TRYING OUR BEST TO TALK TO THESE GENES IN BREAST CANCERS: MED1,6 and 12

With the clinical finding that Bicalutamide, a non steroidal anti-androgen, has a role in some of the luminal forms of Breast cancers, genes affecting the Hormones have quickly become the focus of intensive research. So we venture to explores some of the genes having links to Hormone.  At CRBCM we are looking at DAX1 as it interacts with COPS2 and through the thyroid Hormone Receptor alpha gene will affect the MEDs which ultimately the Glucocorticoid Receptors and a slew of other critical receptors and genes (even the BRCA-1) is in the line of fire!
Now how important this observation is in triple negative breast cancer is still a matter of debates.  Proof of concept work is still needed but it is a clear start, join the discussion!

" MED1 has been shown to interact with Thyroid hormone receptor alpha,^[4] Androgen receptor,^[5] Cyclin-dependent kinase 8,^[6][7] Glucocorticoid receptor,^[8][9] BRCA1,^[10] Hepatocyte nuclear factor 4 alpha,^[11][12] Peroxisome proliferator-activated receptor gamma,^[13] PPARGC1A,^[14] P53,^[15][16] Estrogen receptor alpha,^[7][17] TGS1^[18] and Calcitriol receptor".<sup>[6][17] wikipedia


WHERE ELSE COULD THINGS BE HAPPENING BUT HERE!
THE INVOLVMENT IS THE CALCITRIOL RECEPTOR IS ANOTHER AREA OF INTEREST.  THIS MED1 SEEMS LIKE A GIFT THAT KEEP ON GIVING.   THE ANDROGEN RECEPTOR INVOLVEMENT IS A CRITICAL STEP SINCE IT BELONGS TO THE "WILD GENES"</sup>

The secret of triple negative breast cancer

Common sense tells us that events happening in your women when they acquire childbearing age contribute significantly to the happening of triple negative breast cancer.   The young woman has gone through infancy when events here are more related to the setting of class I HLA antigens first for self tolerance, then comes exposure to the outside world and the building of defense mechanisms.  Implying development of class II HLA Antigens which we know by now are very much linked in their variations to racial disparity.  Then the young woman enters puberty which brings in the reign of the Estrogen with its extensive methylation of genes dampening the Class I HLA to prepare the young lady's body to receive the foreign "body" of the potential infant.  We have touched in one of our precedent writings about the effects of Estrogen on the immune system.   We have extensively discussed the interaction of Interferon and TNF /TGFs on receptors of Estrogen (Activation followed by desensitization or lack thereof.  The female individual with autoimmune disease will be much more affected by the surge of cytokines above.  Then come the menses with their resulting Iron deficiency which prones the body to the danger of Reactive Oxidative species.  But as far as genes are a concern, the most important event is the development of the breasts.  It is the reign of the PROLACTINS.....
Indeed, it is Prolactins that will happen on this background of Estrogen/Cytokines effects.   Don't think of Prolactin as a hormone, it is a Cytokine!  Yes, it comes in to not only have a direct effect on the Janus Kinase 2 and induce the JAK-2-STAT pathways, but through its Dopamin Receptor, it will pound on the c-MET effect and exert numerous pounding on the PIK (effect include on its regulators (AGAP2) pathway....If you happen to have another genetic abnormality such as BRCA, or too much free Iron stimulating the HIF or any other failure....something wrong is bound to happen....such as ...triple negative breast cancer.....The point is, don't forget the Prolactin reign!!!

SOME LITTLE GENES WITH A BIG IDEA: SHP GENE

IF YOU KNOW HOW IMPORTANT ESTROGEN RECEPTORS ARE IN BREAST CANCERS,
IF YOU KNOW HOW IMPORTANT ANDROGEN RECEPTORS ARE IN PROSTATE CANCER
IF YOU REALIZE HOW IMPORTANT THE THYROID FUNCTION IS DRIVING THE RATE OF METABOLISM
IF YOU REALIZE THE DIFFICULTY THAT POSES HEPATOMA IN TERMS OF TREATMENT,
IF YOU KNOW THAT SARCOMA IS TOUGH TO TREAT,

THEN YOU SHOULD DIG DEEPER IN UNDERSTANDING THAT ALL THESE RECEPTORS HAVE ONLY ONE INHIBITOR, THE "SMALL HETERODIMER PARTNER"  GENE!

