hereditary multifocal breast cancer - ucla ctsi · case study 30 year old ... modified radical...
TRANSCRIPT
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Hereditary Multifocal Breast Cancer
Farin Amersi M.D., F.A.C.SDivision of Surgical Oncology
Department of SurgeryCedar Sinai Medical Center
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CASE STUDY
30 year old Ashkenazi Jewish woman Nulliparous Felt left breast mass while showering Gynecologist referred for mammo and U/S Mammogram: no architectural distortion or
mass Ultrasound: solid mass in left breast at 3 o’clock
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CASE STUDY
Physical Examination:Palpable 5 cm mass left breastNo left axillary adenopathyNo masses right breast or axillary adenopathy
core biopsy of palpable mass
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Left breast core biopsy
High grade ductal carcinoma in situ
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FAMILY HISTORY
BC, dx. 41
OC, d. 58= Cancer
58
30 33
BC, dx. 42
OC ,dx 62
34 31
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Case Study
Core biopsy: DCIS
High grade, without necrosis ER 96%/ 3+ and PR 69%/2+
Risk factors: Multiple family members with breast and ovarian cancer BRCA testing: positive for BRCA 2 mutation
Further Imaging: Breast MRI PET/CT
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CASE STUDY
MRI and PET/CT findings: 4 or 5 lesions suspicious for invasive cancer
Next Steps? Biopsy all other lesions in breast ? Proceed to mastectomy ?
Unilateral vs bilateral?
Procedure: bilateral mastectomy – pathology
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Mass #1
Upper Inner Size = 1.1 cm ER+/ PR-/ Her2 + MBR = II/III
Tubules 1 Grade 3 Mitosis 2
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Mass #2
Lower Inner Size = 1.5 cm ER-/PR-/Her2 - MBR III/III
Tubules 3 Grade 3 Mitosis 3
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Mass #3
Mid lateral Size 3.0 cm ER+/PR+/HER2- MBR III/III
Tubules 2 Grade 3 Mitosis 3
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Mass #4
Upper Outer Size 3.0 ER+/PR+/Her2+ MBR
Tubule 1 Grade 3 Mitosis 2
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DCIS
Intermediate and high grade, solid and cribriform
Multifocal admixed with and away from invasive components
Margins negative Lymph nodes negative
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Right breast
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CASE STUDY
4 separate primary breast cancers, LN- 3cm, grade III – ER+/PR+/Her2 + 3cm, grade II- ER+/PR+/Her2 - 1.5 cm, grade III- ER-/PR-/Her2 - 1.1 cm, grade II- ER+/PR-/Her2 +
What is her risk of recurrence? Risk of local recurrence? Risk of distant metastases?
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CASE STUDY
Risk of distant recurrence at 10 yrs (AdjuvantOnline) A) 3cm, grade III - 60% (or 40% no recurrence) B) 3cm, grade II - 50% C) 1.5 cm, grade III – 44% D) 1.1 cm, grade II – 35%
What is her risk of any recurrence? Metastatic spread of any tumor (independent events) Probability of no recurrence p(A) x p(B) x p(C) x p(D) Probablity of any recurrence = 1- p
(courtesy of Jim Mirocha, Biostatistics)
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CASE STUDY
Risk of distant recurrence at 10 yrs (AdjuvantOnline) A) 3cm, grade III - 60% (or 40% no recurrence) B) 3cm, grade II - 50% C) 1.5 cm, grade III – 44% D) 1.1 cm, grade II – 35%
What is her risk of any recurrence? Probability of no recurrence p(A) x p(B) x p(C) x p(D)
.4 x .35 x .56 x .65 = .07 Probability of ANY recurrence = .93, or 93%
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CASE STUDY
Risk of distant recurrence at 10 yrs (AdjuvantOnline) A) 3cm, grade III - 60% (or 40% no recurrence) B) 3cm, grade II - 50% C) 1.5 cm, grade III – 44% D) 1.1 cm, grade II – 35%
What is her risk of any recurrence? Probability of no recurrence p(A) x p(B) x p(C) x p(D)
.4 x .5 x .56 x .65 = .07 Probability of ANY recurrence = .93, or 93%
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CASE STUDY Risk of distant recurrence at 10 yrs (AdjuvantOnline)
A) 3cm, grade III - 60% (or 40% no recurrence) B) 3cm, grade II - 50% C) 1.5 cm, grade III – 44% D) 1.1 cm, grade II – 35%
What is her risk of any recurrence? Probability of no recurrence p(A) x p(B) x p(C) x p(D)
.4 x .5 x .56 x .65 = .07 Probability of ANY recurrence = .93, or 93% Risk reduced by Tam + 3rd gen chemotx + Herceptin~ 70%
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Tamoxifen
Approved 1986 Hormone receptor (ER and PR) positive breast
cancers
Antagonistic and agonistic actions on the estrogen receptor (ER)
