BRCA And Hereditary Breast Ovarian Cancer Syndrome HBOC

1
BRCA And Hereditary Breast Ovarian Cancer
Syndrome ( HBOC )

• A. Gari
• Gynecologic Oncology

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Objectives

• Introduction .

3
Introduction .

• A - Breast cancer
• The most incident cancer in women.
• The 2ed common cause of cancer related deaths.
• Incidence 12 (18) Life time risk.
• Only 5-6 are inherited mutations.

4
Introduction (Cont'd)

• B - Ovarian cancer
• The 7th incident cancer in women.
• The 5th disease as cancer related deaths.
• The leading cause of death from Gyne.
  Malignancies.
• Incidence 1.5 (170) Life time risk.
• Only 5-10 are inherited mutations.

5
Risk modifying factors for Ovarian cancer

• Age .
• Reproductive factors
• - Pregnancy.
• - OCP use.
• - Breast feeding.
• - Infertility / low parity.
• Family history (genetic predisposition).
• Surgery (Hysterectomy, TL, BSO).

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Canadian Cancer Statistics 2005
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Canadian Cancer Statistics 2005
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Major Breast Cancer Susceptibility Diseases

• Li-Fraumeni
• Rare AD.
• P-53 mutation.
• Development of multiple primary tumors
• - Soft tissues sarcomas.
• - Osteosarcomas.
• - Leukeamia
• - Brain tumors.
• - Breast cancer.
• 50 of carriers will develop cancer by age 30y
  90 by age 70y.

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Major Breast Cancer Susceptibility Diseases

• Ataxia-telangiectasia
• AR. (120 000 - 1100 000 births)
• ATM gene.
• Progressive cerebellar ataxia CNS
  abnormalities.
• Oculo-cutaneous telangiactasia.
• Immune deficiency.
• DM.
• Development of multiple primary tumors
• - Lymphoma.
• - Breast cancer.
• - Radiation sensitivity.

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Major Breast Cancer Susceptibility Diseases

• Cowden syndrome
• Rare AD.
• PTEN (MMAC1).
• Development of multiple tumors
• - Hamartomas.
• - Thyroid cancers.
• - Breast cancer (BL)
• - Benign breast diseases.

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Major Breast Cancer Susceptibility Diseases

• Peutz - Jeghers syndrome
• Rare AD.
• STK 11 gene.
• Development of multiple GI Hamartomas / polyps.
• Increased melanin deposit (lips, buccal mucosa,
  fingers toes).
• Development of multiple primary tumors
• - Small large intestine.
• - Stomach.
• - Pancreas.
• - Breast cancer .
• - Ovarian cancer (sex cord).

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Major Breast Cancer Susceptibility Diseases
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HBOC

• BRCA 1
• Autosomal dominant.
• Chr.17 (17q).
• 17-25 are ER ve.

• BRCA 2
• Autosomal dominant.
• Chr.13 (13q).
• 75-80 are ER ve.

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What is BRCA gene ??

• Tumor suppressor gene.
• Important role in ds-DNA repair (radiation or
  chemotherapy).
• Improved survival in BRCA associated ovarian ca.
• Cass et al. cancer 2003.

15
Estimated Cancer Risks Associated with
BRCA1 and BRCA2 Mutations

• Different penetrance for different cancers

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Pre-test counseling

• Ask about concerns and reasons for seeking
  genetic counseling.
• Explain the limitations of the genetic testing.
• Implication of / - ve test.
• Risk.
• Benefits.
• Impact on her and her family.

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Risk of Breast Cancer
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Options for women with ve test

• Increased surveillance.
• Medical prophylaxis. What is the evidence?
• Surgical prophylaxis.
• Others.
• For both Breast and Ovarian cancer.

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1 - Increased surveillance

• A - Breast cancer
• Breast self examination (BSE)
• No trials of BSE in high-risk populations of
  women with known BRCA1 or BRCA2 mutations.
• It is potentially helpful when combined with
  other measures.
• Meta-analyses of randomized controlled trials
  indicate that BSE does not effectively reduce
  mortality.
• It is associated with higher rates of biopsies.
• Promotion of this modality may result in false
  reassurance or create anxiety

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Clinical breast examination (CBE)

• Recently been shown to have a low sensitivity
  (9) but a high specificity (99.3).
• It may detects few cancers that are not detected
  by imaging.
• In high-risk pts it reasonable to do it in
  conjunction with other surveillance measures.

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Imaging Mammography, MRI and Ultrasound

• Mammography
• Surveillance reduces mortality from breast cancer
  in women aged 50 and over.
• Limited evidence of benefit in 40 - 49 years old.
  