WHAT IS IT AND HOW AND WHEN SHOULD IT COME IN?

Small heterodimer partner has been shown to interact with:

• Androgen receptor,^[4]
• Estrogen receptor alpha,^[5]
• Hepatocyte nuclear factor 4 alpha,^[6]
• Liver receptor homolog-1,^[7][8]
• Liver X receptor alpha,^[7]
• Peroxisome proliferator-activated receptor gamma,^[9]
• Retinoic acid receptor alpha,^[10][11] and
• Retinoid X receptor alpha.^[6][7]

I refuse to comment on the PPARgamma for now, did you know that this is the staff that interacts with Rb1?  watch it as it is coming to a Diabetic control and evaluation near you!

At CRBCM we are working hard!

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CPRIT’s Oversight Committee met November 1 for the first time since February beginning a new era for the agency – one with a higher level of transparency, improved processes and strengthened accountability to the taxpayers of Texas. As I reported to the Oversight Committee, in addition to provisions in SB 149 which modified CPRIT’s enabling legislation, the agency has taken action to implement all 41 of the State Auditor’s January 2013 recommendations. We accomplished a number of important items at the meeting that will allow CPRIT’s work to move forward. We also began our commitment to transparency by holding the meeting at the State Capitol and streaming the meeting live over the web – a first for CPRIT. Within days, we’ll post a video of the proceedings to our website as well. Major actions of the Oversight Committee include: Adopting new bylaws for how the Oversight Committee will operate as a governing body, including an updated code of conduct. These bylaws indicate the Oversight Committee commitment to operating with the highest level of integrity; Posting revised administrative rules to the Texas Register for public comment. The rules expanded from 40 to over 120 pages, and implement many of the State Auditor’s recommendations as well as other process and accountability improvements; Restarting our grantmaking process, including the approval of Scientific Review Council appointees. This action allows CPRIT to resume review of grants and enable healthcare and medical professionals to apply for new grants. We expect additional steps at the next Oversight Committee meeting scheduled for November 22, 2013. At that session, I anticipate discussion about research and prevention program priorities, and a number of other actions important to our continuing operations. I want to express my gratitude to the members of the 83rd Legislature and their staffs, state leadership offices and CPRIT staff for getting us to November 1. The new Oversight Committee came to the meeting well-prepared and eager to resume the important responsibilities assigned to CPRIT by the citizens of Texas. It’s nice to be back at work! Regards, Wayne R. Roberts Interim Executive Director Cancer Prevention & Research Institute of Texas P.O. Box 12097 Austin, Texas 78711

WE BELIEVE IN THE CURE FOR BREAST CANCER

In this month of re-commitment to fighting Breast cancer, it is imperative to stop a while in a moment of reflection for those who have lost the fight, remind ourselves of who they were, what lives they touched as they made us who we are today in many ways.   I remember  my mother who was afflicted by this disease, a kind loving soul, who despite our number (family of 15) had managed to make all of us feel special.  I grew up truly believing that of all her kids, I was the one.  But talking to my other siblings, each one of us felt that special feeling! In 1974, 3 years before she was diagnosed and treated in Belgium, she added to my name a secret portion, "Muendela yenda" (the one who will walk alone) and here I am today, far from the country of origin, in  El Paso, Texas, the sole American Citizen of my family!  Preaching to a silent choir on this blog.  Breast cancer victims are our mothers, sisters, daughters and friends who have affected our lives in many ways. Survivors continue their paths and work touching our lives everyday, reminding us that our fight is needed and is just because there is a price to fight for.  Reminding us that until the cure happens, there is no stone that should remain unturned, no places we should not go, no politician we should not talk to, no genes,proteins, and other molecules that could make a difference we should not explore, poke and tease.  We could wander to other matters of our lives, but this month of October, we should renew our commitment to the fight for the cure of breast cancer.

Efforts made so far have made a meaningful difference, our eyes have opened to new dimensions of cancer research, and the belief in the cure has hardened because through advances in targeting therapy and genetic works, THE CURE IS MORE POSSIBLE, REACHABLE AND REAL!
All we need is cast off the doubt, stop infighting, keep the eyes open, and bring the cure to the shores of our daily reality! We have the means, we have the science, we are full of justified hope, let's keep on marching until the victory rings, making the CURE REAL, PALPABLE  AND ALIVE!

