Good afternoon, my name is Patty Tenofsky and I am a breast surgeon at the Via Christi Clinic. I will be discussing Breast Cancer Genetic Testing- It is right for you?
Angelina Jolie said yes it was right for her, making this a very timely and popular recent topic.
This is Angelina Jolie’s mother – Marcheline Bertrand pictured in 2001 at age 50, about the time she was diagnosed with ovarian cancer.
This is a quote from her in a letter to the editor in the New York Times, 5/14/13. Her family history is quite extensive. Her mother had previously battled breast cancer, but then developed ovarian cancer at age 49 and died of the disease at age 56Her GM died of ovarian cancer as well at age 45Her m aunt (Her mother’s sister) died of breast cancer at age 61 just this year.Angelina Jolie is 37 years old and does not have cancer, but she chose to have preventative double mastectomies when she found out that she had the BRCA 1 gene. She has said in interview that she plans to have her ovaries removed when she is certain she does not want to have any more children.
Another famous actress Christian Applegate was being followed very carefully for breast cancer because of family history. She was diagnosed with an early stage of breast cancer at age 36. She was also found to have the BRCA 1 gene like Angelina Jolie. She chose to undergo bilateral mastectomies as well.
In order to know about the breast cancer gene, we first have to know a little about breast and ovarian cancer statistics. In the U.S., there is 200,000 cases of breast cancer/year. That is a 10-13% lifetime risk of developing breast cancer if you are a woman. The two most important risk factors for breast cancer is being a woman and getting older.Other risk factors include FH, Early age at first menstrual cycle, late or no pregnancy, hormone replacement medication, alcohol use, obesity, and lack of exerciseThere are approximately 25,000 cases of ovarian cancer per year which gives a lifetime risk of <2%
The vast majority of breast cancers will occur in women who have NO family history of breast cancer and are not linked to heredity or genetics. These nonhereditary cancers are called Sporadic Breast Cancers and are the most common type of breast cancer (see pie chart). The risk of breast cancer increases as a woman ages. It is less likely to occur before age 50. If you live to 90 then your risk of developing breast cancer is 1 in 8 or about 13% even with no family history. Therefore, ALL women over age 40 should be screened for breast cancer with mammograms, even if they have no family history.25% of woman will develop breast cancer with a family history , but there is no known genetic abnormality. Only 10% will develop breast cancer with a mutation of the BRCA gene. It is rare.
The official name of the BRCA mutation is the Hereditary Breast and Ovarian Cancer Syndrome. The syndrome is characterized by a significantly increased risk of breast and ovarian cancer, but it is RARE: only 1 in 800 people will have it. That means we would have to have 8 roomfuls of people like you to find one mutation on average. BUT, it’s more common if you have a Jewish background – which will discuss in a bit. You will learn that most cases are caused by a mutation in the BRCA 1 or 2 gene. We will discuss it’s characteristics, testing and treatment. Hopefully at the conclusion of our discussion you will understand more about the decision Angelina Jolie made and if genetic testing is something you need to be concerned about.
One of the easier mutations to understand is sickle cell anemiaIn Sickle Cell Anemia there is only 1 letter that is out of place and it completely alters the person’s Red Blood Cell.If you look at the top normal chain – the letters spellGTG- ValineCAC-HistidineCTG-LeucineACT-ThreonineCCT-ProlineGAG-Glutamic AcidGAG-Glutamic AcidNow look at the Lower DNA chain: It is all the same except a T is substituted for an A and GTG spells valine not Glutamic acid. That alters the RBC shape so that it is Sickled instead of donut shaped. It cannot carry oxygen as well and therefore the patient develops sickle cell anemia.
The purpose of the previous gene was to make the Red Blood Cells that carry our oxygen. The purpose of the BRCA gene on the other hand is to make proteins that fight changes in your DNA that can occur when normal cells divide. These proteins seek out and eliminate errors that occur. In other words it is a cancer fighter gene. If a change occurs in your normal DNA, then the cell and DNA start to divide rapidly and can become cancer cells. Think of them as speeders on the highway. The purpose of BRCA is to act as a highway patrol man to stop the speeders and not allow them to proceed on to become cancer. There are many of these repair highway patrolmen throughout your DNA – this is just one of them. If your BRCA gene is mutated – it is like the highway patrolmen has a flat tire and is stuck on the side of the road. He can’t catch the speeders and they can go on to become cancer. If the BRCA gene isn’t right this alteration interferes with normal gene activity and makes the person with the altered gene more susceptible to developing breast or ovarian cancer.
