What Every General Surgeon Should Know About Breast Cancer
Christina A. Finlayson, MDAssociate Professor, Surgery
Director, University of Colorado Hospital Breast Center
Outline
How are we doing in the war against cancer? How do you order a mammogram? How do you stage breast cancer? What does medical oncology have to offer?
Change in the US Death Rates by Cause, 1950 & 2003
21.9
180.7
48.1
586.8
193.9
53.3
190.1231.6
0
100
200
300
400
500
600
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
19502003
Rate Per 100,000
Five-year Relative Survival (%) during Three Time Periods By Cancer Site
Site 1974-1976 1983-1985 1995-2001
All sites 50 53 65 Breast (female) 75 78 88 Colon 50 58 64 Lung and bronchus 12 14 15 Melanoma 80 85 92 Pancreas 3 3 5 Prostate 67 75 100
Cancer Survival UCCC vs. Colorado2006
Breast Cancer - 2008
212,920 women diagnosed with invasive breast cancer
40,970 women will die from breast cancer 2 million women living who have been treated
for breast cancer Risk of developing invasive breast cancer is 1
in 8 Risk of dying from breast cancer is 1 in 33
American Cancer Society, 2006
What Every Surgeon Should Know About Breast Cancer
Radiology
Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society 2003
Patient is asymptomaticInsurance doesn’t require a referralDoesn’t require a physician orderMammographer is not on site
Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society 2003
Yearly screening mammograms are recommended starting at age 40 for women of average risk and continuing for as long as a woman is in good health
Mammogram Prevalence 1991-2002, USA
0
10
20
30
40
50
60
7019
91
1992
1993
1994
1995
1996
1997
1998
1999
2000
2002
Year
Prev
alen
ce (%
)
Women with less than a high school education
Women with no health insurance
All women 40 and older
How Good is Mammography?
8 Randomized Controlled Trials 1960s - 1980 8-30% reduction in breast cancer mortality
Sensitivity Mammography: 85% Physical Exam: 50% But, with the advances in equipment, film, and
training, the sensitivity of mammography has…
… gone down.
The actual sensitivity of screening mammography in clinical practice today is about 70%
False negative mammogram: biopsy proven cancer within a year of a negative screening mammogram
Why is mammography doing worse?
Prevalence cancers – slow growing, large cancers in the population waiting to be foundIncidence cancers – develop more than
one year after initial screenInterval cancers – become clinically
evident less than one year from last screen
Why is mammography doing worse?
The sensitivity of mammography is determined by competing methods of diagnosisWomen are more sensitive to
detecting lumps and much more likely to bring them to medical attention Providers are also more aware
If mammography misses so much, is it worth screening?
About 10 years after mammographic screening became widespread in the U.S., mortality from breast cancer started to drop.
USA - Age-adjusted Breast Cancer Mortality
USA mortality: 1950-1998
If mammography misses so much, is it worth screening?
We cannot be sure that the change is due to screening, but there is a good correlation:
Sweden has a tremendous yearly screening program: 1951-1996
Sweden - Age-adjusted Breast Cancer Mortality
Great Britain also screens, but only every 3 years: 1950-1999
U.K. - Age-adjusted Breast Cancer Mortality
while Denmark has no screening program: 1952-1996
Denmark - Age-adjusted Breast Cancer Mortality
Is there a better screening test? No!
Mammography is the best single screening test for women of average risk.Mammo + Physical Examination is a
potent combination for screening
Screening Guidelines for the Early Detection of Breast Cancer, ACS 2003
Women at increased risk should talk with their doctors about the benefits and limitations of starting mammography screening earlier, having additional tests (i.e., breast ultrasound and MRI), or having more frequent exams.
Who are women at increased risk?