A few questions in triple negative breast cancer

1.Could amplification of PIAS modulate enough the STAT to impact progression of triple negative Breast cancer?
2.Could modifiers of Sumoylation impact the prognosis of triple negative breast cancer?
3.Status of the Zimp10 in triple negative breast cancer?
4. Amplifying ART-27 to stop cellular proliferation?
5.blocking RCHY1 could restore P53 function in patient with non Mutated P53?
6.can anti-cortactin and supervillin block metastatic propensity of triple negative breast cancers?
watch brain mets?

In a retrospective review of Lung cancers , use of Beta blockers may provide survival advantage

*In a retrospective review of Lung cancers , use of Beta blockers may provide survival advantage.

*Ruloxitinib, still the success story in JAK driven diseases.  For JAK driven disease to be seen more in Hematologic malignancy, the receptors for hematologic growth hormones must be stimulated.
COMFORT-1 showed 41.9% of patients on Ruxolitinib had spleen reduction  but in COMFORT-2, only 28% had spleen reduction by week 48.

The JAK inhibitors are now being tried in Pancreatic cancers!

*Obstruction to Cure is not only found in limitation of progress in science, but in man made complications such disparities in funding availability and managed care obstruction to access to known medications!  Cure escapes us for our own doing, in a summary!

*In Breast Cancer, Inhibitors to CD4,6 are proving to be a new approach when given with Letrozole

*In Prostate cancer don't be too eager to use Steroids with enzalutmide.  Steroids may "activate androgen receptors promoting the cancer".   I should confess this point is a bit controversial since that's what we do, stimulate to better kill with chemotherapy (Taxotere-Cabazitaxel).  But the logic may not work for another hormone used for killing.

*In Tivo-1,
they found no survival advantage for TIVOZANIB Vs Sorafenib in patient with Renal Cancer.
Tivozanib is said to be more potent and selective for VEGF receptors!  PFS was superior though with TIVO!

*Check this out!  The global multikinase inhibitor Regorafenib (blocks VEGFR1,KIT,TIE2,PDGFR and RET) got approved for GIST.  patients received 160 mg PO daily x21 Q28. Watch for fatigue hand foot sundrome diarrhea, loss of appetite,HTN,weight loss,rash and fever.  and being an anti-VEGF, bleeding and intestinal perforation of course!  rare cases of Coronary attacks!
*New kid on the block, RAMUCIRUMAB TRIED IN GASTRIC CANCER!

(READ TARGETED THERAPY NEWS)

GENES IN OVARIAN CANCER: (part I)

The notion that there is a particular gene or genes for a specific cancer is attractive, but most of the time only reflects the scientists' tendency to attract the community interest on their findings.  There is nothing wrong with that because their work needs recognition. Recent advances in cure and novel therapeutic approaches have occurred to convince the common of mortals that Researchers are hard at work.  But by now we know that most standard genetic family abnormalities involve only 5-10% of cancers.  That means that no one genetic abnormality stands to justify any specific cancer in-toto. The case of BRCA1 and 2 in Breast cancer.
Breast cancer survivor Women who participated in My talk in El Paso,TX were surprised to learn that 85% of women newly diagnosed with Breast cancer in the US were first in their family.  Everybody was assuming that breast cancer happens because of family predisposition.  This is clearly an underestimation of the heterogeneity of our genetic material.  Don't understand me wrong, there are clear cases of family predispositions, however, we have an approximate 25,000 genes, something and somewhere a significant event can happen anytime.  Also, one should know that there is primary and secondary amplification.  In some cases it is hard to determine which came first (Chicken and egg dilemma ).
Another compounding factor complicating our interpretation in rare cases, is the notion that the cause of cancer can be located in the promoter gene which all of a sudden becomes difficult to methylate or suppress, causing secondary amplification of a gene or of its regulators.
When one wants to look at the genes involved in ovarian cancers, it is good to focus on particular genes (HNF1B) as clearly publicized, but we can't ignore the story of BRCAs, and other family syndromes which harbor Ovarian cancer as a component of the syndrome.  Therapies that are being developed and being effective in Ovarian cancer (Anti MEK) are also pointing to relevant genes.   The story of lung cancer with its ever expanding list of DRIVER MUTATIONS and the advent of MULTIPLEX gene screening is just another proof of the danger of claiming to have discovered THE GENE for a specific cancer!