• No evidence of benefit in women under 40.
• In BRCA mutations ve , it showed a lower
  sensitivity
• - Higher breast density.
• - Interval malignancies.
• - Characteristics of tumors.
• - ?? Detect pre-cancerous lesions.
• Concerns about early/frequent radiation exposure.
  

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MRI

• It is more sensitive than mammography or
  ultrasound.
• Lower specificity.
• Combining MRI with Mamm/US has even
  sensitivity.
• Good modality for younger age group.
• Downsides
• - Cost.
• - Availability.
• - Need for additional
  investigations.
• Does it improve survival in high risk women ???
• It is not a replacement to mammography.

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Ultrasound

• Limited data regarding the effectiveness of US as
  surveillance modalities.
• Can not be used as a screening tool.
• A secondary evaluation only.
• it may increase the detection of small cancers
  when combined with mammography.

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Increased surveillance B - Ovarian cancer

• Pelvic exam
• ?? Sensitivity Specificity.
• low due to the anatomic location of the ovary.
• Ca -125
• Surface glycoprotein.
• Variable sensitivity in ovarian cancer.
• - 50 in stage I.
• - 60 in stage II.
• - 75 in stage III.
• Non specific.
• It is elevated in 1 of normal F and fluctuate
  during the M. cycle.

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Conditions associated with an elevated serum Ca
125

• Gynecologic malignancies
• Epithelial ovarian and endometrial cancers.
• Fallopian tube cancers.
• Adenocarcinoma of the cervix
• Non Gynecologic malignancies
• Breast.
• Colon.
• Lung.
• Pancreas.
• Gallup et al. South Med J 1997

• Benign Gynecologic conditions
• Adenomyosis.
• Benign ovarian neoplasms.
• Endometriosis.
• Functional ovarian cysts.
• Leiomyomata.
• Meigs' syndrome.
• Menstruation.
• Pregnancy.
• Ovarian hyperstimulation.
• Pelvic inflammation.

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Conditions associated with an elevated serum Ca
125 (Cont'd(

• Non Gynecologic conditions
• Liver disease and cirrhosis.
• Colitis.
• Congestive heart failure.
• Diabetes.
• Diverticulitis.
• Lupus.
• Mesothelioma.
• Pericarditis.
• Polyarteritis nodosa.
• Postoperative period.
• Previous irradiation.
• Renal disease.
• Sarcoidosis.
• Tuberculosis.
• Pleural effusion.
• Ascites.
• Gallup et al. South Med J 1997.

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• The average sensitivity of a single Ca-125 is
  70.
• The average specificity of a single Ca-125 is
  98.6.
• PPV 3 .
• 30 FP test for every ovarian cancer detected
• Sjoval et al.Gynecol Oncol 2002.
• Interval change in Ca-125 may improve the
  specificity.
• Improved specificity (99.9) if Ca-125 value
  doubled within 6 month.
• Zuraski et al. Int J Cancer 1998.
• PLCO study (NCI) will be completed in 2008 .
• Buys et al. Am J Obstet Gynecol 2005

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Other markers

• Proteomics
• OVX1
• Ca 72-4
• M-CSF
• Lysophosaditic acid
• Combination of tumor markers improves sensitivity
  specificity.

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Ultrasound

• Variable SS
• Sensitivity 80 - 100 .
• Specificity 94 - 99 .
• 12709 pts.
• A total of 98 women with adnexal masses, 49 gtgtgt
  surgery
• - 37 benign ovarian tumors
• - 12 Gynecologic malignancies ( III A-C
  ).
• In (High risk pts.) poor tool to detect early
  ovarian cancer.
• Fishman et al. Am J Obstet Gynecol 2005.
• 14469 pts. 180 with abnormal US gtgtgt Sx
• - 11 gt I.
• - 3 gt II.
• - 3 gt III.
• In (low risk pts.) it showed a higher detection
  rate for early ovarian cancer.
• Van Nagell et al. Gynecol Oncol 2005.

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Combined approach (Ca 125 US)

• 22000 PM female had Ca125 followed by US.
• Surgical exploration if abn. US gtgt
• Specificity 99.9 and PPV 26.8 (4
  explorations for every ovarian cancer case).
• A fellow up report by the same author showed
• An improved suvival (7 years f/u) in the screened
  pts.
• 73 M vs 42 M (was not significant).
• Jacobs et al. BMJ 1993.
• Jabobs et al. Lancet 1999.

