RECURRENT LIPOSARCOMA

The other day we were in a conference discussing a case of Liposarcoma.  The man was in his 50ies and had been referred to the University surgeon for an extensive abdominal Liposarcoma that needed further resection. The disease had been resected at least twice by the community surgeon before, it had returned with significant peritoneal and pelvic infiltration.  Interval between resections had been in years, but now it was in months.  Clearly, the disease has packed further gene abnormalities now that it is evidently metastatic.  Let me take this back, because despite the widespread invasion in the abdomen, there was no tissue invasion.  There were no clear liver, lung or brain invasion.  This disease was killing a man before our eyes because of clear infiltration of abdominal tissues.
Because of the interval between surgeries, the Oncologist argued that this is a low grade tumor and may not be handled with standard chemotherapy and I strongly believe he was right.  My case with Angiosarcoma did not budge with Gemzar, Taxol followed by MAID,  I am trying AVASTIN ALONE now!
But returning to the case, the hospital and the surgery department are now breathing on the neck of the surgeon because they do not see the point of putting the patient through very expensive surgeries followed by  costly ICU stays every few months. I guess there are potential liabilities linked to the exercise. Particularly because the surgeries were done when this patient was with evident big progression of disease, but asymptomatic still.   Oncologist and Surgeon alike argued we should not wait for symptoms, because it could be inoperable by then, and an aggressive surgery plan is helpful in these local diseases.
With standard chemotherapy out the only thing left is Target therapy as an effective option.  We did not get help from the pathology department since no genetic abnormality testing is done (this is not Mayo or Harvard.  DR KRIS who speaks of gene panels in lung cancer does not live here).  And Votrient, the only  FDA approved drug is indicated in those who failed chemotherapy.  Basically, you have to put this man on chemotherapy that you know will harm him unnecessarily in order to get to Votrient (Pazopanib), an anti-VEGFR(s), Anti-c-KIT, anti-PDGFR a/Beta.  with 3-4 months advantage over placebo.
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FDA NEWS RELEASE

For Immediate Release: April 26, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA approves Votrient for advanced soft tissue sarcoma
The U.S. Food and Drug Administration today approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.
Votrient is a pill that works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.
A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.
“Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”
The safety and effectiveness of Votrient was evaluated in a single clinical study in 369 patients with advanced soft tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive Votrient or a placebo. The study was designed to measure the length of time a patient lived without the cancer progressing (progression-free survival). The disease did not progress for a median of 4.6 months for patients receiving Votrient, compared with 1.6 months for those receiving the placebo.
The most common side effects in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.
Votrient was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. Votrient was first approved in October 2009 for the treatment of advanced kidney cancer.

Votrient is marketed by GlaxoSmithKline of Research Triangle Park, N.C.
For more information:
FDA: Office of Hematology and Oncology Products
FDA: Approved Drugs: Questions and Answers
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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For the sake of argument

1. In this man we know it is a Liposarcoma

therefore the primary deficiency is in the handling of lipid.  Insulin Receptor, may be?  IGFR, IGFBP, PPR1. CCR11
(GOT TO RUN TO CONFERENCE WITH XCENDA IN CHICAGO---TO BE CONTINUED!)

-

INTERESTING DEBATES

1.NF1 Mutation is upstream from
BRAF
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!

2.  Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!

3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?

CHANGES ARE COMING TO YOU, LIKE IT OR NOT!

SOME PEOPLE REALLY BELIEVE THEY ARE THEY TOO BIG FOR CRITICISM, THEY FEEL OFFENDED WHEN YOU CONFRONT THEM WITH A TRUTH THEY CAN'T BELIEVE.
Everyday Big professors are reminded how important they are by our praises and regular consultations.  Professors grow on us because they have knowledge we believe to be the truth, and because often they are right rather than wrong.  But every time they are solicited, they practice a certain logic they have perfected to come to a logical conclusion.  They pass on this logical process to their students and friends and, as a result, a university culture is created and passed on!  Such a system, however, needs to be challenged once in a while to be made better.  It is made better when it accepts change, because accepting new plausible changes prepares us to wider sorts of challenges, it is the strength of diversity, it prepares us against challenges to come, challenges we will have to reckon with at one point or another. It is the strength of these United States. It is why this country is better prepared than other countries which is somewhat monolithic, culture wise!

When monolithic systems are confronted, when our professors are confronted and when they refuse to face the truthful difference, they reject it with anger and become defensive and somewhat violent (not necessarily physical violence) in their tone.
I was in a recent meeting where I suggested to an eminent oncologist that we look into potential new targeting therapy for a rare type of sarcoma.  An eminent man who I admire became irate or vexed at an unexpected level which surprised me.  It is the truth that everyone nowadays should be looking to target therapy for answers in cancer.  But his reaction was off the wall!   I can understand that evidence based medicine forces us to argue only what has been proven,  but in a university setting, the non-proven should challenge us to look for more, it should be where we start if the goal is to push the envelope further.  I don't know what was in the man's drink to be so offended by the truth we all face, the puzzle that is cancer. I don't know under what "University environment" political pressure he finds himself, so I give him a break, give him slack !  He was just defending his turf !

