Dr Rafael Trujillo Vilchez Hospital Xanit Internacional http://www.rafaeltrujillovilchez.com

1. Xanit Hospital Internacional
Avenida de los Argonautas s/n, 29630, Benalmádena, Málaga. Tlf: 952 367 190 - Fax: 952 367 191 - www.xanit.net
Xanit Oncology InstituteXanit Oncology Institute
Cancer screening and Genetics Risk Assessment CounselingCancer screening and Genetics Risk Assessment Counseling
programprogram
Dr Rafael Trujillo VilchezDr Rafael Trujillo Vilchez
Hospital Xanit InternacionalHospital Xanit Internacional

2. In this conference I will explained our Cancer screening and Genetics Risk
Assessment Counseling program at Xanit Oncology Institute and the scientific basis
that support both programs. Here is a brief resume of the conference; estimation of
the premature deaths that could have been avoided through screening varies from
3% to 35%, depending on a variety of assumptions. Beyond the potential for avoiding
death, screening may reduce cancer morbidity since treatment for earlier-stage
cancers is often less aggressive than that for more advanced-stage cancers.
Individuals are considered to be candidates for cancer risk assessment if they have
a personal and/or family history (maternal or paternal lineage) with features
suggestive of hereditary cancer.[5] These features vary by type of cancer and
specific hereditary syndrome. Criteria have been published to help identify families
who may benefit from a referral to genetic counseling.[2,6]
INTRODUCTIONINTRODUCTION

3. The following are features that suggest hereditary cancer:The following are features that suggest hereditary cancer:
 Unusually early age of cancer onset (e.g., premenopausal breast cancer).
 Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
 Bilateral cancer in paired organs or multifocal disease (e.g., bilateral breast cancer or
multifocal renal cancer).
 Clustering of the same type of cancer in close relatives (e.g., mother, daughter, and
sisters with breast cancer).
 Cancers occurring in multiple generations of a family (i.e., autosomal
dominant inheritance).
 Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa
cell tumor of the ovary, ocular melanoma, or duodenal cancer).
 Unusual presentation of cancer (e.g., male breast cancer).
 Uncommon tumor histology (e.g., medullary thyroid carcinoma).
 Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary
abnormalities).
 Geographic or ethnic populations known to be at high risk of hereditary cancers. Genetic
testing candidates may be identified based solely on ethnicity when a strong founder
effect is present in a given population (e.g., Ashkenazi heritage
and BRCA1/BRCA2 mutations). [7,8]

4. Process of genetic education and counselingProcess of genetic education and counseling
 As part of the process of genetic education and counseling, genetic testing may be
considered when the following factors are present:
 An individual's personal history (including ethnicity) and/or family history is suspicious
for a genetic predisposition to cancer.
 The genetic test has sufficient sensitivity and specificity to be interpreted.
 The test will impact the individual's diagnosis, cancer management or cancer risk
management, and/or help clarify risk in family members.[9,10]
 A candidate for genetic testing receives genetic education and counseling before testing to
facilitate informed decision making and adaptation to the risk or condition.[11] Genetic
education and counseling gives an individual time to consider the various medical
uncertainties, diagnosis, or medical management based on varied test results, and the risks,
benefits, and limitations of genetic testing.
 All this issues will be fully thoroughly explained during the conference at Xanit Hospital.