This type of mutation is considered autosomal dominant which means that if one of your parents have the gene then you have a 50:50 chance of having the mutation.We are all born with 2 copies of our genes. One from our Mom and one from our Dad. In this slides the little b means normal BRCA gene and the capital B means a mutated BRCA gene. The father has 2 normal BRCA genes and the Mother has one normal and one mutated BRCA gene. The mutated gene is dominant, so the mother has the BRCA syndrome.Look at the 4 children now:1st Daughter – She got the mutated gene from her mother and the normal gene from her father – she is therefore BRCA +2nd Daughter – Normal genes from both parents and therefore she is BRCA-3rd Son – He got the mutated gene from his mother and is therefore BRCA +4th Son – He got two normal genes and is therefore BRCA –Statistics say that if there are 4 children two would be positive and two would be negative. But each child has a 50:50 chance. You could flip a coin 4 times and turn up heads each time. So it would be possible that all 4 could be positive or negative. The only way to know would be to test.
These are the “Red Flags” for women and men who do not have cancer, but are at risk – like Angelina Jolie.
Research on women who have a certain type of cancer called triple negative has shown a very high risk of carrying the breast cancer gene – even without a family history. Triple negative means that the cancer was NOT sensitive to estrogen, progesterone, or Herceptin. If a women has a triple negative breast cancer under age 60 then she is a candidate for testing.Unfortunately, Pancreatic cancer has also been linked to this gene. If two or more people in the family have had pancreatic cancer, this could be a criteria for testing and the gene could be found in 17-19% of those families.The risk of pancreatic cancer is only 0.05 % by age 50 and is .5% by age 70.With the BRCA gene it increases that risk to .5% and 5%Overall it increases the risk of pancreatic cancer 3.5 to 10x over the general population.If you have pancreatic cancer and no family history your risk of having the gene is 5-10%SO the BRCA gene has been linked to breast, ovarian, pancreatic and prostate cancer in men
Now that we have a positive BRCA test there are three main management strategies. SurveillanceChemopreventionProphylactic surgery
If your ovaries are removed, then you will go into menopause. Is it safe to take HRT when you still have breasts with the BRCA gene. Surprisingly it is safe for a short period of time 10-15 years or until natural menopause age. But, only with unopposed estrogen NOT with combination with progesterone. Unfortunately unopposed estrogen increases the risk of uterine cancer. Adding a hysterectomy to BSO would eliminate that risk but is a bigger operation.
The last picture showed mastectomies without reconstruction. Reconstruction has come a long way. In this picture the woman had a mastectomy on one side and has her native breast on the other. Her nipple was removed. Notice that the match is pretty good and the newly created nipple looks fairly normal.
Even newer is nipple sparing mastectomies which in smaller breasted women can give an exceptionally good cosmetic result with preventative surgery. The incision is hidden below the breast so it looks like the breasts are scarless.
Because of concern that genetic mutations could be potentially used against persons who have them, President George Bush signed into law the GINA legislation (Genetic Information Nondiscrimination Act). It is considered a civil rights law and protects persons against losing their health care or their job due to finding a genetic mutation.
If you have red flags – and are concerned about the BRCA mutation – what do you do?Talk to your PCPThey may test or send you to a breast specialist to discuss it further.If your family history is extensive and the test is negative it may be beneficial to see a genetic counselor to see if there are other rare mutations such as p53 or pten. The closest breast genetic counselor is Dr. Klemp in KC
Let’s do a case together: This is Rachel and she is 40. This is her family tree. She has 2 sisters who are affected by cancer – breast and ovarian, a niece with breast her own mother with ovarian. Her mother has passed. Rachel is at significant risk for the BRCA gene mutation. Rachel’s sisters were tested and were positive so they want to test Rachel at the same site of mutation has her sisters.
Here is her test result. She unfortunately is also positive. Remember we get a normal gene from our one parent and the bad gene from the other parent. This is her DNA test showing the deletion of AG at the 185 position. This is one of the most common BRCA one mutations known.
She is positive so let’s discuss what to do about her ovarian cancer risk which is 40-50%.The recommendation would be ovarian removal with or without a hysterectomyOvarian removal decreases risk of breast cancer by over 50%Estrogen is okay but will increase her risk of uterine cancer if she doesn’t have a hysterectomy
Now we discuss her breast options. Remember her risk of cancer is 50-87% depending on what she does with her ovaries and if she goes on tamoxifen.Her options are:ScreeningScreening + tamoxifenPreventative mastectomies.