But one thing for sure, let's be more receptive to change, because it will come, and impose on us whether we like it or not!  You can resist it for a while, but one of these days even your own son or a dear friend will wake you up to it!

CABOZANTINIB

	COMETRIQ™ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET, and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

COMETRIQ was approved based on a pivotal trial in metastatic MTC patients (N=330) who were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry.

• Significantly prolonged progression-free survival (PFS) vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) — Median PFS was 11.2 months with COMETRIQ vs 4.0 months with placebo • Objective response rate (ORR) was 27% with COMETRIQ vs 0% with placebo (P<0.0001) — Median duration of tumor response was 14.7 months (95% CI: 11.1, 19.3) • Adverse reactions occurring in ≥25% of patients treated with COMETRIQ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Exelixis® Access Services comprehensive support program* For you and your patients — call 1-855-253-EASE (1-855-253-3273) 8:00 am to 11:00 pm ET, Monday to Friday

Easing access to COMETRIQ with a full range of services, provided by trained professionals, to meet the needs of healthcare professionals in prescribing and of patients in obtaining COMETRIQ.

• Access and reimbursement support (including benefit coverage and appeals) • Assistance with coding information and obtaining COMETRIQ • Financial assistance to enroll eligible patients into available programs (Co-pay Assistance, Patient Assistance, and Alternate Funding Investigation)

* This description of the Exelixis Access Services program is for informational purposes only. Exelixis makes no representation or guarantee concerning reimbursement or coverage for any service or item. Information provided through the Exelixis Access Services program does not constitute medical or legal advice and is not intended to be a substitute for a consultation with a licensed healthcare provider, legal counsel, or applicable third-party payer(s). Exelixis reserves the right to modify the program at any time without notice. Financial aid for people in need may be available from certain government programs and charities. These include state pharmaceutical assistance programs (SPAPs), Medicaid, Medicare Part D, low-income subsidies, and charitable foundations. An Exelixis Access Services program specialist can explain these options to you.

IMPORTANT SAFETY INFORMATION

	BOXED WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

ADDITIONAL IMPORTANT SAFETY INFORMATION Gastrointestinal (GI) perforations (3%) and GI fistulas (1%), all serious, were reported with COMETRIQ, including 1 (<1%) fatal GI fistula. Non-GI fistulas including tracheal/esophageal were reported (4%), including 2 (1%) fatal events. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher with COMETRIQ (3%) than with placebo (1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Increased incidence of thrombotic events (venous thromboembolism: 6% vs 3%; arterial thromboembolism: 2% vs 0%) was reported with COMETRIQ vs placebo, respectively. Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ ≥28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Increased incidence of treatment-emergent hypertension, stage 1 or 2 (modified JNC† criteria), was identified with COMETRIQ (61% vs 30% with placebo). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the jaw (ONJ) occurred with COMETRIQ (1%). ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for ≥28 days prior to scheduled surgery, if possible.

Palmar-plantar erythrodysesthesia syndrome (PPES) occurred (50%) with COMETRIQ and was severe (Grade ≥3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome, compared with 0 patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.

The COMETRIQ dose was reduced in 79% of patients vs 9% for placebo.

†Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

For the full Prescribing Information, including Boxed Warning, please click here.

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		© 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080     02/13     [03-13-00043-B]

Challenge with diet and food supplements

It is nice to understand the potential activity or mechanism of action of food supplements and act on it. Example: "Vitamin C: MedlinePlus Medical Encyclopedia

www.nlm.nih.gov/medlineplus/ency/article/002404.htm

Function. Vitamin C is needed for the growth and repair of tissues in all parts of your body. It is used to: Form an important protein used to make skin, tendons, ..."

That knowledge empowers you and helps you take action.  You run to the store and buy a good supply of vitamin C and take it for now and the future.  What the information can not tell you is just as important.  How much Vitamin C you need to actually have the benefit described? How long you should be doing this?  Is your body just getting rid of the extra or all of it?  Based on your chromosome heterogeneity, was it safe for you to have done it?  Are you missing a critical enzyme to process the vitamin?
The NIH is finding out that things that are promised by food supplements, when put to the test and scientific scrutiny, do not deliver a clearly evident output.  "Taking an apple a day" (low methionine food item) will prolong your life.  While the scientific evidence as to how this is possible is established:  Does it really happen? No.  Why? Because what is left out is even more important.  How many apples  a day should you eat, what type of apple, what else should accompany this practice to make this goal achievable (low calory diet)? And so on and so forth. We all know that food supplements can impact some of the signal transduction pathways in our cells and, as a result, they could potentially impact our lives in some beneficial ways.  But is it safe to constantly be bothering our signal transduction pathways?  Do you believe it is right to do so constantly?  Who said this pathway needs to be switched on all the time?  What guarantees you that the body will not respond and shut it off anyway as it always reacts to action that we deliberately impose upon it!
Keeping a pathway on all the time may impact another pathway all the time, and if you just happen to have the wrong gene for this particular game, you may start on some road you should not be on!  So please, just because it may make sense, it does not yet mean that it is true and relevant for YOU! 

