 2Her- 2Gene Gene microarraymicroarray


The most significant prognostic The most significant prognostic indicator for patients with early indicator for patients with early stage breast cancer is the stage breast cancer is the presence or absence of axillary presence or absence of axillary lymph node involvement. lymph node involvement.

The most significant prognostic The most significant prognostic indicator for patients with early indicator for patients with early stage breast cancer is the stage breast cancer is the presence or absence of axillary presence or absence of axillary lymph node involvement. lymph node involvement.


Recognized Factors Potential factorsRecognized Factors Potential factors

Nodal statusNodal statusTumor sizeTumor sizeHistologic typeHistologic typeER/PRER/PR

Proliferative Proliferative indexindexTumor gradeTumor gradeVascular Vascular invasioninvasionHer- 2Her- 2Gene Gene microarraymicroarray

Prognostic factors in breast cancerPrognostic factors in breast cancerMultigene assay:Multigene assay:

Paik et al.NEJM 2004;351:2817-26

Gene MicroarrayGene Microarray

Multigene assay to predict Multigene assay to predict recurrence in node negative breast recurrence in node negative breast

cancercancer

HER- 2/neuHER- 2/neu

Her-2/neu oncogene encodes for Her-2/neu oncogene encodes for transmembrane receptor transmembrane receptor belonging to EGFR familybelonging to EGFR family

Amplified in 25-30% breast Amplified in 25-30% breast cancercancer

Overexpression associated with Overexpression associated with tumor aggressiveness and tumor aggressiveness and increased rates of recurrenceincreased rates of recurrence

Her-2/neu oncogene encodes for Her-2/neu oncogene encodes for transmembrane receptor transmembrane receptor belonging to EGFR familybelonging to EGFR family

Amplified in 25-30% breast Amplified in 25-30% breast cancercancer

Overexpression associated with Overexpression associated with tumor aggressiveness and tumor aggressiveness and increased rates of recurrenceincreased rates of recurrence

Her-2/neuHer-2/neu

Basis for molecular targeted therapy with Herceptin

NCI clinical alert –April NCI clinical alert –April 25,200525,2005

NSABP B-31NSABP B-31

Operable breast cancerHer 2 +, node +

Randomization

AC x4cyclesTaxol x4 cycles

AC x4cyclesTaxol x4 cycles +Herceptin

52% decrease in disease recurrence

52% decrease in disease recurrence

Thank you !Thank you !

breast cancer kristi mcintyre m.d. resident’s lecture

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