Family history – first degree relativeExtended family history
Previous biopsyAtypical hyperplasiaLCIS
BRCA1/BRCA2 (Radiation to chest wall)
Imaging options
MammographyUltrasoundMRI, contrast enhanced
Mammography
Gold-standardMultiple studies with mortality as end-pointDecreases mortality from breast cancer by at
least 25-50% Detection rate: 5-7/1000 for first mammogram 2-3/1000 for subsequent mammograms
Screening Ultrasound
Ultrasound plus mammography finds more cancers than mammography aloneCancers seen by ultrasound are
usually invasiveMany false positives -- many extra
biopsiesU/S adds 1-2 cancer / 1000 screens
Not covered by insurance for screening
Screening MRI
Warner, E. JAMA, 2004
Screening BRCA1/2:22 Cancers Detected
99%96%97%NPV
42%23%83%PPV
93%95%99.6%Specificity
85%25%38%Sensitivity
236229236Screened
MRIUltrasoundMammogram
Warner, E. JAMA, 2004
ACS Guidelines for Breast Screening with MRI
Recommend Annual MRI Screening (Based on Evidence) BRCA mutation First-degree relative of BRCA carrier, but
untested Lifetime risk ~20–25% or greater, as defined
by BRCAPRO or other models that are largely dependent on family history
CA Cancer J Clin 2007
ACS Guidelines for Breast Screening with MRI
Recommend Annual MRI Screening (Based on Expert Consensus Opinion) Radiation to chest between age 10 and 30
years Li-Fraumeni syndrome and first-degree
relatives Cowden and Bannayan-Riley-Ruvalcaba
syndromes and first-degree relatives
CA Cancer J Clin 2007
ACS Guidelines for Breast Screening with MRI
Insufficient Evidence to Recommend for or against MRI Screening
Lifetime risk 15–20%, as defined by BRCAPRO or other models that are largely dependent on family history
Lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH)
Atypical ductal hyperplasia (ADH) Heterogeneously or extremely dense breast on
mammography Women with a personal history of breast cancer,
including ductal carcinoma in situ (DCIS)CA Cancer J Clin 2007
ACS Guidelines for Breast Screening with MRI
Recommend Against MRI Screening (Based on Expert Consensus Opinion )
Women at <15% lifetime risk
CA Cancer J Clin 2007
High Risk Screening: Cost
Clinical Breast Exam $ 150.00Mammogram 170.00Bilateral MRI 1000.00
Diagnostic Imaging
Diagnostic Imaging
• Workup of an abnormal screening mammogram
• Evaluation of a palpable abnormality or other breast complaint• Evaluates characteristics of palpable mass• Screens remainder of breast
• Imaging of breast cancer after diagnosis• No emergency mammograms
• Radiologist available to interpret at time of imaging
Diagnostic Imaging
• Workup of an abnormal screening mammogram
BIRADS® Assessments
0 – Additional imaging evaluation needed 1 - Negative (routine screening) 2 - Benign (routine screening) 3 - Probably (6m f/u) 4- Suspicious (biopsy) 5 - Highly suspicious (biopsy) 6 – Known, biopsy proven cancer (**New!!**)
CC MLO
Spot compressionMagnification
Spot compressionMagnification
Ultrasound evaluates a mammographic mass
Diagnostic Imaging
• Evaluation of a palpable abnormality or other breast complaint• Evaluates characteristics of palpable
mass• Screens remainder of breast
Evaluation of a Palpable Abnormality
• Ultrasound is the mainstay • Identifies over 99% of palpable cancers• 99+% negative predictive value• Not perfect (but close)
• Mammography• Mainly useful for screening the remainder of
the breast• Required by COPIC• A negative mammogram does not exclude
cancer
Ultrasound of palpable mass
Diagnostic Imaging
• Imaging of breast cancer after diagnosis• No emergency mammograms
Imaging after diagnosis
MRI Ipsilateral Breast
Multifocal/Multicentric
Pre-Contrast Post-Contrast
MRI Contralateral Breast
“MRI Evaluation of the ContralateralBreast in Womenwith Recently Diagnosed Breast Cancer”Lehman CD, et al
NEJM Mar 29, 2007
MRI Contralateral Breast
25 institutions Minimum 50 MRIsMinimum 5 MRI biopsies
969 participants30 cancers detected (3.1%)10% false positive biopsiesNPV 99%
MRI Contralateral Breast
“The current cost of MRI precludes its widespread use in general populations, but this imaging tool appears to improve the detection of cancer in women at increased risk, such as women with a recent diagnosis of breast cancer.”