ACTIVITY AT THE CRBCM:

*WAITING FOR IRS TO FINALIZE ITS WORK INVOLVING THE CRBCM.  THIS WILL BE APPRECIATED, REALLY.
*WE HAVE SUBMITTED ON TIME 3 LETTERS OF INTENT (LOI) FOR RESEARCH WORK
FOR ONCE NOW WE HAVE A LOT OF SUPPORT FROM THE  NIH.
*REPORTING TO CHICAGO FOR UPDATE IN CANCER TREATMENT CONFERENCE, WILL GIVE YOU ALL KIND OF REPORTS FROM THIS CONFERENCE. THIS IS DATA MINING.
(CRBCM IS ON THE MOVE)
*WILL START FIELD WORK FOR 4 WEEKS.
*BY THE WAY, THE MD ANDERSON HAS AGREED TO SEE OUR PATIENT WITH METASTATIC PENILE CANCER.  THANKS!

BRCA1 and BRCA2: Cancer Risk and Genetic Testing

Key Points  (THIS BEAUTIFUL ARTICLE IS WORK OF THE NIH, PLEASE KNOW THIS!)

• BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer.
• A woman's risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation. Men with these mutations also have an increased risk of breast cancer. Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers.
• Genetic tests are available to check for BRCA1 and BRCA2 mutations. A blood sample is required for these tests, and genetic counseling is recommended before and after the tests.
• If a harmful BRCA1 or BRCA2 mutation is found, several options are available to help a person manage their cancer risk.
• Federal and state laws help ensure the privacy of a person’s genetic information and provide protection against discrimination in health insurance and employment practices.
• Many research studies are being conducted to find newer and better ways of detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutation carriers. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.

1. What are BRCA1 and BRCA2?

   BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors.
   In normal cells, BRCA1 and BRCA2 help ensure the stability of the cell’s genetic material (DNA) and help prevent uncontrolled cell growth. Mutation of these genes has been linked to the development of hereditary breast and ovarian cancer.
   The names BRCA1 and BRCA2 stand for breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2, respectively.

2. How do BRCA1 and BRCA2 gene mutations affect a person's risk of cancer?

   Not all gene changes, or mutations, are deleterious (harmful). Some mutations may be beneficial, whereas others may have no obvious effect (neutral). Harmful mutations can increase a person’s risk of developing a disease, such as cancer.
   A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2. Such a woman has an increased risk of developing breast and/or ovarian cancer at an early age (before menopause) and often has multiple, close family members who have been diagnosed with these diseases. Harmful BRCA1 mutations may also increase a woman’s risk of developing cervical, uterine, pancreatic, and colon cancer (1, 2). Harmful BRCA2 mutations may additionally increase the risk of pancreatic cancer, stomach cancer, gallbladder and bile duct cancer, and melanoma (3).
   Men with harmful BRCA1 mutations also have an increased risk of breast cancer and, possibly, of pancreatic cancer, testicular cancer, and early-onset prostate cancer. However, male breast cancer, pancreatic cancer, and prostate cancer appear to be more strongly associated with BRCA2 gene mutations (2–4).
   The likelihood that a breast and/or ovarian cancer is associated with a harmful mutation in BRCA1 or BRCA2 is highest in families with a history of multiple cases of breast cancer, cases of both breast and ovarian cancer, one or more family members with two primary cancers (original tumors that develop at different sites in the body), or an Ashkenazi (Central and Eastern European) Jewish background (see Question 6). However, not every woman in such families carries a harmful BRCA1 or BRCA2 mutation, and not every cancer in such families is linked to a harmful mutation in one of these genes. Furthermore, not every woman who has a harmful BRCA1 or BRCA2 mutation will develop breast and/or ovarian cancer.
   According to estimates of lifetime risk, about 12.0 percent of women (120 out of 1,000) in the general population will develop breast cancer sometime during their lives compared with about 60 percent of women (600 out of 1,000) who have inherited a harmful mutation in BRCA1 or BRCA2 (4, 5). In other words, a woman who has inherited a harmful mutation in BRCA1 or BRCA2 is about five times more likely to develop breast cancer than a woman who does not have such a mutation.
   Lifetime risk estimates for ovarian cancer among women in the general population indicate that 1.4 percent (14 out of 1,000) will be diagnosed with ovarian cancer compared with 15 to 40 percent of women (150–400 out of 1,000) who have a harmful BRCA1 or BRCA2 mutation (4, 5).
   It is important to note, however, that most research related to BRCA1 and BRCA2 has been done on large families with many individuals affected by cancer. Estimates of breast and ovarian cancer risk associated with BRCA1 and BRCA2 mutations have been calculated from studies of these families. Because family members share a proportion of their genes and, often, their environment, it is possible that the large number of cancer cases seen in these families may be due in part to other genetic or environmental factors. Therefore, risk estimates that are based on families with many affected members may not accurately reflect the levels of risk for BRCA1 and BRCA2 mutation carriers in the general population. In addition, no data are available from long-term studies of the general population comparing cancer risk in women who have harmful BRCA1 or BRCA2 mutations with women who do not have such mutations. Therefore, the percentages given above are estimates that may change as more data become available.

3. Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?

   Yes. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and/or ovarian tumors (4, 6, 7). However, the majority of hereditary breast cancers can be accounted for by inherited mutations in BRCA1 and BRCA2 (8). Overall, it has been estimated that inherited BRCA1 and BRCA2 mutations account for 5 to 10 percent of breast cancers and 10 to 15 percent of ovarian cancers among white women in the United States (6).

4. Are specific mutations in BRCA1 and BRCA2 more common in certain populations?

   Yes. For example, three specific mutations, two in the BRCA1 gene and one in the BRCA2 gene, are the most common mutations found in these genes in the Ashkenazi Jewish population. In one study, 2.3 percent of participants (120 out of 5,318) carried one of these three mutations (9). This frequency is about five times higher than that found in the general population (10). It is not known whether the increased frequency of these mutations is responsible for the increased risk of breast cancer in Jewish populations compared with non-Jewish populations.
   Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have higher frequencies of specific BRCA1 and BRCA2 mutations.
   In addition, limited data indicate that the frequencies of specific BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (11–13).
   This information about genetic differences between racial and ethnic groups may help health care providers in selecting the most appropriate genetic test(s) (see Question 5).

5. Are genetic tests available to detect BRCA1 and BRCA2 mutations, and how are they performed?

   Yes. Several methods are available to test for BRCA1 and BRCA2 mutations (14). Most of these methods look for changes in BRCA1 and BRCA2 DNA. At least one method looks for changes in the proteins produced by these genes. Frequently, a combination of methods is used.
   A blood sample is needed for these tests. The blood is drawn in a laboratory, doctor's office, hospital, or clinic and then sent to a laboratory that specializes in the tests. It usually takes several weeks or longer to get the test results. Individuals who decide to get tested should check with their health care provider to find out when their test results might be available.
   Genetic counseling is generally recommended before and after a genetic test. This counseling should be performed by a health care professional who is experienced in cancer genetics (see Question 17). Genetic counseling usually involves a risk assessment based on the individual’s personal and family medical history and discussions about the appropriateness of genetic testing, the specific test(s) that might be used and the technical accuracy of the test(s), the medical implications of a positive or a negative test result, the possibility that a test result might not be informative (an ambiguous result) (see below), the psychological risks and benefits of genetic test results, and the risk of passing a mutation to children.

6. How do people know if they should consider genetic testing for BRCA1 and BRCA2 mutations?

   Currently, there are no standard criteria for recommending or referring someone for BRCA1 or BRCA2 mutation testing.
   In a family with a history of breast and/or ovarian cancer, it may be most informative to first test a family member who has breast or ovarian cancer. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members can be tested to see if they also have the mutation.
   Regardless, women who have a relative with a harmful BRCA1 or BRCA2 mutation and women who appear to be at increased risk of breast and/or ovarian cancer because of their family history should consider genetic counseling to learn more about their potential risks and about BRCA1 and BRCA2 genetic tests.
   The likelihood of a harmful mutation in BRCA1 or BRCA2 is increased with certain familial patterns of cancer. These patterns include the following (15):
   
   • For women who are not of Ashkenazi Jewish descent:
     • two first-degree relatives (mother, daughter, or sister) diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger;
     • three or more first-degree or second-degree (grandmother or aunt) relatives diagnosed with breast cancer regardless of their age at diagnosis;
     • a combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person);
     • a first-degree relative with cancer diagnosed in both breasts (bilateral breast cancer);
     • a combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis;
     • a first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis; and
     • breast cancer diagnosed in a male relative.
   • For women of Ashkenazi Jewish descent:
     • any first-degree relative diagnosed with breast or ovarian cancer; and
     • two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer.
   These family history patterns apply to about 2 percent of adult women in the general population. Women who have none of these family history patterns have a low probability of having a harmful BRCA1 or BRCA2 mutation.

