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Xanit Oncology Institute Cancer screening and Genetics Risk Assessment Counseling program

Dr Rafael Trujillo Vilchez Hospital Xanit Internacional

Xanit Hospital Internacional Avenida de los Argonautas s/n, 29630, Benalmdena, Mlaga. Tlf: 952 367 190 - Fax: 952 367 191 -

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).

Cancer risk assessment is a multi-step process

Disclose results Provide post-test counseling and follow-up

Identify hereditary Provide risk risk assessment patients

Provide informed consent

Select and offer test

Normal gene Somatic mutation

Germline mutation Somatic mutation

Somatic mutation

Later age at onset (60s or 70s)

Little or no family history of cancer Single or unilateral tumors

Early age at onset (<50)

Multiple generations with cancer Clustering of certain cancers (i.e. breast/ovarian)

Autosomal Dominant Inheritance

Carrier Parent Non-carrier Parent













The cancer family history is the key to:

Accurate risk assessment Effective genetic counseling Appropriate medical followup

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

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

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

Cancer and Steroid Hormone Study

Three-generation pedigree
d. 70 d. 52 Breast Ca, dx 49

d. 80 d. 85

62 Breast Ca, dx 41




59 Diabetes, dx 45




Misconceptions about family history

MYTHS: Cancer on the fathers side of the family doesnt 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. 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.

Hereditary Breast and Ovarian Cancer

BRCA1 (62%)

Other genes (16%) BRCA2 (32%)

Sporadic Hereditary

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

BRCA1-Associated Cancers: Lifetime Risk

Breast cancer 50%85% (often early age at onset) Second primary breast cancer 40%60% Ovarian cancer 15%45%

Possible increased risk of other cancers (eg, prostate, colon)


BRCA1-Linked Hereditary Breast and Ovarian Cancer


Breast, dx 45 86 d. 89 Noncarrier BRCA1-mutation carrier Affected with cancer





Ovary, dx 59 Breast, d. 62 dx 59

Breast, dx 36


BRCA2-Associated Cancers: Lifetime Risk

breast cancer

ovarian cancer

(50%85%) male breast cancer (6%)

Increased risk of prostate, laryngeal, and pancreatic cancers (magnitude unknown)


Westman experience (1996-2009): 5 positive results

TP53 mutation R181C

Renal Ca, 81

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

Clinical Management of BRCA Mutation-Positive Patient

Positive BRCA1 or BRCA2 test result
Possible testing for other adult relatives

Increased surveillance

Lifestyle changes


Prophylactic surgery

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

Cancer risk reduction with prophylactic surgery

Domchek and Weber, Oncogene 2006; 25:5825-5831

Chemoprevention of Breast Cancer in BRCA1/2 Carriers


Risk reduction of 50% or more in both BRCA1 and BRCA2 carriers

Gronwald J et al, Int J Cancer 2006;118(9):2281-4

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

Causes of Hereditary Susceptibility to CRC

Sporadic (65%85%)

Familial (10%30%) Lynch syndrome (3%)

Rare CRC syndromes (<0.1%) Familial adenomatous polyposis (FAP) (1%)

Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

Lynch Syndrome


Genetic Features of Lynch Syndrome

Genes belong to DNA mismatch repair (MMR) family Mutations in MMR genes lead to microsatellite instability MMR proteins are missing in the tumor tissue making immunohistochemical staining useful

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+





Clinical Features of Lynch syndrome

Early but variable age at CRC diagnosis (~45 years) Tumor site in proximal colon predominates

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

The Family History is Key to Diagnosing Lynch syndrome

CRC dx 50s

CRC dx 45

CRC dx 61

CRC dx 75

Ovarian Ca, dx 64

CRC dx 48

CRC dx 52

Endometrial Ca, dx 59


CRC dx 42

Surveillance Options for Patients with Lynch syndrome

Malignancy Intervention Recommendation
Begin at age 2025, repeat every 12 years

Colorectal cancer Colonoscopy

Endometrial cancer

Transvaginal ultrasound

Annually, starting at age 2535 Endometrial aspirate

Lindor NM, et al. JAMA 2006;296(12):1507-1517.

Surveillance Reduces Risk of Colorectal Cancer in Lynch syndrome Families

30 % of subjects 20 with CRC 10 0 0 3 6 Years of follow-up 9
Jarvinen HJ et al. Gastro 108:1405, 1995

No surveillance Surveillance
11.9% 4.5%

Prophylactic Surgery Options for Patients with Lynch syndrome

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.