Lehman et al, 2007
What Every Surgeon Should Know About Breast Cancer
Lymph Node Staging
Predictors of Breast Cancer Survival
Tumor size Lymph node metastasis
Predictors of Breast Cancer Survival - Tumor size
Tis noninvasive T1 < 2 cm T2 greater than 2 cm but not greater than 5
cm T3 greater than 5 cm T4 chest wall, skin or inflammatory
involvement
Predictors of Breast Cancer Survival Lymph node metastases
Clinical staging cN0 no regional lymph node metastases cN1 positive lymph nodes, movable cN2 matted lymph nodes or positive internal
mammary nodes cN3 positive infraclavicular nodes or
internal mammary + axillary nodes orsupraclavicular nodes
Predictors of Breast Cancer Survival Lymph node metastases
Pathologic staging– pN0 no regional lymph node metastases
Single tumor cells or clusters < 0.2 mm pN0(i-) IHC negative pN0(i+) IHC positive pN0(mol-) RT-PCR negative pN0(mol+) RT-PCR positive
Predictors of Breast Cancer Survival Lymph node metastases
pN1 positive regional nodespN1a 1-3 positive axillary LNpN1b positive internal mammary
nodes found by SNBx onlypN1c = pN1a+pN1c
Predictors of Breast Cancer Survival Lymph node metastases
pN2 positive regional nodespN2a 4-9 positive axillary LN (at
least one >2 mm)pN2b positive internal mammary
nodes clinically apparent
Predictors of Breast Cancer Survival Lymph node metastases
pN3 positive regional nodespN3a >10 positive axillary LN (at
least one >2 mm) or infraclavicularLN positive
pN3b positive internal mammary nodes clinically apparent + pos axillary nodes
pN3c positive supraclavicular nodes
Predictors of Lymph Node Metastasis
Tumor size Lymphovascular invasionTumor gradePatient age
Axillary Node Dissection
Axillary Node Dissection
Lymphedema Parasthesias Pain Shoulder dysfunction
Definitions –Axillary lymph node dissection
Definitions-Lymphatic Mapping
Definitions-Sentinel lymph node
Lymph nodes identified by lymphatic mapping
Clinically suspicious lymph nodes
Definitions-Sentinel lymph node biopsy
Consensus statements
American Society of Breast Surgeons Institute for Clinical Systemic Improvement Canadian Steering Committee Consensus Conference Committee,
Philadelphia German Society of Senology
Philadelphia Consensus Conference
Sentinel node biopsy can replace routine axillary lymph node dissection for patients with no disease in the sentinel lymph node, with no further axillary treatment necessary.
Schwartz GF, Giuliano AE, Veronesi U, et alCancer, 2002
Specific situations
Positive sentinel node biopsy Large tumors Inflammatory breast cancer Multicentric tumors DCIS Male breast cancer Pregnancy Internal mammary nodes Prior breast or axillary surgery
Positive sentinel lymph nodes
48% of patients with a positive sentinel lymph node will have additional disease found at axillary node dissection
Positive sentinel lymph nodes
Immunohistochemistry upstages H&E negative lymph node status in 10% of patient pN0i+
Node deposits <0.2 mm are also pN0 No recommendation on axillary node
dissection
Positive sentinel lymph nodes
MicrometastasesNode deposits 0.2<2.0 mm20-35% will have additional positive
LNs
Are there alternatives?