7. How much does BRCA1 and BRCA2 mutation testing cost?

   The cost for BRCA1 and BRCA2 mutation testing usually ranges from several hundred to several thousand dollars. Insurance policies vary with regard to whether or not the cost of testing is covered. People who are considering BRCA1 and BRCA2 mutation testing may want to find out about their insurance company’s policies regarding genetic tests.

8. What does a positive BRCA1 or BRCA2 test result mean?

   A positive test result generally indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers, as described above. However, a positive test result provides information only about a person’s risk of developing cancer. It cannot tell whether an individual will actually develop cancer or when. Not all women who inherit a harmful BRCA1 or BRCA2 mutation will develop breast or ovarian cancer.
   A positive genetic test result may have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person’s relatives. Both men and women who inherit harmful BRCA1 or BRCA2 mutations, whether they develop cancer themselves or not, may pass the mutations on to their sons and daughters. However, not all children of people who have a harmful mutation will inherit the mutation. 

9. What does a negative BRCA1 or BRCA2 test result mean?

   How a negative test result will be interpreted depends on whether or not someone in the tested person’s family is known to carry a harmful BRCA1 or BRCA2 mutation. If someone in the family has a known mutation, testing other family members for the same mutation can provide information about their cancer risk. If a person tests negative for a known mutation in his or her family, it is unlikely that they have an inherited susceptibility to cancer associated with BRCA1 or BRCA2. Such a test result is called a “true negative.” Having a true negative test result does not mean that a person will not develop cancer; it means that the person’s risk of cancer is probably the same as that of people in the general population.
   In cases in which a family has a history of breast and/or ovarian cancer and no known mutation in BRCA1 or BRCA2 has been previously identified, a negative test result is not informative. It is not possible to tell whether an individual has a harmful BRCA1 or BRCA2 mutation that was not detected by testing (a “false negative”) or whether the result is a true negative. In addition, it is possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test(s) used.

10. What does an ambiguous BRCA1 or BRCA2 test result mean?

    If genetic testing shows a change in BRCA1 or BRCA2 that has not been previously associated with cancer in other people, the person’s test result may be interpreted as “ambiguous” (uncertain). One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (16).
    Because everyone has genetic differences that are not associated with an increased risk of disease, it is sometimes not known whether a specific DNA change affects a person’s risk of developing cancer. As more research is conducted and more people are tested for BRCA1 or BRCA2 changes, scientists will learn more about these changes and cancer risk.

11. What are the options for a person who has a positive test result?

    Several options are available for managing cancer risk in individuals who have a harmful BRCA1 or BRCA2 mutation. However, high-quality data on the effectiveness of these options are limited.
    
    • Surveillance—Surveillance means cancer screening, or a way of detecting the disease early. Screening does not, however, change the risk of developing cancer. The goal is to find cancer early, when it may be most treatable.
      Surveillance methods for breast cancer may include mammography and clinical breast exams. Studies are currently under way to test the effectiveness of other breast cancer screening methods, such as magnetic resonance imaging (MRI), in women with BRCA1 or BRCA2 mutations. With careful surveillance, many breast cancers will be diagnosed early enough to be successfully treated.
      For ovarian cancer, surveillance methods may include transvaginal ultrasound, blood tests for CA–125 antigen, and clinical exams. Surveillance can sometimes find ovarian cancer at an early stage, but it is uncertain whether these methods can help reduce a woman's chance of dying from this disease.
    • Prophylactic Surgery—This type of surgery involves removing as much of the "at-risk" tissue as possible in order to reduce the chance of developing cancer. Bilateral prophylactic mastectomy (removal of healthy breasts) and prophylactic salpingo-oophorectomy (removal of healthy fallopian tubes and ovaries) do not, however, offer a guarantee against developing cancer. Because not all at-risk tissue can be removed by these procedures, some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. In addition, some evidence suggests that the amount of protection salpingo-oophorectomy provides against the development of breast and ovarian cancer may differ between carriers of BRCA1 and BRCA2 mutations (17).
    • Risk Avoidance—Certain behaviors have been associated with breast and ovarian cancer risk in the general population (see Question 16). Research results on the benefits of modifying individual behaviors to reduce the risk of developing cancer among BRCA1 or BRCA2 mutation carriers are limited.
    • Chemoprevention—This approach involves the use of natural or synthetic substances to reduce the risk of developing cancer or to reduce the chance that cancer will come back. For example, the drug tamoxifen has been shown in numerous clinical studies to reduce the risk of developing breast cancer by about 50 percent in women who are at increased risk of this disease and to reduce the recurrence of breast cancer in women undergoing treatment for a previously diagnosed breast tumor. As a result, tamoxifen was approved by the U.S. Food and Drug Administration (FDA) as a breast cancer treatment and to reduce the risk of breast cancer development in premenopausal and postmenopausal women who are at increased risk of this disease. Few studies, however, have evaluated the effectiveness of tamoxifen in women with BRCA1 or BRCA2 mutations. Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (18–20). Two of these studies examined the effectiveness of tamoxifen in helping to reduce the development of cancer in the opposite breast of women undergoing treatment for an initial breast cancer (19, 20).
      Another drug, raloxifene, was shown in a large clinical trial sponsored by the National Cancer Institute (NCI) to reduce the risk of developing invasive breast cancer in postmenopausal women at increased risk of this disease by about the same amount as tamoxifen. As a result, raloxifene was approved by the FDA for breast cancer risk reduction in postmenopausal women. Since tamoxifen and raloxifene inhibit the growth of breast cancer cells in similar ways, raloxifene may be able to help reduce breast cancer risk in postmenopausal BRCA1 and BRCA2 mutation carriers. However, this has not been studied directly. 

