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Xanit Oncology Institute Xanit Oncology Institute Cancer screening and Genetics Risk Assessment Counseling Cancer screening and Genetics Risk Assessment Counseling

programprogram

Dr Rafael Trujillo Vilchez

Hospital Xanit Internacional

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).

Cancer risk assessment is a multi-step process

Provide Provide post-test post-test counselincounselin

g and g and follow-upfollow-up

Identify Identify hereditarhereditar

y risk y risk patientspatients

Provide Provide risk risk

assessmenassessmentt

Provide Provide informed informed consentconsent

Select and Select and offer testoffer test

Disclose Disclose resultsresults

Sporadic Inherited

• 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(i.e. breast/ovarian)

Normal gene

Somatic mutation

Somatic mutation

Germline mutation

Somatic mutation

Carrier Parent Non-carrier Parent

Aa aa

Aa Aa aa aa

Carrier Carrier Non-carrier Non-carrier

Autosomal Dominant Inheritance

1/2 1/2

The cancer family history is the key to:

Accurate risk assessment

Effective genetic counseling

Appropriate medical follow-up

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

Breast Ca,

dx 41

35

German/Polish English/Irish

Breast Ca, dx 49

d. 80

67 5565Diabetes,

dx 45

52

30

d. 70 d. 85

5962

d. 52

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.

Hereditary Breast and Ovarian Cancer

Sporadic

BRCA1 (62%) Other Other

genesgenes

(16%)(16%)

BRCA2 (32%)

7-10%7-10%

Hereditary

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

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%

ASCO

BRCA1-Linked Hereditary Breast and Ovarian Cancer

Noncarrier

BRCA1-mutation carrierAffected with cancer

Breast, dx 59

Breast, dx 45d. 89

92 86

73 68 Ovary, dx 59d. 62

71

Breast, dx 36

36

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%)

Westman experience (1996-2009): 5 positive results

TP53 mutation R181C

BrCadx 43

Lymphoma, 9

Brain, 46

Renal Ca, 81

Bone, 18 Renal, 51

Brain, 12

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

Clinical Management of BRCA Mutation-Positive Patient

Positive BRCA1 or BRCA2 test result

Possible testing for other adult relatives

Increasedsurveillance

Prophylacticsurgery

Lifestyle changes

Chemo-prevention

ASCO

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

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

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

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

Sporadic (65%–85%)

Familial (10%–30%)

Lynch syndrome (3%)

Familial adenomatous polyposis (FAP) (1%)

Rare CRC syndromes

(<0.1%)

Lynch Syndrome

MLH1

MSH2

MSH6

PMS2

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

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+

MSH2MLH1

MSH6PMS2

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 HNPCC-associated 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

CRCCRCdx 45dx 45

OvarianOvarianCa, dx 64Ca, dx 64

CRCCRCdx 50sdx 50s

CRCCRCdx 61dx 61

CRCCRCdx 75dx 75

CRCCRCdx 48dx 48

CRCCRCdx 52dx 52

EndometrialEndometrialCa, dx 59Ca, dx 59

CRCCRCdx 42dx 42

4545

Surveillance Options for Patients with Lynch syndrome

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

InterventionColonoscopy

Transvaginal ultrasound

Endometrial aspirate

RecommendationBegin at age 20–25,

repeat every 1–2 years

Annually, starting at age 25–35

MalignancyColorectal cancer

Endometrial cancer

Surveillance Reduces Risk of Colorectal Cancer in Lynch syndrome Families

Jarvinen HJ et al. Gastro 108:1405, 1995

Years of follow-upYears of follow-up

% of % of subjects subjects

with CRCwith CRC

3030

2020

1010

4.5%4.5%

11.9%11.9%

00 33 66 99

SurveillanceSurveillanceNo surveillanceNo surveillance

00

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.

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