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Xanit Hospital Internacional Avenida de los Argonautas s/n, 29630, Benalmdena, Mlaga. Tlf: 952 367 190 - Fax: 952 367 191 - www.xanit.net
Sporadic
Normal gene Somatic mutation
Inherited
Germline mutation Somatic mutation
Somatic mutation
Aa
aa
Aa
Aa
aa
aa
Carrier
Carrier
Non-carrier
Non-carrier
1/2
1/2
Gail model
Breast Cancer Detection and Demonstration Project
2852 cases, 3146 matched controls J Natl Cancer Inst 81:1879-86, 1989
Used to determine lifetime breast cancer occurrence risk Used to determine appropriateness for prophylactic tamoxifen therapy Incorporates
Age Reproductive history Benign breast disease history Breast cancers in mother or sisters
Does not include paternal side Does not include age of breast cancer diagnosis in relatives
Three-generation pedigree
German/Polish
d. 70 d. 52 Breast Ca, dx 49
English/Irish
d. 80 d. 85
62 Breast Ca, dx 41
67
65
55
59 Diabetes, dx 45
52
35
30
BRCA1 (62%)
7-10%
Sporadic Hereditary
Breast cancer 50%85% (often early age at onset) Second primary breast cancer 40%60% Ovarian cancer 15%45%
92
73
68
71
Ovary, dx 59 Breast, d. 62 dx 59
Breast, dx 36
36
breast cancer
ovarian cancer
(10%20%)
ASCO
Brain, 46
Bone, 18
Renal, 51
Lymphoma, 9
BrCa dx 43
Brain, 12
Who to test?
Use software tool (BRCAPro) Individuals cancer status History of breast and ovarian cancer in 1st and 2nd degree relatives Number of affected vs unaffected in family Risk >10% with clear benefit Person affected with cancer Early onset breast preferably Ovarian at any age Any Ashkenazi Jewish or Icelandic person Any person in family with known mutation Most health insurers have published guidelines
Increased surveillance
Lifestyle changes
Chemoprevention
Prophylactic surgery
ASCO
Tamoxifen
Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996
Lynch Syndrome
MSH2 MSH6 MLH1
PMS2
Immunohistochemistry
Identify MMR proteins Normally present If protein is absent, gene is not being expressed (mutation or methylation) Helps direct gene testing by predicting likely involved gene If abnormal IHC (absent), MSI+
MLH1
MSH2
PMS2
MSH6
Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors
Amsterdam Criteria II
3 or more relatives with verified HNPCCassociated cancers* in family One case a first-degree relative of the other two Two or more generations One CRC by age 50 FAP excluded
Vasen HFA et al. Gastroenterology 116:1453, 1999
*HNPCC associated cancers: CRC, endometrial, small bowel, ureter, renal pelvis
CRC dx 45
CRC dx 61
CRC dx 75
Ovarian Ca, dx 64
CRC dx 48
CRC dx 52
Endometrial Ca, dx 59
45
CRC dx 42
Endometrial cancer
Transvaginal ultrasound
No surveillance Surveillance
11.9% 4.5%
Options include subtotal colectomy, hysterectomy, and oophorectomy Surgery does not eliminate cancer risk Recent data that hysterectomy with BSO eliminates the risk of endometrial and ovarian cancer in LS patients
Schmeler KM, et al. NEJM 2006;354:261-269.
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