12. What are some of the benefits of genetic testing for breast and ovarian cancer risk?

    There can be benefits to genetic testing, whether a person receives a positive or a negative result. The potential benefits of a negative result include a sense of relief and the possibility that special preventive checkups, tests, or surgeries may not be needed. A positive test result can bring relief from uncertainty and allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, many people who have a positive test result may be able to participate in medical research that could, in the long run, help reduce deaths from breast cancer.

13. What are some of the risks of genetic testing for breast and ovarian cancer risk?

    The direct medical risks, or harms, of genetic testing are very small, but test results may have an effect on a person’s emotions, social relationships, finances, and medical choices.
    People who receive a positive test result may feel anxious, depressed, or angry. They may choose to undergo preventive measures, such as prophylactic surgery, that have serious long-term implications and whose effectiveness is uncertain.
    People who receive a negative test result may experience “survivor guilt,” caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.
    Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal choices, such as marriage and childbearing. Issues surrounding the privacy and confidentiality of genetic test results are additional potential risks (see below).

14. What can happen when genetic test results are placed in medical records?

    Clinical test results are normally included in a person’s medical records. Consequently, individuals considering genetic testing must understand that their results might not be kept private.
    Because a person’s genetic information is considered health information, it is covered by the Privacy Rule of the Health Information Portability and Accountability Act (HIPAA) of 1996 (21). The Privacy Rule requires that health care providers and others protect the privacy of health information, sets boundaries on the use and release of health records, and empowers individuals to control certain uses and disclosures of their health-related information. Many states also have laws to protect the privacy and limit the release of genetic and other health information.
    In 2008, the Genetic Information Nondiscrimination Act (GINA) became Federal law (see Question 15). GINA prohibits discrimination based on genetic information in relation to health insurance and employment, but the law does not cover life insurance, disability insurance, and long-term care insurance. When applying for these types of insurance, people may be asked to sign forms that give an insurance company permission to access their medical records. The insurance company may take genetic test results into account when making decisions about coverage.
    Some physicians keep genetic test results out of medical records. However, even if such results are not included in a person’s medical records, information about a person’s genetic profile can sometimes be gathered from that person’s family medical history.

15. What is genetic discrimination, and are there laws to protect people from this type of discrimination?

    Genetic discrimination occurs when people are treated differently by insurance companies or employers because they have a gene mutation that increases their risk of a disease, such as cancer. However, in 2008, GINA was enacted to protect U.S. citizens against discrimination based on their genetic information in relation to health insurance and employment (22, 23). The parts of the law relating to health insurers will take effect between May 2009 and May 2010, and those relating to employers will take effect by November 2009. The law does not cover life insurance, disability insurance, and long-term care insurance. In addition, the law does not cover members of the military.
    Some of the protections under GINA with regard to health insurance include the following:
    
    • Premiums or contributions to a group health plan cannot be increased based on the genetic information of an individual(s) enrolled in the plan.
    • Insurers cannot require an individual or family member to undergo a genetic test before enrollment in a group health plan.
    • Insurers cannot request, require, or purchase genetic information about an individual before the person’s enrollment in a group health plan or in connection with that person’s enrollment in the plan.
    • Health insurers cannot use genetic information as the only basis upon which to claim a pre-existing condition is present and, therefore, to deny coverage.
    Some of the protections under GINA with regard to employment include the following:
    
    • Employers cannot refuse to hire and cannot fire individuals based on their genetic information.
    • Employers cannot discriminate against employees with regard to salary, terms and conditions of employment, privileges, and opportunities for the future because of their genetic information.
    • Employers cannot request, require, or purchase genetic information about an employee except under specific circumstances.
    • Employers cannot disclose an employee's genetic information except under specific circumstances.
    Before GINA was passed, many states enacted laws against genetic discrimination. The amount of protection provided by these laws varies widely from state to state. GINA sets a minimum standard of protection that must be met by all states. It does not weaken the protections provided by any state law.