Her sister both tested positive. Her Brother can consider testing. If he is negative then he can not pass it to his daughter which can lower her anxiety of developing breast and ovarian cancerAs for Rachel’s children – they all have a 50:50 chance of inheriting the gene.
Heather is 38 and has a paternal aunt who had breast cancer at age 41. Is Heather at risk and who would you test if you could test any of these patients?
Why test her aunt – Because if she is positive then her 3 siblings could be tested to see if they inherited the gene. It would also help heather know that the gene does run in her family Why test her Dad first? Because there are three children and if he is positive they are all at risk but if he is negative then none are at risk.
The BRCA gene is rare, but can significantly increase the risk of both breast and ovarian cancer in patient’s who have this mutation.In patient’s who meet criteria, the test can easily be doneIf positive, there are many options available to follow and potentially prevent cancer
This a poster from an old movie staring Madeline Kahn and Gilda Radner. (FIRST FAMILY, 1980) Both women were Jewish and both died of ovarian cancer at young ages. It is very likely that they both had BRCA mutations, but they died before science discovered the genes. The hope is that now that we know about these mutations, we can test and hopefully we can prevent deaths such as with these women.
Breast cancer genetic testing: Is it right for you?
Breast cancer genetic testing:
Is it right for you?
Patty Tenofsky, MD FACS
October 8, 2013
Angelina Jolie‘s decision
• “The truth is I carry a „faulty‟ gene, BRCA 1,
which sharply increases my risk of
developing breast cancer and ovarian
• Her mother had previously battled breast cancer, but
then developed ovarian cancer at age 49 and died of
the disease at age 56
• Her Grandmother died of ovarian cancer at age 45
• Her maternal aunt died of breast cancer
• She chose to have bilateral preventive double
• She plans to have her ovaries removed once she has
decided that she does not want any more children.
• She was diagnosed
with breast cancer,
and then found to
have the BRCA 1
gene at age 36
• She chose to have
Breast & Ovarian Cancer
• 200,000 cases of Breast Cancer/year in the U.S.
– Lifetime risk is around 10-13%
– Risk factors
• Being a woman and getting older
• Family history, early menarche, late or no
pregnancy, hormone replacement, alcohol use,
obesity, lack of exercise
• 25,000 cases of Ovarian Cancer/year in the U.S.
– Lifetime risk is <2%
Most Women Develop Breast Cancer
WITHOUT a Family History
Hereditary Breast & Ovarian
Cancer Syndrome (BRCA)
• Characterized by significantly
increased risks for breast and ovarian
– 1:800 people in the general population
have a BRCA genetic mutation
– 1:40 people of Eastern European Jewish
descent will have the gene.
• Most cases are caused by a BRCA1
or BRCA2 mutation
• Clinical testing is available to identify
individuals with mutations
• Double Helix
• Made up of 4 building blocks
that get together in pairs
– Adenine (A), thymine (T) ,
guanine (G), cytosine (C)
• These 4 ―letters‖ create a
―word‖ that codes for a certain
amino acid. Amino Acids are
the building blocks of our
proteins – these proteins are
what lead to our characteristics
• Misplaced letters or words can
lead to severely incorrect
Sickle Cell Anemia – only
one base code incorrect
What is the purpose of our
normal BRCA genes?
• BRCA gene‘s purpose: It codes for proteins
that function to fight changes in your DNA that
can lead to breast and ovarian cancer.
– Changes may occur in your DNA which can
lead to cancer when normal cells divide and
are exposed to cancer inducing substances
– BRCA gene is therefore a cancer fighter
• BRCA gene that is mutated: The body is less
able to find and repair mistakes and cancer is
• 1990 – Families who had many women
with breast and ovarian cancer underwent
DNA studies and scientists identified the
first gene associated with breast cancer:
BRCA 1 on Chromosome 17.
• 1994 – BRCA 2 gene was discovered on
• Jewish families were found to have a
much higher rate of the gene mutations.
• By the late 1990s – we were able to test
for the gene mutations.
• The majority of people tested have a unique mutation –
one that is specific to them and their family.
– Hundreds of unique mutations have been found.
– Some are recurring, however.