5. Cancer risk assessment is a multi-step
process
ProvideProvide
post-testpost-test
counselingcounseling
andand
follow-upfollow-up
IdentifyIdentify
hereditaryhereditary
riskrisk
patientspatients
Provide riskProvide risk
assessmentassessment
ProvideProvide
informedinformed
consentconsent
Select andSelect and
offer testoffer test
DiscloseDisclose
resultsresults

6. The cancer family history
is the key to:
Accurate risk
assessment
Effective
genetic
counseling
Appropriate
medical follow-
up

7. Taking a cancer family history
• Obtain at least a three-generation pedigree
• Ask about all individuals in the family
and record:
– age at cancer diagnosis, age at and cause of death
– primary vs metastatic cancer
– precursor lesions, bilateral cancer
• Record ethnicity and race
• Verify with medical records when possible

8. Cancer Risk Assessment
(for high risk breast cancer)
• Attempts to assist patient in understanding:
– Medical facts
– Mode of inheritance
– Risk of getting breast and/or ovarian cancer (again)
– Implications for daily life
• Options for dealing with the risk
– Breast surveillance
– DNA testing
– Prophylactic mastectomy and/or oophorectomy
– Chemoprevention (tamoxifen, SERM, OCP)

9. 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

11. Pitfalls of Gail model
• Does not include other cancers in model
– Ovarian, pancreatic, thyroid, male breast
• Does not include second-degree relatives
– Aunts, uncles, grandparents
• Does not include paternal side
• Does not include age of breast cancer
diagnosis in relatives

12. Cancer and Steroid Hormone Study

14. Three-generation pedigree
Breast Ca,
dx 41
35
German/Polish English/Irish
Breast Ca,
dx 49
d. 80
67 5565
Diabetes,
dx 45
52
30
d. 70 d. 85
5962
d. 52

15. Claus risk for breast cancer
• Claus table for two second-degree relatives
• Probability to age 79 = 20.9%
– To age 39 = 2.4%
– To age 49 = 6.1%
– To age 59 = 11.4%
– To age 69 = 16.9%
• Risk can be “used up”
– A 59 year old woman with no cancer
• 20.9% risk of breast cancer by age 79?
• Or 9.5% risk of breast cancer by age 79?

16. MYTHS:
• “Cancer on the father’s side
of the family doesn’t count.”
• “Ovarian cancer in the
family history is not a factor
in breast cancer risk.”
• “The most important thing
in the family history is the
number of women with
breast cancer.”
Misconceptions about family history
TRUTHS:
•Half of all women with
hereditary risk inherited it from
their father.
•Ovarian cancer is an
important indicator of
hereditary risk, although it is
not always present.
•Age of onset of breast cancer
is more important than the
number of women with the
disease.

17. Hereditary Breast and Ovarian Cancer
Sporadic
BRCA1
(62%) OtherOther
genesgenes
(16%)(16%)
BRCA2
(32%)
7-10%7-10%
Hereditary

18. ASCO
Features that indicate increased likelihood
of having BRCA mutations
• Multiple cases of early onset breast cancer
• Ovarian cancer (with family history of breast or
ovarian cancer)
• Breast and ovarian cancer in the same woman
• Bilateral breast cancer
• Ashkenazi Jewish heritage
• Male breast cancer

19. ASCO
BRCA1-Associated Cancers: Lifetime Risk
Possible increased risk of other
cancers (eg, prostate, colon)
Breast cancer 50%−85% (often early age at onset)
Second primary breast cancer 40%−60%
Ovarian cancer 15%−45%

20. ASCO
BRCA1-Linked Hereditary
Breast and Ovarian Cancer
Noncarrier
BRCA1-mutation
carrier
Affected
with cancer
Breast,
dx 59
Breast, dx 45
d. 89
92 86
73 68 Ovary, dx 59
d. 62
71
Breast,
dx 36
36

21. ASCO
BRCA2-Associated Cancers: Lifetime Risk
Increased risk of prostate,
laryngeal, and pancreatic cancers
(magnitude unknown)
breast cancer
(50%−85%)
ovarian cancer
(10%−20%)
male breast cancer
(6%)

23. Westman experience (1996-2009): 5 positive results

24. TP53 mutation R181C
BrCa
dx 43
Lymphoma,
9
Brain, 46
Renal Ca,
81
Bone, 18 Renal, 51
Brain, 12

27. Who to test?
• Use software tool (BRCAPro)
– Individual’s 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

28. Who to test?
Breast Ca,
dx 41
35
German/Polish English/Irish
Breast Ca,
dx 49
d. 80
67 5565
Diabetes,
dx 45
52
30
d. 70 d. 85
5962
d. 52