16. In general, what factors increase or decrease the chance of developing breast cancer and/or ovarian cancer?

    The following factors have been associated with increased or decreased risk of developing breast and/or ovarian cancer in the general population. It is not yet known exactly how these factors influence risk in people with BRCA1 or BRCA2 mutations. In addition, a significant portion of hereditary breast cancers are not associated with BRCA1 or BRCA2 mutations (8).
    
    • Age—The risks of breast and ovarian cancer increase with age. Most breast and ovarian cancers occur in women over the age of 50. Women with harmful BRCA1 or BRCA2 mutations often develop breast or ovarian cancer before age 50.
    • Family History—Women who have a first-degree relative (mother, sister, or daughter) or other close relative with breast and/or ovarian cancer may be at increased risk of developing these cancers. In addition, women with relatives who have had colon cancer may be at increased risk of developing ovarian cancer.
    • Medical History—Women who have already had breast cancer are at increased risk of developing breast cancer again, or of developing ovarian cancer.
    • Hormonal Influences—Estrogen is a hormone that is naturally produced by the body and stimulates the normal growth of breast tissue. It is thought that excess estrogen may contribute to breast cancer risk because of its natural role in stimulating breast cell growth. Women who had their first menstrual period before the age of 12 or experienced menopause after age 55 have a slightly increased risk of breast cancer, as do women who had their first child after age 30. Each of these factors increases the amount of time a woman’s body is exposed to estrogen. Removal of a woman’s ovaries, which are the main source of estrogen production, reduces the risk of breast cancer. Breast-feeding also reduces breast cancer risk and is thought to exert its effects through hormonal mechanisms (24).
    • Birth Control Pills (Oral Contraceptives)—Most studies have shown a slight increase or no change in risk of breast cancer among women taking birth control pills (24). In contrast, numerous studies have shown that taking birth control pills decreases a woman’s risk of developing ovarian cancer (25). This protective benefit appears to increase with the duration of oral contraceptive use and persists up to 25 years after discontinuing use. It also appears that the use of birth control pills lowers the risk of ovarian cancer in women who carry harmful BRCA1 or BRCA2 mutations (26).
    • Hormone Replacement Therapy—Doctors may prescribe hormone replacement therapy (HRT) to reduce the discomfort of certain symptoms of menopause, such as hot flashes. However, the results of the Women’s Health Initiative (WHI), a large clinical study conducted by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), showed that HRT with the hormones estrogen and progestin is associated with harmful side effects, including an increased risk of breast cancer and increased risks of heart attack, blood clots, and stroke. The WHI also showed that HRT with estrogen alone was associated with increased risks of blood clots and stroke, but the effect on breast cancer risk was uncertain (27). In addition, the WHI showed an increase in ovarian cancer risk among women who received estrogen and progestin HRT, but this finding was not statistically significant (28). Because of these potential harmful side effects, the FDA has recommended that HRT be used only at the lowest doses for the shortest period of time needed to achieve treatment goals.
      No data have been reported to date regarding the effects of HRT on breast cancer risk among women carrying harmful BRCA1 or BRCA2 mutations, and only limited data are available regarding HRT use and ovarian cancer risk among such women. In one study, HRT use did not appear to affect ovarian cancer risk among women with BRCA1 or BRCA2 mutations (29).
      When considering HRT use, both the potential harms and benefits of this type of treatment should be discussed carefully by a woman and her health care provider.
    • Obesity—Substantial evidence indicates that obesity is associated with an increased risk of breast cancer, especially among postmenopausal women who have not used HRT (24). Evidence also suggests that obesity is associated with increased mortality (death) from ovarian cancer (30).
    • Physical Activity—Numerous studies have examined the relationship between physical activity and breast cancer risk, and most of these studies have shown that physical activity, especially strenuous physical activity, is associated with reduced risk. This decrease in risk appears to be more pronounced in premenopausal women and women with lower-than-normal body weight (24).
    • Alcohol—There is substantial evidence that alcohol consumption is associated with increased breast cancer risk. However, it is uncertain whether reducing alcohol consumption would decrease breast cancer risk (24).
    • Dietary Fat—Although early studies suggested a possible association between a high-fat diet and increased breast cancer risk, more recent studies have been inconclusive. In the WHI, a low-fat diet did not help reduce breast cancer risk (31).

17. Where can people get more information about genetic testing for cancer risk?

    A person who is considering genetic testing should speak with a professional trained in genetics before deciding whether to be tested. These professionals may include doctors, genetic counselors, and other health care workers trained in genetics (such as nurses, psychologists, or social workers). For help finding a health care professional trained in genetics, please visit NCI’s Cancer Genetics Services Directory at http://www.cancer.gov/cancertopics/genetics/directory on the Internet. Alternatively, please contact NCI’s Cancer Information Service (CIS) (see below for contact information). The CIS can provide more information about genetic testing and help in finding a health care professional trained in genetics.