• Ashkenazi Jewish population has 3 specific genes that
recur: Two BRCA1 and One BRCA2
– 185delAG; 5382insC; 6174delT
– 1996 study by Muto,et.al:
• 19% of Jewish women with ovarian cancer in Mass and
Israel had 185delAG
• 12% of breast cancers in Ashkenazi Jews are attributable to
BRCA 1 or BRCA 2 (Journal of National Cancer Institute,
– Genes come from groups of people who do not go
out of their small groups to find a mate
BRCA Mutation Increases Breast
and Ovarian Cancer Risks
Science 2003: 643-646
JCO 2005 23 (8): 1656-63
by age 50
by age 70
by age 70
BRCA Mutation Increases Risk
of Second Breast Cancer
Gynecol Oncol. 2005 Jan;96(1):222-6
after 5 years
by age 70
Ca Epi Biomarkers Prev. 1999;8(10):855-61
Risks in Men With a
by age 80
by age 80
*Risks refer to BRCA2 mutation carriers.
Risks for male BRCA1 mutation carriers are less characterized
―Red Flags‖ for Hereditary Breast
and Ovarian Cancer Syndrome
• For Women or Men with a newly diagnosed breast
– Diagnosed at < 45 with or without FH
– Diagnosed at 45-50 with at a least one close blood relative
with breast cancer and/or at least one close blood relative
with ovarian cancer. Some would test all women in their
– Bilateral breast cancer
– Diagnosed >50 with two or more close blood relatives with
breast or ovarian cancer at any age
– Close male relative with breast cancer
– Personal history of ovarian cancer
– Specific ethnicity associated with founder mutations
(Ashkenazi Jewish, Icelandic, Swedish, Hungarian)
especially along with family history
―Red Flags‖ for Women & Men
who do not have Cancer
• Women or Men who do not currently have cancer are at
– Family member with known BRCA 1 or BRCA 2 mutation
– Previous history of breast cancer from the previously stated risk
factors. (The test has only been available for ten years)
– Personal history of ovarian cancer
– One or more close male relatives with breast cancer
– Two or more female relatives with breast cancer especially at age <50
on either maternal or paternal side
– One or more close female relatives with ovarian cancer
– Specific ethnicity as stated previously along with family history
• REMEMBER: The family member who had the cancer
diagnosis should always be tested FIRST if possible.
Family History Considerations
• One-half of BRCA carriers inherit the
mutation from their father
• Ovarian cancer is a very important
• Early onset breast cancer is more
important than the number of affected
• Triple Negative Breast Cancer:
– Research has shown that women who have breast
cancer not sensitive to hormones or a drug called
Herceptin are more inclined to have the BRCA
gene even without a family history.
– Testing is indicated if you have triple negative
breast cancer under age 60
• Pancreatic Cancer:
– If two or more people in the family have had
pancreatic cancer that may be a criteria for testing
– The gene will be found in 17-19% of those families
Prevalence of BRCA
Mutations – Non Jewish
in one relative,
<50, no ovarian
No breast cancer
<50 or ovarian
Prevalence of Mutations in
Ashkenazi Jewish Individuals
<50, no ovarian
No breast cancer
<50 or ovarian
in one relative,
Negative Test (no
• Does not mean that the patient cannot
or will not develop breast cancer.
• Only means that they are not at risk
for developing hereditary breast
cancer related to the BRCA mutations
for which they were tested.
Family History & BRCA
Positive and Negative
30 50 70
Positive for deleterious
Risk based on family
Negative for familial
Reprinted with permission from Ponder B: Genetic Testing for Cancer Risk. Science 1997; 278:1050-4.
Copyright 1997 American Association for the Advancement of Science
• Prophylactic surgery
*Individual risk reduction may vary
based on personal health history
• Screening for Familial Ovarian Cancer
– Poor Survival
– Most cancers are diagnosed at Stage 3 and 4
– Transvaginal U.S. & CA 125 are ineffective in
detecting tumors at a sufficiently early stage to
influence survival. Only detect 57% stage 1
– Ovarian cancer is 1/8 as common as breast, but
3 times more lethal
• Should be followed by an OB/GYN
• Recommend bilateral salpingo-
oophorectomy (BSO) at age 35 or after
childbearing is complete
– ~96% ovarian cancer risk reduction in
– Can reduce breast cancer risk by up to
68% for both BRCA1 and BRCA2
mutation carriers if the woman is pre-
Clin Oncol. 2005 Mar
Prophylactic Ovarian removal -
Bilateral Oophorectomy (BSO)
• Does HRT increase cancer risk after
oophorectomy (ovarian removal)?
