Genetics

Breast cancer didn't change my perspective but only added to the frustration at the relatively low number of genes that have been discovered o date. So far there have been five cancers among the four of us in my family - two brothers, my sister and myself. My brother has now just experienced his third primary cancer. Obviously my family's cancer experience is out of the realm of BRAC 1 & 2 and touches on genes not yet discovered.

I was aware of the breast cancer genetic variations before I was diagnosed from a researcher I worked with at a science/technology center. But I had hoped that --- between the time of diagnosis and now --- there would be further discoveries to help me make sense of my experience. And that hasn't happened. Yet.

It is clear that you may possibly have a predisposition from your family history and yourself that there may be a genetic mutation running in your family. You did not say how old were you when you were diagnosed with your breast cancers. Or what ethic background you have or how old were your relatives when they were first diagnosed with breast cancer.

We all have breast cancer genes in our bodies that are supposed to protect us from breast cancer. People who have the BRCA1 mutation, BRCA2 mutation has a higher risk of getting breast cancer and or ovarian cancer, because the mutation comes from your mother or father and you can receive them at the time of your conception. However, because a person may have the mutation, it does not mean that they will get these cancers in their lifetime.

The BRAC Analysis Rearrangement Test (BART) is an additional level of analysis, which goes beyond DNA sequences of genes. Having this additional test, one has to look at the risk and benefits of this test for you. If you are searching for answers of why breast cancer is prevalent in your family and feel that this test will help resolve issues that are concerning your health, perhaps you should speak to a genetic counselor and your oncologist about this test.

Genetic testing can mean several things. Testing a patient’s melanoma for the presence of a BRAF or C-KIT mutation can be done anytime, although it is important to have those results before starting a BRAF or C-KIT inhibitor. Genetic testing is also being investigated in families where 3 or more members have had melanoma. This type of genetic testing has less of a direct impact on the therapies we choose, but it will, some day, help our understanding of why certain people are at risk for the disease.

Genetic mutations play a key role in NSCLC. Identifying certain, key mutations can help select targeted therapy. The two most important mutations in lung cancer right now are the EGFR and EML-4ALK mutation and are found in the subtype of lung cancer called adenocarcinoma. These mutations are more commonly found in female, asian, non-smokers. However, they are also found in smokers and males, but to a lesser degree.

Patients with the EGFR mutation are generally treated with a drug (pill) called Tarceva as first line treatment, rather than chemotherapy. Similarly, patients with the EML-4 ALK mutation are treated with a recently approved drug (pill) called Xalqori (Crizotinib). Generally patients with these mutations who are treated with the appropriate drug do very well when compared to patients who don't have the mutation and are treated with chemotherapy

Due to the dramatic responses with the use of these drugs when a mutation is identified, it is important to test for these mutation at diagnosis. Generally, when the initally biopsy is done, I make sure that there is enough material left over to send for molecular testing. It takes roughly 2 weeks to get the results back, so based on patient preference, I may start the patient on chemotherapy until the results come back.

To note, the testing of these mutations should routinely be performed in patients with stage IV NSCLC, not in patients with stage I-III (yet). Outside of a clinical trial, there is just not enough evidence yet on how to use these molecular markers in stage I to III NSCLC although this may change very soon.

Hello there! I'm sure my surgical team did some tests, and I was told that I would get a "copy" of the study I took part in when it was done, but I never received it. I would have like to know what it said. I don't even know now where or if I could obtain it. It was at University of Alabama Birmingham. Things have changed alot medically, but I still would like to know. They even sent someone out to my house to interview me. I was counting on the information!

Since my uterus was not fully developed in the womb (the mouth, or opening), while I was in-utero, I have wondered if my mother had gene abnormalties, because she had cervical cancer at 36 (I was 12). Her's was caught in a Pap Test early and treated. She did well. But that was so long ago. If both occurrences happened today, I believe at least some of the outcomes would have been different, in a positive way.

My mother did smoke, and drink alcohol occasionally while pregnant. And while there are differences in opinion about this, some medical, some take offense to the suggestion; I believe it has to have a negative effect just by common sense. Especially with two babies at the same time are needing nutrition from the mother.

p.s. Would love to hear from you on this (if you have any thoughts)!

All patients with stage IV NSCLC who have the most common type, called adenocarcinoma, should have their tumor tested for at least two mutations prior to treatement. These mutations are called EGFR and ELM4-ALK and mutually exclusive (they don't ever occur together). Patients who have the EGFR mutation should be treated with a drug called Tarceva, while those who have the ELM4-ALK mutation should be treated with a relatively new comer, called Crizotinib. This is a new era in lung cancer where we are able to identify a mutation and treat with a drug targeting the mutation, rather than standard chemotherapy. Keep in mind only 15% of patients with adenocarcinoma will have the EGFR mutation and even less have the ELM4-ALK mutation (3-5%), so chances are that you will not have the mutation. Once the mutation is identified and you are treated with the appropriate drug, the mutation does not need to be tested again. That said, there is a significant interest in rebiopsying patients who progress (their tumor grows) on the drugs mentioned above (Tarceva or Crizotinib) to see if the mutation in the tumor has changed to something different. This is being done in clinical trials but is not, to date, considered the standard of care. So, in short, once your tumor has been identified as having the mutation and you are started on the drug, it does not need to be tested again unless part of a clinical trial and you progress on the drug.