Predictive models Axillary Radiation
Predictive models:Van Zee: Ann Surg Oncol, 2003
Axillary Radiation
NSABP B-04 (1985) 818 patients clinically node negative MRM, TM+XRT, or TM alone 10 year axillary recurrence 1.4% (MRM) vs
3.1% (TM+XRT)
Axillary Dissection vsRadiation
Where is the sentinel lymph node?
Surgeons view of the axilla
Radiation Oncologistsview of the axilla
What we did:
2: Interest point viewed on AP DRR; vertebral body level and distance toinferior border of clavicle evaluated
T4
What we did:
3: Interest point evaluated relative to previously designed tangential whole breast fields
Relationship of SLN to Tangent
A: inside treated field - 78%
B: under corner block - 12%
C: outside of field -10%
A+B: if removed corner block -90% A=78%
B=12%C=10%
Rabinovitch et al University of Colorado Cancer Center
SLN Position and Tangent FieldsKey Findings/Conclusions
Position of SLN relative to vertebral body level Ranges from T2-T7 most often opposite T4 on an AP view
Relationship of SLN to tangents Outside of field 10% Under supero-posterior block 12% Within treated field 78%
Relationship of SLN to clavicle Located inferior to clavicle in 94% Most superior SLN was located 1.5 cm above base of clavicle
Conclusions: Extension of tangents to 1.5 cm above bottom of clavicle would
include SLN in 100% of patients Nearly all SLNs (94%) are located outside of traditional axillary
radiotherapy fields If corner block removed, SLN within treated tangents 90%
90% within treated field if remove corner block
Ongoing studies
NSABP B-32 Randomized SN- patients to ALND vs. no
further surgery EORTC 10981
Randomized SN+ patients to ALND vs. axillary radiation
ACOSOG Z0011 Randomized SN+ patients to ALND vs. no
further therapy (tangential breast radiation only)
Panel recommendations
Macrometastases>2mm
Deposits <0.2 mm
Micrometastases0.2mm<2 mm
IHC+ SNNegative SN
ALNDNo recommendation
No ALND
Multicentric Tumors
10% of presenting breast cancers Tumor in more than one quadrant or
separated by more than 2 cm Peritumoral vs. Subareolar injections SNBx performance similar to patients with
unifocal disease
Ductal Carcinoma in Situ
5-15% are IHC positive SNBx if local treatment is mastectomy
Male Breast Cancer
1700 male breast cancers diagnosed annually
Survival equivalent for women with similar stage
Treatment of male breast cancer parallels treatment for women
Unlikely the SNBx would be less accurate
Pregnancy
Vital dye (lymphazurin) contraindicated Radiolabled colloids probably safe Insufficient data for specific recommendations
Internal mammary lymph nodes
No survival advantage Rarely site of local recurrence Likelihood of SN site 10% Likelihood of metastatic involvement 1% Insufficient data for specific recommendations
Prior breast surgery
Prior diagnostic or excisional breast biopsy not a contraindication
Breast reduction may be contraindication for tumors in the lower or medial aspect of the breast
Breast augmentation with submammary or subpectoral implants probably not a contraindication
Minimal data
Conclusions
Sentinel lymph node biopsy replaces axillary dissection in most situations
An axillary dissection should be performed for most patients with positive sentinel nodes
Morbidity from breast cancer treatment is decreased by limiting axillary dissection to patients with positive lymph nodes.
