Prevention of Hereditary Cancer

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Prevention of Hereditary Cancer

• Presented by
• Dr Haseena Hamdani

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Significance of presentations

• 5-10 of cancers are Hereditary.
• Hereditary cancers are caused by germ-line
  mutation.
• Possible to diagnose mutant genes.
• Life time risk for cancer is significantly high
  in an individual with positive mutant genes.
• Possible to prevent cancer by high surveillance,
  chemoprevention, and surgical intervention.

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Introduction

• Brief discussion about genetics in cancer
• Gene test for mutation detection
• Risk reduction management plan for high risk
  populations

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Abnormal genes
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How is hereditary cancer different

• The risk for cancers are higher than the general
  population
• Often occur at a younger age than sporadic
• The cancer risk may be passed down through the
  generations
• High risk for 2nd or 3rd cancer diagnoses
• There are options for lowering the risk for
  hereditary cancer or for detecting it early

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Common gene mutations, and cancer

• BRCA1, BRCA2 Hereditary Breast ovarian Syndrome
• CHEK2 -( in absence of BRCA1, BRCA2 gene mutation
• increase the chances of breast cancer by double)
• TP 53- Li-Fraumeni syndrome
• PTEN- Cowden syndrome
• CDH1-Hereditary Diffuse Gastric Cancer, lobular
  Breast Ca
• MLH1, MSH2, MSH6- HNPCC ( MMR)-HNPCC

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BRCA1/2 Mutation Incidence

•  
• 1 in 800 women in the general population
• 5-10 of all women with breast CA
• 18 of women with breast CA lt50 and one close
  relative with breast CA lt50 
• 2 of all women of Ashkenazi Jewish ancestry
• 25 of all Ashkenazi Jewish women with ovarian
  cancer

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Hereditary Breast and Ovarian Cancer BRCA1
Breast cancer 50-85
Second primary breast cancer 40-60
Ovarian cancer 20-60
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Hereditary Breast and Ovarian Cancer BRCA2
breast cancer (50-85)
male breast cancer (6)
ovarian cancer (10-20)
Increased risk of prostate (8), colon
(6),melanoma and pancreas cancers (7), larynx
(7 fold increase), Fallopian Tube 120 folds
increase)
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HNPCC

• hereditary nonpolyposis colorectal cancer (HNPCC)
• , an inherited mutation in one of the mismatch
  repair (MMR) genes appears to be a critical
  factor.
• MMR genes normally produce proteins that identify
  and correct sequence mismatches that can occur
  during DNA replication. A mutation that
  inactivates an MMR gene leads to the

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t

• High penetrance genes (BRCA1,2-4 of cancers)
• Beast
• Ovary
• Colon
• Stomach
• prostate

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Genetic Predisposition Testing Is a Multi-Step
Process
Provide post-test counseling and follow-up
Disclose results
Select and offer test
Provide informed consent
Provide pretest counseling
Identify at-risk patients
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Features Suggestive of Hereditary cancers

• Cancer in 2 or more close relatives on same side
  of family
• Early onset cancer, eg. Breast, colorectal,
  endometrial etc.
• Ovarian cancer at any age.
• Breast and ovarian cancer in the same woman
• Bilateral breast cancer
• Ashkenazi Jewish heritage
• Male breast cancer at any age
• Relatives of a BRCA mutation carrier
• Multiple primary tumors.
• Evidence of Autosomal dominant transmission

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Factors that Influence the Cancer Pattern within
a Family

• Penetrance
• Gender
• Environment
• Genotype
• Risk-Reduction
• Early death
• Modifier genes

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Risk Assessment

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• Likelihood of developing breast cancer
• Gail model
• Claus model
• Likelihood of having a BRCA1 or 2 mutation
• Myriad risk tables
• BRCAPRO, Couch, Shattuck-Eidens, CAGene
• Likelihood of other breast cancer syndrome
• Pedigree analysis

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Gail Model

• Calculate 5yrs, and life time risk of breast
  cancer based on multiple criteria
• Best application
• For individuals with no family history of breast
  cancer or 1 first-degree relative with breast
  cancer at age 50 years
• For determining eligibility for chemoprevention
  studies
• Strenth
• Risk factors other than family history
• Limitations- Does not include
• Age of onset
• 2nd degree relatives
• Paternal History
• Ovarian cancer

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Claus model

• Calculate the life time risk based on
• Age of onset of breast cancer in 1st and 2nd
  degree relatives including paternal side.
• Best Application for
• individuals with 0, 1, or 2 first-degree or
  second-degree relatives with breast cancer
• Limitations
• Underestimate risk in families with 3 or
  moreaffected members
• Ethnicity not included.

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Myriad risk table

• Identifies the chance of detecting a BRCA1 or
  BRCA2 mutation in women with a family history of
  early-onset breast and/or breast and ovarian
  cancer
• Limitations
• breast cancergt50 yrs not included
• clinical data not validated

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Cancer Risk Evaluation Program
Models
gt10
lt10
Genetic Testing
Gail and Claus

-
gt25
BSO Screening studies Prevention studies PM
Screening studies Chemoprevention
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Genetic counselling

• The probability to develop a neoplasia.
• The probability to transmit the cancer
  predisposition to their offspring.
• The probability that, they in turn, have to
  develop a neoplasia.
• The prognosis and the strategies for the early
  detection and the most suitable therapeutic
  approach.