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• PLCO study (NCI) will be completed in 2008 .
• In high risk group for HBOC
• In a multicenter cohort study
• Patients were drawn from 68 families. A BRCA1
  mutation was detected in 53 of these families,
  and a BRCA2 mutation in 15 families.a
• age 30-35. 138 relatives from the 68 families
  (37M).
• Six advanced ovarian cancers were detected.
• Vasen, et al., 2005(2005) et al. Gynecol Oncol
  2005.
• 312 pts. (4 years)
• 10 women with an abn. Screening.
• Three screening carcinomas and one interval
  carcinoma detected (advanced).
• Sensitivity 40 Specificity 99.
• Five occult tumors with early ovarian cancer
  (PBSO).
• Oliver et al. Gynecol Oncol 2006.

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2 - Chemoprevention

• A - Breast cancer
• SERMs
• Tamoxifen
  Raloxifene
• Estrogen receptors agonist / antagonist (site
  dependant)

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Mixed Estrogenic Agonist and Antagonist Effects
of Tamoxifen (SERM)
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• Tamoxifen
• NSABP P-1 and IBIS and most of the trials
• A statistically significant decrease in the risk
  of invasive and noninvasive breast cancer (DCIS
  and LCIS).
• The effect was in BRCA 2 gt BRCA 1.
• 50 reduction was found (RR0.5) in high risk
  pts.
• 50 reduction in contralateral breast cancer in
  BRCA mutations pts.
• will it lead to a reduction in overall or breast
  cancer-related mortality ??
• The side effect profile was a concern in the
  studies.
• It is approved in the United States for the
  prevention of breast cancer for women at high
  risk for breast cancer.
• Metcalfe et al J Clin Oncol 2004.
• Pierce et al. J Clin Oncol 2006.

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Rates per 1000 women of invasive and noninvasive
breast cancer in NSABP P-1 study
36

• Raloxifene
• The STAR trial and others gtgt equal efficacy to
  Tamoxifen.
• No evidence it prevent pre-invasive disease
  (DCICLCIC).
• Lower side effect profile in VTE disease.
• Not yet approved for chemoprevention drug in
  breast canser.
• Land et al.JAMA 2006.

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A - Ovarian cancer

• OCP
• Decrease ovarian cancer (up to 50 reduction if
  used ) for 5 years RR 0.5
• Similar findings in BRCA mutants .
• Dual impact of OCP ( Breast/Ovarian cancers ).
• Narod et al. N Eng J Med 1998.

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Pregnancy and Breast feeding

• 1601 BRCA ve (850 with breast cancer)
• 14 reduction in Breast cancer with each term
  pregnancy.
• 965 BRCA cohort and matched control
• BRCA-1 Carriers with H/O breast feeding for 1year
  got odds ratio of 0.55.
• Was not applicable to BRCA-2 (OR 0.95).
• 5 years of OCP use term pregnancy may
  Ovarian cancer by 70 (RR 0.3).
• Andrieu et al. J Natl Cancer Inst. 2006.
• Jernstrom et al. J Natl Cancer Inst. 2004.

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3 - Risk reducing surgery

• A - Breast cancer
• Bilateral mastectomy.
• Contralateral mastectomy
• Risk by 90 .
• Risk by 95 if with BSO.
• Simple mastectomy.
• Subcutaneous mastectomy.
• Skin sparing mastectomy.

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Risk reducing surgery (mastectomy)
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B - Ovarian cancer

• BSO
• Ovarian Cancer by 90 .
• Breast Cancer by 50 .

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Family History and Risk of Breast Cancer
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Recommendations from the United States Preventive
Services Task Force

• A - For non-Ashkenazi Jewish women
• Two first-degree relatives with breast cancer,
  one of whom was diagnosed at age 50 or younger.
• A combination of three or more first or
  second-degree relatives with breast cancer
  regardless of age at diagnosis.
• A combination of both breast and ovarian cancer
  among first and second-degree relatives.
• A first-degree relative with bilateral breast
  cancer.
• A combination of two or more first or second
  degree relatives with ovarian cancer, regardless
  of age at diagnosis.
• A first or second-degree relative with both
  breast and ovarian cancer at any age.
• History of breast cancer in a male relative.

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Recommendations from the United States Preventive
Services Task Force (Cont'd)

• B - For women of Ashkenazi Jewish descent
• Any first-degree relative (or two second degree
  relatives on the same side of the family) with
  breast or ovarian cancer .