What Every Surgeon Should Know About Breast Cancer
Medical Oncology
Medical Oncology
Neoadjuvant chemotherapyGenetic profiling - Oncotype
Medical Oncology
Neoadjuvant chemotherapy
Inflammatory breast cancer: T4d N3c M1
Rational of Neoadjuvant Chemotherapy
What we learned from inflammatory breast cancerLocal vs. systemic disease
Effect of Preoperative Chemotherapy on Local-Regional Disease in Women With Operable Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-18
Bernard Fisher, et alJ Clin Oncol 1998
Effect of Preoperative Chemotherapy
Disease Free Survival no effect
Distant DFS no effect
Overall Survival no effect
Breast conservation 20% increase
Pre-contrast Post-contrast
Pre-NeoAdjuvant Chemotherapy
Pre-contrast Post-contrast
Post-NeoAdjuvant Chemotherapy
Neoadjuvant Chemotherapy
Who should get it? Inflammatory breast cancerT3/4 tumors not amenable to immediate
surgeryLarge tumor volume to breast volume
ratio desiring breast conservationClinically palpable lymph nodes
Neoadjuvant Chemotherapy
What should they get?Chemotherapy
Adriamycin?Herceptin?
Antiendocrine therapyAromatase Inhibitor
Medical Oncology
Genetic profiling Oncotype
Medical Oncology
55 year old woman treated with lumpectomy/sentinel node biopsy 3 cm High grade ER 60% PR 10% Her-2-neu negative
Oncotype Dx
Produced by Genomic HealthRNA from tumor extracted and purifiedRT-PCR of 21 genesReverse transcription polymerase chain
reactionRecurrence score calculatedBased on “proprietary” Oncotype algorithm
of gene expression
Oncotype Dx21 Gene Assay
21 Gene PanelAnalyzed by RT-PCR
What is sent in?
•10 micron section of breast tumor from formalin fixed paraffin embedded tissue submitted x 6
•1 H&E slide from same block
$3460
A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative
Breast CancerSoonmyung Paik, M.D., Steven Shak, M.D., Gong Tang, Ph.D., Chungyeul
Kim, M.D., Joffre Baker, Ph.D., Maureen Cronin, Ph.D., Frederick L. Baehner, M.D., Michael G. Walker, Ph.D., Drew Watson, Ph.D., Taesung Park, Ph.D., William Hiller, H.T., Edwin R. Fisher, M.D., D. Lawrence Wickerham, M.D.,
John Bryant, Ph.D., and Norman Wolmark, M.D.
Number 27December 30, 2004Volume 351:2817-2826
Tumors from patients enrolled on 2 NSABP trials analyzed:
NSABP B-14 ER+ LN- breast cancer Tamoxifen (n= 290) vs. Placebo (n=355)
NSABP B-20 ER+ LN- breast cancer Tam (n=227) vs. Tam/CMF (n=434)
Recurrence Score
30%14%7%
10-yr distant
recurrence rate
>3118-300-17Oncotype
Score
HighRisk
IntermedRisk
LowRisk
Treatment benefit
T amoxi f en benef i t by r ecur r ence scor e
0
20
40
60
80
100
120
R e c u r r e n c e s c o r e
Pl acebo
T amoxi f en
Treatment benefit
CMF benefit by recurrence score
0
20
40
60
80
100
Recurrence score
Surv
ival Tamoxifen
CMF
When to order Oncotype Dx
Newly diagnosed breast cancer Stage I/II, node negativeT1N0 or T2N0
ER+To be treated with Tamoxifen No data on aromatase inhibitors, ER-, or
node + patients
Rate of Distant Recurrence as a Continuous Function of the Recurrence Score
Implications for Therapy
Recurrence score of <18 (Low Risk)No benefit from chemotherapyBenefit from tamoxifen
Recurrence score of > 31(Hi risk)Large absolute benefit from chemotherapyAbsolute increase in DRFS at 10 yrs
27.6%
Medical Oncology
55 year old woman treated with lumpectomy/sentinel node biopsy 3 cm High grade ER 60% PR 10% Her-2-neu negative
Oncotype Score 37
Oncotype Score 37
Average 10 year Risk of Distant Recurrence Tamoxifen only - 25% Tamoxifen + CMF - 9%
Absolute benefit – 16% Relative benefit – 66%
Conclusion
Breast cancer is not “one” disease Biologic markers are being identified that
predict response to treatment Therapy is being tailored to specific tumor
characteristics, increasing benefit and decreasing risk