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Benefits, Risks, and Limitationsof geneTesting

• Benefits
• Identifies high-risk individuals
• Identifies non-carriers in families with a known
  mutation
• Allows early detection and prevention strategies
• May relieve anxiety, and uncertainity
• Information about individual, and family.
• Life-style decisions making

• Risks and Limitations
• Does not detect all mutations
• Continued risk of sporadic cancer
• Efficacy psychosocial of interventions unproven
• Variant of uncertain significance
• May result in or economic harm
• False sense of security
• Change in family dynamics
• Discrimination by employer, and insurer
• Loss of privacy

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Ideally, Begin Testing With an Affected Person
Breast Ca, 42
Test first, if possible
Ovarian Ca, 38 d.45
Breast Ca, 65
Person seeking counseling (proband)
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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
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Clinical Management of BRCA Mutation-Negative
Patient
Negative BRCA1 and BRCA2 test result
Member of family w/ known BRCA1 or BRCA2 mutation?
NO
YES
Emphasize risk of sporadic cancer
Emphasize risk of unidentified familial mutation
Encourage adherence to population screening
guidelines
Provide individualized risk-management plan
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Preventive lifestyle measures

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• Good for all risk categories!
• Intensive exercise 30 min. or more most days
• Weight control
• Diet
• Less saturated, animal and trans fat, more fish
• Less refined flour, sugar
• More fruits/vegetables, whole grains, beans,
  nuts, fiber
• Alcohol less than 1-2 drinks/day
• No Smoking

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After Conservative surgery in mutant positive

• After BCT
• 50 life time risk of
• in-breast tumor recurrence (IBTR)
• Contra-lateral breast cancer
• ovarian cancer
• 30-40 risk for next 10 years.
• After segmental resection of colon
• 30 risk of developing second cancer within 10
  years.
• 50 risk of developing second cancer within 15
  years.

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Affected mutant positive
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Surgical options for mutant positivecancer
patient

• Total colectomy with ileorectal anastomosis or
• hemicolectomy are the recommended surgical
  procedures, rather than segmental colectomy for
  Colorectal Cancer.
• Radical mastectomy with prophylactic mastectomy
  of contra lateral breast are the recommended
  surgical procedure rather than breast
  conservative surgery, followed by radiotherapy,
  and chemotherapy

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Surgical Interventions

• Bilateral Prophylactic Mastectomy
• Bilateral Prophylactic Salpingo-oophorectomy
• Prophylactic Gastrectomy
• Prophylactic total abdominal hysterectomy and
  bilateral salpingo-oophorectomy jn colorectal
  cancer with mutation positive.
• Prophylactic total colectomy with ileorectal
  anastomosis may be presented as an option based
  on carrier status alone.

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Risk Reduction

• Prophylactic bilateral mastectomy
• reduces the risk for developing breast
• cancer by nearly 90.
• Prophylactic Salpingo -oophorectomy before age 40
• 90 reduction in the risk to develop ovarian
  cancer
• 75 reduction in the risk to develop breast
  cancer.
• Prophylactic salpingo- oophorectomy between age
  40 to 49.
• reduction in breast cancer risk was 40  

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Efficacy of prophylactic surgery
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Chemoprevention strategy for breast cancer

• Blocking the effects of Oestradiol by Tamoxifen,
  or Raloxifen.
• Reducing circulating levels of Oestradiol from
  fat cells, and adrenal cells by Aromatase
  inhibitors (Anastrazole, Letrozole, and
  Exemestane ) in postmenopausal women and by LHRH
  agonists (Deslorelin) in premenopausal
  women,Deslorelin reduces the risk by stopping
  estrogen production from ovaries in, and by
  reducing breast density.
• Fenretinide ( vitamin A) In premenopausal women
  under the age of 40
• .

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• Tamoxifen in affected carriers 75 reduction for
  contralateral breast cancer
• Unaffected BRCA2 carriers 62 reducion
• Unaffected High Risk patient 45 reduction
• Over the age of 50, aspirin for five years in
  doses
• 325 mg reduces the risk by 21.
• Ibuprofen reduces the risk by 49.
• Regular use of Statins reduce the risk by
• 51.

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Take Home messege

• Individualize management to our high risk
  patients, and their families.
• Intensive surveillance
• Prophylactic bilateral salpingo-oophorectomy to
  be offered to selected people.

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Acknowledgment

• www.cancer.gov, National Cancer Institute, USA
• www.breastcancer.org,
• www.medscape.com

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Chemopreventive Agents

• Vitamin E
• Vitamin B
• Beta carotene
• Minerals
• NSAIDs
• COX -2 inhibitors
• Hormonal Agents (SERMs, AI)
• Retinoids,
• breast Cancer Vaccine (Neuvenge)