Adjuvant endocrine agent of choice for premenopausal, ER/PR positive patients
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Her-2/Neu Positive Breast Cancers
Over expression of Her-2/neu protein or amplification of Her-2 gene occurs in 15 to 25% of breast cancers More aggressive tumor biology
Herceptin (Trastuzumab) therapy established as beneficial in metastatic disease Monoclonal antibody against anticellular domain of
HER2
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Breast Cancer Most frequently diagnosed cancer in women
ACS reports 182,460 new cases of invasive breast cancer, and 67,770 cases of in-situ breast cancer in 2008
1 in 7 will develop breast cancer in their lifetime
Second most common cause of cancer death in women
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Risk Factors for Breast Cancer
Age
Family history of breast cancer
Inheritance of a genetic mutation
Radiation to the chest
History of atypical ductal hyperplasia on a breast biopsy
Long menstrual history
Nulliparous (never having children)
Use of oral contraception/hormonal therapy after menopause
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Signs and Symptoms of Breast Cancer
Abnormality of mammogram
Palpable, painless mass
Skin thickening
Skin dimpling
Skin redness, ulceration, scaling
Nipple ulceration, scaling
Spontaneous bloody nipple discharge
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General Features of Hereditary Cancer
Cancer diagnosed at a young age (<50) Uncommon/unusual cancers (e.g. ovarian,
male breast) Multiple primary cancers in the same
individual Combination of certain cancers in a family
(e.g. breast and ovarian, colon and uterine, melanoma and pancreatic)
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Hereditary Breast and Ovarian Cancer
Sporadic
Am J Hum Genet 1998; 62:676-89
BRCA1(52%)
Other genes(16%)BRCA2(32%)
15-20%
Hereditary
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A BRCA Mutation Increases Breast and Ovarian Cancer Risks
20
40
60
80
100
Breast cancerby age 50
Breast cancerby age 70
Ovarian cancerby age 70
2%
Up to 50%
7%
Up to 87%
Ris
k of
Can
cer
(%)
<2%
Up to 44%
General PopulationBRCA Mutation
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A BRCA Mutation Increases Risk of Second Cancer
0
20
40
60
Ovarian Cancer Breast Cancerafter 5 yrs
Breast Cancer by age 70
General PopulationBRCA Mutation
16%
~5%
Up to 27%
Up to 11%
Up to 64%
Ris
k of
Can
cer (
%)
* no statistic available
*
* no statistic available
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Prevalence of BRCA Mutations
Ovarian cancer in one relative, no breast cancer <50
26.1%23.1%14.8%Ovarian cancer, no breast cancer
16.9%15.8%9.8%Breast cancer <50
5.6%4.5%2.8%No breast or ovarian cancer
Breast cancer <50, no ovarian cancer
No breast cancer <50 or ovarian cancer
Patient’s History
Family History
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Prevalence of Mutations in Ashkenazi Jewish Individuals
42.0%37.0%22.2%Ovarian cancer, no breast cancer
38.8%24.2%14.0%Breast cancer <50
15.6%13.7%6.9%No breast or ovarian cancer
Breast cancer <50, no ovarian cancer
No breast cancer <50 or ovarian cancer
Patient’sHistory
Family History
Ovarian cancer in one relative, no breast cancer <50
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“Red Flags” for Hereditary Breast and Ovarian Cancer
• Breast cancer before age 50• Ovarian cancer at any age• Male breast cancer at any age• Ashkenazi Jewish ancestry• Every woman with simultaneous breast cancers• Every woman who develops a second breast
cancer• Every first degree relative in a family where a
positive test has been found
Science 2003;302:643-6
www.nccn.org
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Surveillance for Breast Cancer
www.nccn.orgCancer 2004;100:479-89NEJM 2004;351:427-37
Procedure Age to begin FrequencyBreast self-exam 18 yrs Monthly
Clinical breast exam
25 yrs Twice a year
Mammography 25 yrs Yearly
MRI 25 yrs Yearly
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Prophylactic Mastectomy
Greater than 95% breast cancer risk reduction in BRCAcarriers
NEJM 2001;345:159-64JNCI 2001;93:1633-7
JCO 2004;22:1055-62BJC 93(3):287-92
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Surveillance for Ovarian Cancer
• CA-125
• Pelvic exams
• Transvaginal ultrasound
Additional screening techniques under investigation due to limited efficacy of current options
J Clin Oncol. 2005 Mar 10; 23(8): 1656-63
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Prophylactic Oophorectomy
Recommend bilateral salpingo-oophorectomy (BSO) at age 35 or after childbearing is complete