18. What research is currently being done to help individuals with harmful BRCA1 or BRCA2 mutations?

    Research studies are being conducted to find newer and better ways of detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutation carriers. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.
    Information about active clinical trials (research studies with people) for individuals with BRCA1 or BRCA2 mutations is available on NCI’s Web site. The following links will initiate searches of NCI’s clinical trials database and retrieve lists of trials open to individuals with BRCA1 or BRCA2 mutations.
    
    • BRCA1 mutation carriers
    • BRCA2 mutation carriers
    In addition, NCI’s CIS can provide information about clinical trials and help with clinical trial searches (see below for contact information).

Selected References

1. Kadouri L, Hubert A, Rotenberg Y, et al. Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. Journal of Medical Genetics 2007; 44(7):467–471.
2. Thompson D, Easton DF, the Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. Journal of the National Cancer Institute 2002; 94(18):1358–1365.
3. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. Journal of the National Cancer Institute 1999; 91(15):1310–1316.
4. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Genetics of Breast and Ovarian Cancer (PDQ®) - Health Professional. Date last modified 04/24/2009. Available at: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/healthprofessional. Accessed 05/15/2009.
5. National Cancer Institute. SEER Cancer Statistics Review, 1975–2005. Retrieved April 20, 2009, from: http://seer.cancer.gov/csr/1975_2005/index.html.
6. Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008; 124(1):31–42.
7. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Journal of the American Medical Association 2006; 295(12):1379–1388.
8. Lynch HT, Silva E, Snyder C, Lynch JF. Hereditary breast cancer: Part I. Diagnosing hereditary breast cancer syndromes. The Breast Journal 2008; 14(1):3–13.
9. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 1997; 336(20):1401–1408.
10. Warner E, Foulkes W, Goodwin P, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. Journal of the National Cancer Institute 1999; 91(14):1241–1247.
11. John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 U.S. racial/ethnic groups. Journal of the American Medical Association 2007; 298(24):2869–2876.
12. Vogel KJ, Atchley DP, Erlichman J, et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: Mutation prevalence and evaluation of the BRCAPRO risk assessment model. Journal of Clinical Oncology 2007; 25(29):4635–4641.
13. Malone KE, Daling JR, Doody DR, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Research 2006; 66(16):8297–8308.
14. Palma M, Ristori E, Ricevuto E, Giannini G, Gulino A. BRCA1 and BRCA2: The genetic testing and the current management options for mutation carriers. Critical Reviews in Oncology/Hematology 2006; 57(1):1–23.
15. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Retrieved April 20, 2009, from: http://www.ahrq.gov/clinic/uspstf05/brcagen/brcagenrs.htm.
16. Peshkin BN, DeMarco TA, Brogan BM, Lerman C, Isaacs C. BRCA1/2 testing: Complex themes in result interpretation. Journal of Clinical Oncology 2001; 19(9):2555–2565.
17. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. Journal of Clinical Oncology 2008; 26(8):1331–1337.
18. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP–P1) Breast Cancer Prevention Trial. Journal of the American Medical Association 2001; 286(18):2251–2256.
19. Narod SA, Brunet JS, Ghadirian P, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Lancet 2000; 356(9245):1876–1881.
20. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An update. International Journal of Cancer 2006; 118(9):2281–2284.
21. U.S. Department of Health and Human Services. HIPAA Frequent Questions: About the Privacy Rule FAQs. Retrieved April 20, 2009, from: http://www.hhs.gov/hipaafaq/about/354.html.
22. H.R. 493. The Genetic Information Nondiscrimination Act of 2008. Retrieved April 20, 2009, from:
    http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_bills&docid=f:h493enr.txt.pdf.
23. The National Human Genome Research Institute. GINA: The Genetic Information Nondiscrimination Act of 2008: Information for Researchers and Health Care Professionals. Retrieved April 30, 2009, from: http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf.
24. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Breast Cancer Prevention (PDQ®) - Health Professional. Date last modified 04/30/2009. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/breast/healthprofessional.
25. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Ovarian Cancer Prevention (PDQ®) - Health Professional. Date last modified 04/03/2008. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/ovarian/healthprofessional.
26. Whittemore AS, Balise RR, Pharoah PDP, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. British Journal of Cancer 2004; 91(11):1911–1915.
27. National Heart, Lung, and Blood Institute. Women’s Health Initiative. Retrieved April 20, 2009, from: http://www.nhlbi.nih.gov/whi.
28. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women's Health Initiative randomized trial. Journal of the American Medical Association 2003; 290(13):1739–1748.
29. Kotsopoulos J, Lubinski J, Neuhausen SL, et al. Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Gynecologic Oncology 2006; 100(1):83–88.
30. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. New England Journal of Medicine 2003; 348(17):1625–1638.
31. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. Journal of the American Medical Association 2006; 295(6):629–642.

Related Resources

• Cancer Genetics
• What You Need To Know About™ Breast Cancer
• What You Need To Know About™ Ovarian Cancer

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