– No measurable effect with ―short term
usage‖ of Estrogen alone
– Estrogen until menopausal age – 50
• Unopposed estrogen does increase the
risk of uterine cancer. Adding a
hysterectomy to the BSO would
eliminate that risk, however, a much
Surveillance for Breast Cancer
Procedure Age to begin Frequency
Breast self-exam 18 yrs Monthly
25 yrs Twice a year
Mammography 25 yrs Yearly
MRI 25 yrs Yearly
Screening with MRI in
• JAMA, 2004: MRI most
sensitive in detecting cancer
and can decrease mortality
in high risk women.
• Adequacy of screening
women with BRCA mutations
with only Mammo was not
shown to be good enough
even if the women had fatty
or low-dense breasts.
• Waiting a year between
screening is too long –
BRCA patient‘s cancers grow
faster than sporadic cancers.
• Selective Estrogen Receptor Modulator (SERM)
– it blocks hormones from affecting breast cells
• Affected BRCA carriers: 50% decrease for
contralateral breast cancer
• Unaffected BRCA2 carriers: 62% decrease in
the risk of cancer
• Unaffected high-risk: 45% decrease
• Risks – increased risk of uterine cancer and
clotting. Low risk in women who took the
medication under age 50
Int J Cancer.
• Greater than 90% breast
cancer risk reduction
in BRCA carriers. May be
has high as 95-98%
• 100 women having
prophylactic surgery 1995-
• 18/100 had abnormal lesions
• 3 invasive cancer
• 8 in situ cancer
• 7 ADH
•Eur J Surg Oncol 2008,
Reconstruction after Mastectomy
has come a long way
Postoperative left mastectomy – left latissimus flap and implant
• Federal and state laws prohibit the use of
genetic information as a ‗pre-existing
– Federal HIPAA legislation
– The majority of states have additional
• Over 175,000 clinical tests performed to date
• No documented cases of genetic
• U.S. President George
W. Bush signed into law
May 21, 2008 the first
civil rights legislation of
the new millennium, the
• GINA is the first and only
federal legislation that will
based on an individual‘s
genetic information in
How do you test?
• Talk to your Primary Care Physician
– Your Doctor may feel comfortable with the discussion
and go ahead and test you; or they may send you to a
breast specialist to discuss your risks and whether the
test is right for you.
– The test is either blood or saliva
– The results are available in 2-3 weeks if insurance
• Genetic Counselors
– If your BRCA test is negative but you have a very strong
FH – may need additional testing
• Other rare mutations exist – p53. pTEN/MMAC1
• Dr Jennifer Klemp in Kansas City: 913-588-7750
• Her risk of ovarian cancer is 40-50%
• She is 40 and has completed child-
– Recommend: bilateral oophorectomy
(ovary removal) +/- hysterectomy
– Ovarian removal decreases her risk of
breast cancer by over 50%
– Unopposed Estrogen for 10 years okay,
but it increases her risk of uterine cancer if
she doesn‘t have a hysterectomy
Rachel – Breast
• Risk of Breast Cancer: 50-87%
– Increase screening with Mammogram and
MRI yearly separated by 6 months
– Above + Tamoxifen for 5 years to
decrease her risk by 50%
– Bilateral prophylactic mastectomies with
or without reconstruction
Rachel – Family
• Consider testing her
Brother – If he tests
Negative then his
inherit the gene from
• Rachel‘s Children –
each has a 50:50
chance of inheriting
• Heather is at risk because her p Aunt
had breast cancer at a young age
• The best person to test would be
– Heather‘s Aunt – the person affected by
• If her aunt is positive then I would test
– Heather‘s Father
• If he is positive then I would test
• Heather‘s aunt was positive
• Heather‘s Dad was negative
• What is Heather‘s risk?
– 10-13%, same as the general population
• Does she or her brother or sister need to
– No, their Dad was negative
• Does her uncle and other two aunts need
to be tested?
– Yes, they all have a 50:50 chance of having the
• The BRCA gene is rare, but can
significantly increase the risk of breast and
ovarian cancer in patient‘s who have this
• In patients who meet criteria, the test can
easily be done.
• If positive, there are many options
available to follow and potentially prevent