GENES OF OVARIAN CANCER (to follow)

PROOF OF CONCEPTS: THE CASE OF PANCREATIC CANCER

1.  "P" ARM VERSUS  "Q"
-----------------------------
As you look at the location of Genes, one will quickly notice that various genes have their family counterpart not close on the same chromosome. But instead on a different chromosome altogether.  In general we almost treat this  information in a profane manner in that we overlook the meaning of this.  Nature, however, has no place for randomness. Everything has deep meaning and NUANCES OR MINIMAL VARIATIONS can make a world of difference. Should you doubt this statement, ask the people with Sickle cell, they are not laughing about that nuance in Hemoglobins.  So when a family member has put in a different chromosome, there is no pun intended.

ERBB1 is on chromosome 7p12 (involved in Glioblastoma and Squamous cell head and neck cancers)
ERBB2 is on chromosome 17q11.2-q12 (involved in breast, Ovarian and cervical cancer)

Also however, we note that the family member is put on a "p" rather than "q" location.  This also has a profound meaning.   It just turn out that mutation on "q" location seems to have the worse prognosis and are more likely to be expressed  than those on "p" location.

The bad guy MYC is located 8q24 and is found on advanced forms of cancers (Ovarian, Breast, small cell, Esophageal and cervical but also in the Burkitt (ALL))
The nice MYCN, often a better prognosis indicator, is located on 2p24  but still can be involved in Neurobalstoma.

These are in fact speculation but check it out!

Another example
just go ahead and compare
breast cancer with FGFR1 located 8p11
and breast cancer with EGFR1 located 10q25
and call me if you find different!

PROOF OF CONCEPT NEEDED FOR PANCREATIC CANCER:

One of the complication or hurdle you encounter when you are dealing with abnormal genes
in pancreatic cancers is the the genes found in abnormal cancers are also found in benign conditions such as Adenoma or even pancreatitis.  Now if we assume that this is an Adenocarcinoma of the same origin embryonically as the colon (check that assumption out), we could apply the colon cancer model where
EARLY CANCER FOR ADENOCARCINOMA IS ANNOUNCED BY LOSS OR MUTATION IN CHROMOSOME 17:   IE GENES     (FOLLOWING THE COLON MODEL)
-----------------------------------
-KRT20
-TEM 7
-MAP2K4
BAT-26
ALOX 12
TP53
BIRC5
NME1
ERBB2
GAS
TM4SF5

LATE CANCER,  LOSS OF CHROMOSOME 8 (FOLLOWING THE COLON MODEL)

CDH4
PSCA
MYC
 (FGFR1 AND BAG4 ARE HAVE A "p" LOCATION ON THE CHROMOSOSME)

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

This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.

Random News: MELATONIN and NIH GrantsInfo

RANDOM NEWS

*Melatonin which helps with sleep at 3mg, was tested at 20 mg to see if it could help to stop or delay cachexia.  It was not different then placebo.  Case closed. IT FAILED!

*IT IS ESTIMATED THAT 12000 DEATHS COULD BE PREVENTED WITH AN INSTITUTION OF AN AGGRESSIVE LUNG CANCER SCREENING IN THOSE WITH HISTORY OF 1 PACK/DAY FOR 30 YEARS OF MORE!

*We have shown that in the united states more than 3000 African women could be saved yearly if the Breast cancer paradox (low incidence, but high mortality) was corrected by the institution of a comprehensive prevention program.  Well, things are getting worse as recent studies continue to show a decrease of screening in world of corruption and politics.  At CPRIT, they want Commercialization.  The NIH is heavily political.  Just look at a recent submission response:

Thank you for your e-mail to GrantsInfo at the National Institutes of Health (NIH).  We provide general information about NIH extramural medical and behavioral research, research training programs, and the grant application process.

I suggest you discuss potential funding of your project with the appropriate Scientific/Research staff linked in the announcement’s Section VII:  http://grants.nih.gov/grants/guide/pa-files/PA-11-260.html#_Section_VII._Agency

Regards from GrantsInfo
Web:   http://www.nih.gov

Linking you to NIH Funding

This is an automatic reply when you submit a project
no referral to some review board
they will keep you going here and there
leading nowhere because they have their political friends to award money to. another example, not here go somewhere else!