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Kaiser Permanente criteria for consideration of
BRCA1/2 genetic testing

• A. Women with breast cancer plus one of the
  following
• ltage 30.
• ltage 50, and with at least one relative who
  developed breast or ovarian cancer ltage 50.
• At any age, and with a family history of at least
  2 relatives with breast cancer ltage 50 or at
  least one relative with ovarian cancer.
• Both breast and ovarian cancer or multiple
  primary breast cancers.
• Ashkenazi Jewish women with breast cancer before
  age 40 or ovarian cancer at any age.
• B. Women with ovarian cancer plus one of the
  following
• Breast cancer in at least two relatives.
• Ovarian cancer in at least one relative.
• First or second degree relative.
• Kaiser Permanente Guideline. BRCA genetic
  screening, 1998.

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Kaiser Permanente criteria for consideration of
BRCA1/2 genetic testing

• C. Men with breast cancer plus one of the
  following
• Breast and/or ovarian cancer in at least one
  relative
• D. Women or men without personal history of
  breast cancer, but with family history of breast
  and/or ovarian cancer plus one of the following
• 1st degree relative with a known deleterious
  mutation.
• At least two relatives with breast cancer, both
  diagnosed ltage 50 and at least one a first degree
  relative.
• At least three relatives with breast cancer, 1
  diagnosed ltage 50.
• Ovarian cancer in at least two relatives.
• Breast and ovarian cancer, each in at least one
  relative.
• First or second degree relative.
• Kaiser Permanente Guideline. BRCA genetic
  screening, 1998.

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Risk Assessment Criteria for Inherited Breast -
Ovarian Cancer Syndrome

• A - Non-Jewish families ( Any of the following )
  
• One case of breast cancer 40 y in a FDR or SDR.
• One FDR or SDR with breast and ovarian cancer, at
  any age.
• Two or more cases of breast cancer in FDRs or
  SDRs if one is diagnosed at 50 years old, or is
  bilateral.
• One FDR or SDR with breast cancer at 50 years
  old, or bilateral and one FDR or SDR with ovarian
  cancer.
• Three cases of breast and ovarian cancer (at
  least one case of ovarian cancer) in FDRs and
  SDRs.
• Two cases of ovarian cancer in FDRs and SDRs.
• One case of male breast cancer in an FDR or SDR
  if another FDR or SDR has (male or female) breast
  or ovarian cancer.
• FDR first-degree relative SDR, second-degree
  relative.
• Adapted from Hampel, H, et al. J Med Genet 2004.

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Risk Assessment Criteria for Inherited
Breast-Ovarian Cancer Syndrome (Cont'd)

• B - Jewish families ( Any of the following )
• One or more cases of breast cancer 50 years old
  in an FDR or SDR.
• One or more cases of ovarian cancer at any age in
  a FDR or SDR.
• One or more FDRs or SDRs with breast cancer at
  any age, if another FDR or SDR has breast and/or
  ovarian cancer at any age.
• One or more cases of male breast cancer in an FDR
  or SDR.
• FDR first-degree relative SDR, second-degree
  relative.
• Adapted from Hampel, H, et al. J Med Genet 2004.

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Points to discuss before deciding to have genetic
testing for Breast / Ovarian cancer

• What are the risks of cancer associated with a
  gene alteration?
• Who should have genetic testing?
• What are the possible results of genetic testing?
• What do the results mean?
• What are the limits of genetic testing?
• What are the potential benefits of genetic
  testing?
• What are the potential risks of genetic testing?
• What needs to be done before testing?
• What are the options for reducing the risk of
  cancer if testing is positive?

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• Options for breast and ovarian cancer
  surveillance and prophylaxis in BRCA mutation
  carriers
• Modality
  Comments
• I A - Breast Screening
• Mammography Every 6 to 12
  months, begin age 25
• MRI Annually
  in selected patients
• Clinical breast exam Two to four times
  yearly, begin age 20-25
• Self breast exam Monthly, begin
  at age 18
• B - Chemoprevention
• Tamoxifen
• C -Risk reducing surgery
• Mastectomy
• BSO

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Options for breast and ovarian cancer
surveillance and prophylaxis in BRCA mutation
carriers (Cont'd)

• II A - Ovarian Screening
• TV ultrasound Once - Twice
  yearly, begin age 35
• Serum CA-125 Once - Twice
  yearly, begin age 35
• B - Chemoprevention
• Oral contraception
• C - Risk reducing surgery
• BSO
  Recommended after childbearing
• TL
• D - Others
• Pregnancy

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Estimated impact of options on breast and
ovarian cancer risk in women with inherited
genetic mutations
53
History items necessary to identify possible
BRCA1 or BRCA2 carriers
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Flow diagram depicting the process of risk
evaluation and management of women with a family
history of breast cancer
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Risk factors for ovarian cancer

