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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

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

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]

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.

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

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

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)

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 4135

German/Polish English/Irish

Breast Ca, dx 49

d. 80

67 5565Diabetes,

dx 45

52

30

d. 70 d. 85

5962

d. 52

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?

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

NoncarrierBRCA1-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 43Lymphoma,

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

Who to test?

Breast Ca,

dx 4135

German/Polish English/Irish

Breast Ca, dx 49

d. 80

67 5565Diabetes,

dx 45

52

30

d. 70 d. 85

5962

d. 52

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

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

BRCA risk modifiers

• Family history alone– 3-7%, breast– 23% with pancr

• With path– 7-10%

Breast, 70s

Pancr, 73

Breast, 35

basal

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

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

Cancer risk reduction with prophylactic surgery

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

Modifying risk for relatives

56, Breast, 51Ovarian, 51

d. 49Breast, 44

58Fallopian tube,

53

BRCA1 +BRCA1 + BRCA1 -

BRCA1 -

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

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

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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