~98% ovarian cancer risk reduction in BRCA carriers
Can reduce breast cancer risk by up to 68% for both BRCA1 and BRCA2 mutation carriers
JAMA. 2006;296:185-92Clin Oncol. 2005 Mar 10;23(8):1656-63
NEJM 2002;346:1609-15 www.nccn.org
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Surgical Options for the Breast
Mastectomy Radical Mastectomy Modified Radical Mastectomy Total Mastectomy
Breast Conservation Therapy (BCT) Quadrantectomy Segmental Mastectomy
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Halstedian Theory
1890’s
Breast cancer spreads in step-wise fashion: primary tumor regional lymphatics distant
sites
Radical resections advocated
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Radical Mastectomy
En bloc resection Breast
Skin Nipple Areola
Pectoralis muscle Axilla
Full axillary lymph node dissection
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Radical Mastectomy
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Fisher’s Theory
1960’s and 1970’s
Argument: Systemic disease from inception Challenged necessity of radical procedures
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Modified Radical Mastectomy
En bloc resection: Breast
Skin Nipple Areola
Axilla Full axillary lymph node dissection
Pectoralis muscle spared
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Modified Radical Mastectomy
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NSABP B-04
1971 to 1974 25 year follow-up published in 2002
Fisher B, Jeong JH, Anderson S, et al. “Twenty-five Year Follow-up of a Randomized Trial Comparing Radical Mastectomy, Total Mastectomy, and Total Mastectomy Followed by Irradiation.” New England Journal of Medicine, 2002; 347: 567-75.
Comparison of radical versus total mastectomy
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NSABP B-04
Clinically node negative patients: Radical mastectomy Total mastectomy
with axillary radiation Total mastectomy
without radiation
Clinically node positive patients: Radical mastectomy Total mastectomy
with axillary radiation
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NSABP B-04
Equivalency among all groups: Disease-free survival Distant-disease-free survival Over-all survival
“Variations in local and regional treatment- from radical to conservative- all involving removal of the breast, result in the same outcome.”
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Total Mastectomy
En bloc resection Breast
Skin Nipple Areola
Axilla Sentinel node biopsy
Axillary lymph node dissection if SLND positive
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Total Mastectomy
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Breast Conservation Therapy (BCT)
Removal of cancer without sacrifice of remainder of breast negative surgical margins radiation therapy to breast
Terminology: Quadrantectomy Lumpectomy Partial Mastectomy
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Segmental Mastectomy
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NSABP B-06
1976 to 1984 3 treatment arms:
Total mastectomy and axillary node dissection Lumpectomy and axillary node dissection with/without
breast irradiation
20 year follow-up published in 2002 Fisher B, Anderson S, Bryant J, et al. “Twenty-year Follow-
up of a Randomized Trial Comparing Total Mastectomy, Lumpectomy, and Lumpectomy Plus Irradiation for the Treatment of Invasive Breast Cancer.” New England Journal of Medicine, 2002; 347: 1233-41.
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NSABP B-06
Mastectomy and lumpectomy equivalent: Disease-free survival Distant-disease-free survival Overall survival
Breast irradiation required after lumpectomy
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In-Breast Recurrence
Breast conservation
therapy
Mastectomy
Risk 10 to 15% 1 to 3%
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BCT Contraindications
Absolute: Multicentric disease Multifocal disease Prior breast irradiation Persistent positive
margins after resection Patient choice History of collagen
vascular disease Active SLE scleroderma
Relative: History of other collagen
vascular diseases Large tumor in a small
breast Breast size Pregnancy
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Post-Mastectomy Reconstruction
Two main types of constructs: Expander, followed by implant
Autologous tissue transfers: TRAM flap DIEP flap Latismus dorsi flap Gluteal flaps
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Expander Reconstruction
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Tissue Reconstruction
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TRAM Flap Reconstruction