• Indicates probability for ovarian cancer in a
  50-year-old woman.
• Gotlieb et al. Surg Oncol 2000 Ness et al. Am J
  Epidemiol 2002

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American Society of Clinical Oncology criteria
for high risk of ovarian cancer (based upon
family history)

• First degree relative diagnosed with ovarian
  cancer before age 40.
• Single first degree relative diagnosed with
  breast and ovarian cancer, with one of these
  cancers diagnosed before age 50.
• Two cases of ovarian cancer among first and
  second degree relatives of the same lineage.
• Two cases of breast cancer and one case of
  ovarian cancer among first or second degree
  relatives of the same lineage.
• One case of breast and one case of ovarian cancer
  among first or second degree relatives of the
  same lineage if either breast cancer diagnosed
  before age 40 or ovarian cancer diagnosed before
  age 50.
• Two cases of breast cancer among first or second
  degree relatives of same lineage, both of which
  were diagnosed before age 50.
• Two cases of breast cancer among first or second
  degree relatives of same lineage, one of which
  was diagnosed before age 40.

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• Recommendation for Breast Cancer Surveillance by
  Breast Examination1BSE is not recommended as a
  routine approach to surveillance for breast
  cancer.2Women who wish to use BSE as a primary
  surveillance option should be counselled about
  its benefits and limitations so that they have
  realistic expectations. If they continue using
  this approach, they should be offered information
  on the technique. CBE should be offered at
  six-month intervals.3Regular CBE is not
  recommended as a sole cancer surveillance
  modality. It should be performed as part of an
  individualized surveillance program that includes
  imaging appropriate to the patients age, breast
  density, and preferences.4Occasionally, breast
  cancer surveillance is indicated in a woman under
  age 30 (e.g., if there is a history of breast
  cancer under age 30 in the family). In this
  setting, CBE should be combined with MRI.5After
  prophylactic mastectomy, regular clinical
  examination of the chest wall, reconstructed
  breast, or breast implant is recommended.6Surveill
  ance of pregnant women should consist of CBE
  every three months with ultrasound for any
  questionable findings and mammography plus
  ultrasound for any suspicious findings.7For women
  who choose not to breast-feed, CBE should resume
  six months after delivery. Otherwise, it may be
  resumed three months after weaning.

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• Recommendation for Breast Cancer Surveillance by
  ImagingClass1In general, no imaging modality
  should be used in isolation, particularly in
  younger women and/or those with dense breast
  tissue. See exception, recommendation No.2
  below.I2Mammography is not recommended for
  screening women under 30 years of age because of
  concerns relating to a potential radiation risk.
  MRI should be used if imaging is considered
  clinically indicated.I3For women aged between 30
  and 69 years, mammography should be done annually
  and complemented by MRI where it is
  available.B4In women 70 years and over, the
  decision to continue screening by imaging depends
  on the womans health, life expectancy, and
  preference.I5All women should be counselled
  regarding the current evidence relating to
  different imaging modalities and should receive
  written information on their benefits, radiation
  risks, and the potential psychological impact of
  false positive or false negative findings.I6After
  mammography, a woman and her physician should be
  informed of her breast density score, as this may
  influence other surveillance and treatment
  options.I7Routine imaging is not recommended for
  women who have undergone bilateral prophylactic
  mastectomies and/or breast reconstruction.I8Mammog
  raphy and MRI are not recommended for screening
  during pregnancy or lactation.I9Where possible,
  imaging should ideally be delivered by an
  experienced team of radiologists with experience
  in all three imaging modalities. The imaging
  centre should be accredited by the Canadian
  Association of Radiologists.I

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• Recommendation for Ovarian Cancer
  Surveillance1With currently available
  technologies, ovarian cancer surveillance is not
  routinely recommended.2Women should be counselled
  on the limitations of current surveillance
  methods.3Recognition of ovarian cancer symptoms
  should be emphasized for both the patient and the
  clinician.4If, despite counselling, a woman
  strongly prefers surveillance, it should be
  performed every 6 to 12 months and should be
  accompanied by clear advice on the importance of
  acting on suspicion of symptoms.5If a woman
  strongly prefers surveillance by ultrasound, it
  should be scheduled to take place immediately
  following menses in premenopausal
  women.6Individualized psychosocial support should
  be made available to all women whether or not
  they opt for surveillance.

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• abdominal swelling or abdominal pain
• vaginal bleeding between periods or after
  menopause
• bloating, gas, indigestion or cramps
• pelvic pain
• loss of appetite
• feeling full after a small meal, or feeling full
  very easily
• changes in bowel or bladder habits
• weight loss or weight gain

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