Dear Dr. Kankonde,

In the table shown below, you will find all currently active NIH funding opportunities related to support of tissue, specimen, and biospecimen banks.  It does not appear that there is any specific funding opportunity that will work for your purposes.  You can search further in the NIH Guide for Grants and Contracts by going to http://grants1.nih.gov/grants/guide/search_guide.htm.  You might also try to connect and collaborate with scientists and pathologists who have mutual interests to find out if your proposed tissue bank might be supported through affiliation with a large research program (e.g., medical center, cancer center, program project, clinical trials network/consortium, special program of research excellence, epidemiology/population cohort, etc.)

Good luck with your efforts.

Comment: and it goes on and on, you get nowhere and after many attempts, you just give up (but at the CRBCM, we do never give up!)

It is a rough world, and they claim to help, but indeed they try to discourage any pursuit of new research and prevention with good old political tactics!

DRUGS ON THE MOVE

 DRUGS  ON THE MOVE

1.   In Breast cancer

-Everolimus
-Pertuzumab
-T-DM-1

2.   In Prostate  cancer

-Abiraterone (Zytiga)
-Enzalutmide (Xtandi)
-Alpharadin (Radium 223)

3.   Other
-Cabozantinib
-Orteronel
-Curtisen
-Tasquinimod

4.   Melanoma

-Dabrafenib
-Trametinib
-GDC- 0973
-Vemurafenib (Zelboraf)
-Nivolumab
-Ipilimumab
-MK3754

5.   Lung cancers

-Crizotinib
-Afatinib
-Dacomitinib
-Nivolumab
- Selumetinib

5.   Thyroid cancer

-Pazopanib

RANDOM NEWS with updates for Letrozole

*BIG 1-98 showed that LETROZOLE was more effective in post-menopausal patient with any histology of breast cancer that is ER positive and Her-2 Negative, with the effect being greater in lobular type of Carcinoma.  And in Luminal B versus Luminal A.

* In HER-2 positive, one year Vs 2 Years.
"2 year long treatment not recommended",
finding of the HERA trial remains the standard of care.

In the study of 6 months Vs 12 months of Herceptin, there was a trend toward better results with 12 months also statistically no difference was detected.

*In Early Breast cancer, High Baseline of Vitamin D level was a predictor of 3 things:
1. better prognosis
2. low risk bone relapse
3. better outcome with use of Zometa.

recommendation is to measure Vit D at diagnosis and to replenish it!

*In triple negative breast cancer, the disease would be amenable to new type combinations of medications such as
A/  Cisplatin /PARP (olaprib) and Vandetanib (EGFR/VEGF).
B/  Cisplatin/PARP inhibitor and   Vorinostat (Histone deacetylase inhibitor)
C/  Androgen Inhibitors and MTOR

*PD 0332991, an oral Cyclin dependent Kinase (CDK 4/6) inhibitor added to Letrozole  increased the progression free from 7.5 months to 26.1 months.  This is an impressive performance if confirmed. 
 *PIM-1 may be a surrogate of c-MYC  amplification, and is being targeted.

* Routine Breast MRI still not recommended

*32mg IV Ondansetron  can cause Arrhythmia and has been withdrawn.

BETTER IMAGING FOR BREAST CANCER: TOMOSYNTHESIS

*Tomosynthesis gives "200 one-millimeter-thick images for an average sized breast, compared to 4 images in a regular 2-D digital mammogram" leading to 41 to 61% increase of cancer detection compared to standard 2-D digital mammography.   It also reduces the return for additional imaging, according to a report by Donna Plecha, MD, Director of the Dept. of Radiology at UH, Case Western School of Medicine.

*Thomas Bachelot et al. submitted results of a phase II study related to use of Capecitabine and Lepatinib as first line therapy for patients with Brain metastasis from HER-2 positive Breast cancer.  45 patients enrolled, Median follow-up 21 months.  65.9% of patients had a partial response noted.

*Another Disparity:  Although white Americans have twice as high an incidence of Bladder cancers, at similar grade and stage of disease, Black Americans do have a higher mortality!".  There is a 5 fold relative risk for those who smoked  20cigarettes/day for over 40 years, compared, of course, to non smokers.