29. Risk assessment
• 35 year old daughter
– Claus, 19.5% lifetime risk for breast cancer
– Risk of carrying BRCA gene = 2-9%
• 67 year old father
– Risk of carrying BRCA gene = 5-9%
• 62 year old aunt, cancer at 41
– Risk of carrying BRCA gene = 9-15%
Upper risk figures from Myriad Laboratory, lower from BRCAPro

30. Use of pathology to refine risk
•BRCA1 breast tumors
– 80% basal subtype (triple negative)
– DCIS rare in carriers vs controls (now under
reconsideration)
•BRCA2 breast tumors
– Typical distribution of molecular subtypes
•Ovary
– Predominantly papillary serous adenocarcinoma
– Prognosis may be better than for sporadic ovarian cancer
Narod SA, Offit K J Clin Oncol 2005;
23:1656-1663

31. BRCA risk modifiers
• Family history
alone
– 3-7%, breast
– 23% with pancr
• With path
– 7-10%
Breast,
70s
Pancr,
73
Breast,
35
basal

32. Clinical Management of
BRCA Mutation-Positive Patient
Positive BRCA1 or BRCA2
test result
Possible testing for
other adult relatives
Increased
surveillance
Prophylactic
surgery
Lifestyle
changes
Chemo-
prevention
ASCO

33. Primary prevention of breast cancer
• Prevents cancers from occurring in the first place
• Prophylactic mastectomy
• Lifestyle changes
– Breast feeding (BRCA1)
– Small family size (BRCA2)
– Exercise, maintain stable weight
• Pre-menopausal oophorectomy (~40 years)
• Chemoprevention

34. Chemoprevention of Breast Cancer in BRCA1/2 Carriers
Tamoxifen
Risk reduction of 50% or more
in both BRCA1 and BRCA2 carriers
Gronwald J et al, Int J Cancer 2006;118(9):2281-4

35. Secondary prevention of breast cancers in
BRCA1/2 carriers
• Early detection of tumors when surgery alone would
be feasible
• Early clinical surveillance (begin at age 25)
– Clinical breast exams every 6-12 months
– Annual mammography
– Monthly breast self-exams
• Breast MRI instead of mammography
Narod SA, Offit K J Clin Oncol 2005; 23:1656-1663

36. Cancer risk reduction with prophylactic
surgery
Domchek and Weber, Oncogene 2006; 25:5825-5831

38. Modifying risk for relatives
56,
Breast, 51
Ovarian, 51
d. 49
Breast, 44
58
Fallopian tube,
53
BRCA1 +
BRCA1 + BRCA1 -
BRCA1 -

39. Other breast cancer syndromes
• Li Fraumeni syndrome
– Clearance of individual if mutation negative and
mutation is known in family
– Few prophylactic options available for mutation
positive
• Cowden syndrome
– Clearance of individual if mutation negative and mutation
is known in family
– Few prophylactic options available for mutation positive

40. Colorectal cancer
• 5% strongly inherited risk
– Familial adenomatous polyposis
– MUTYH-associated polyposis
– Lynch syndrome (hereditary nonpolyposis
colorectal cancer)
• Colon cancer, predominately right sided early onset
(60%)
• Endometrial cancer (50% of women)
• Ovarian cancer (10-15% of women)
• Genetic testing available for all

41. Risk alteration in hereditary CRC
• Clearance if individual is mutation negative
and mutation is known in family
• Mutation positive
– FAP
• Prophylactic colectomy, other sites problematic
– MAP
• Prophylactic colectomy, not known to affect other sites
– Lynch
• Annual colonoscopy, hysterectomy/oophorectomy

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