*Marginal Zone Lymphoma.includes:
-MALT
-Nodal type
-Primary splenic type which can have villious cells that can be confused with Hairy cell morphologically on peripheral blood.

has CD20+, CD5-, CD10-, CD23-
In extranodal cases, 60% have Trisomy 3 and t(11;18) which produce fusion API2and MLT, and will mark resistance to Antibiotics
API2 is an inhibitor of Apoptosis
MALT1 (procaspase) bind to Bcl-10 leading to activation of NF-bK which ultimately impair Apoptosis
Associated to Sjogren disease in some cases, in the stomach, associated with H.Pylori
Rituxan as a single agent, local RT,

FDA Approval for Ixabepilone

Brand name: Ixempra™       (this is old news)

• Approved for breast cancer

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
On October 16, 2007, the U.S. Food and Drug Administration (FDA) approved ixabepilone for injection (Ixempra™, made by Bristol-Myers Squibb) for the following two indications:

• Ixabepilone is indicated in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated.
• Ixabepilone is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

A randomized, multinational, open-label trial of 752 patients with locally advanced or metastatic breast cancer evaluated the efficacy and safety of ixabepilone (40 mg/m2 IV once every three weeks) plus capecitabine compared to therapy with capecitabine alone. Patients had previously received an anthracycline and a taxane, had evidence of disease progression or resistance, or, in the case of the anthracycline, received a minimum required cumulative dose.
Treatment arms were balanced with regards to prior therapies, disease sites, hormone receptor status and HER2 expression. Patients receiving combination therapy had a statistically significant improvement in progression-free survival (PFS), defined as radiologic progression or death from any cause (hazard ratio 0.69, p<0.0001). The median PFS was 5.7 months in the combination arm and 4.1 months in the capecitabine alone arm. Patients in the combination arm also had an increased objective tumor response rate. Survival data for this trial are not yet mature.
Ixabepilone monotherapy was evaluated in a single arm trial of 126 patients with metastatic or locally advanced breast cancer who had previously received an anthracycline, a taxane and capecitabine, and who had disease progression or, in the case of the anthracycline, received a minimum required cumulative dose. Ixabepilone was administered at the same dose and schedule as in the combination trial. The objective response rate based on independent radiologic review was 12.4 percent (95 percent CI: 6.9, 19.9). The objective response rate based on investigator assessments was 18.3 percent (95 percent CI: 11.9, 26.1). The median response duration was 6.0 months (95 percent CI: 5.0, 7.6).
Treatment with ixabepilone caused new or worsening peripheral neuropathy in approximately 65 percent of patients treated. Grade 3 or 4 peripheral neuropathy occurred in 23 percent of patients treated with ixabepilone and capecitabine, with no grade 3 or 4 peripheral neuropathy reported in the capecitabine arm. In the ixabepilone monotherapy trial, 14 percent experienced grade 3 or 4 peripheral neuropathy. Neuropathy was generally reversible to grade 1 or better with cessation of therapy.
Ixabepilone in combination with capecitabine resulted in a 68 percent incidence of grade 3 or 4 neutropenia compared to 11 percent with capecitabine alone. Twelve patients receiving ixabepilone in combination with capecitabine died from complications arising from neutropenia.
The incidence of neutropenia related deaths was higher in patients with baseline moderate or severe hepatic impairment when treated with both ixabepilone and capecitabine. This combination should not be used in patients with moderate or severe hepatic impairment. When used as monotherapy, 54 percent of patients treated with ixabepilone experienced grade 3 or 4 neutropenia.
Other commonly observed toxicities (>20 percent) included anemia, leukopenia, thrombocytopenia, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The following additional reactions occurred in ≥20 percent in the combination treatment arm: palmar-plantar erythrodysesthesia (hand-foot) syndrome, anorexia, abdominal pain, nail disorder, and constipation.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.
=====================================================from FDA pages.
Ixabepilone,
from Sorangium cellulosum
promote tumor cell death by causing cell arrest in G2/Mphase.
has unique Beta -tubulin binding site
given 16mg/m2  (Vs 40mg Q21D )weekly for 3 weeks every 4weeks. (with Bevacizumab) or in combination with Xeloda as recommended appears to have been used in clinical trial.