A nice review of hereditary breast cancer is found in the textbook The Breast by Bland and Copeland. The chapter by Lynch, Marcus, Lynch Snyder and Rubenstein (chapter 21), reviews hereditary predisposition.

BRCA 1 and 2 account for the majority of inherited breast cancer. Other syndromes which include increased risk of breast cancer are:
Li-Fraumeni (p53)
Cowden's disease (pTEN)
Hereditary diffuse gastric cancer (CDH1)
CHEK 2
Peutz-Jeghers syndrome

Ataxia telangiectasia, Fanconi's anemia and Bloom's syndrome also confer increased risk.

You will learn if you have a gene mutation on BRCA1 or 2. Just b/c you are negative does not mean you do not have some type of genetic predisposition for breast cancer, just means you do not have that specific mutation.
Check out my section on BRCA as its very informative
http://www.mybreastcanceranswers.com/brca/brca

Heather
www.mybreastcanceranswers.com

I think the first thing that must be said about BRCA testing is that I sat with a social worker who specialized in the potential emotion impact of the results of genetic testing. Even though I already had a cancer diagnosis, had I tested positive for the gene, I would now have my daughter with a burden over HER head. To test or not. And when? I had enough of a family cluster of disease from a fairly detailed pedigree. I made all my treatment choices before I even got the results.

When the test came back with mutations of unknown significance on BOTH BRCA1 and BRCA2 I was stunned. Immediately, my mom was tested and she tested completely clean. She was the one with the first breast cancer but NO mutations. I sat with the social worker and the head of genetics to review the results and what they meant. He explained how "a mutation starts somewhere" so I could have inherited from my dad or I could simply be the first person with that particular mutation.

I remember how weird it was to see the results because they were so detailed (stuff I do not remotely understand) but what struck me was the fact that they indicated the number of times they had previously seen the mutation and why they couldn't classify them as "cancer causing genes" ..... and they also couldn't classify them as harmless either. One of them was seen seven times before me. The other one, they never saw before. I was the first. Last year, my youngest sister was dx'd with DCIS right on her chest wall. She tested for the gene and she was clean on one but matched the other one..... obviously came from dad.

It's a little frustrating to have a test done and basically be told, it could be something, it could be nothing or because of the family cluster of disease, it could be a gene not yet identified. Because I had been counseled through all of these scenarios, I was okay with still having no answer.

I know that I will be notified once these genes are classified and hopefully, both of them will be harmless so my daughter is off the BRCA hook. Unfortunately, she is still a "previvor" because of my family cluster.

A bit confusing to answer, but then that's exactly what the results were.... they took an entire page filled with four paragraphs to say, "we don't know" .... Since I tend to be the wordy one, every once in a while it will cross my mind and I'll laugh. Sometimes, you just gotta laugh.

Myriad Genetics (http://www.myriad.com/) has had BRCA 1 and 2 testing available since 1996. Currently there are over 2000 variations in BRCA 1 and 2 genes that have been shown to be "deleterious" mutations, in that they are responsible for an increased risk in breast and ovarian cancer. New deleterious mutations are being discovered and confirmed with some regularity.

At this point, approximately 5% of mutations identified are labeled "mutations of undetermined significance" - this means that there is a gene abnormality, but there is not enough data to know if the mutation is a harmful one or not - realize that many gene mutations do not confer an increased risk. According to one of the researchers at Myriad, when they first started testing in 1996, "15 to 40% of the people getting tested had a variant of uncertain significance. That is now under 5%, because we have made enormous progress in our ability to study variants and figure out if they cause an increased risk for cancer. But there are still a lot of variants for which we need more information".

One can divide the answer to this question into two parts, firstly, patients who have been diagnosed with breast/ovarian cancer, and secondly, unaffected family members.
For the first part I will list the current (April 2011) NCCN guidelines for BRCA 1 and 2 testing:
Women aged 45 or younger at age of diagnosis of breast cancer.
Women aged 50 or younger with 2 breast cancers, first cancer diagnosed less than 50 years of age.
Women aged 50 or younger with breast cancer with a close relative diagnosed with breast cancer age 50 or less (or ovarian cancer any age).
Women aged 50 or younger with breast cancer and limited family structure.
Women aged 60 or younger with triple negative breast cancer (ER,PR, Her-2-neu negative).
Woman with breast cancer at any age and 2 other family members with breast, ovarian or pancreatic cancer.
Woman with breast cancer at any age and one male family member with breast cancer.
For unaffected individuals who have a relative with a known BRCA1 or 2 mutation, site specific testing can be done. In families in whom there are no affected individuals still living, then the person whose result would yield the most meaningful information should be tested first. For example, if an unaffected patient came to me with a family history of four paternal aunts with breast cancer, all deceased, and an unaffected father still living, then the father should be tested before his daughter. If he tests negative, there is no need to test his daughter.

Yes, I also had a preventative hysterectomy/oophorectomy. I am also being monitored quite closely. Then, of course, there are the life style things we all should be doing anyway; eating healthy, exercising, maintaining a healthy weight. Sound familiar? I think I've done about all I can now to prevent another cancer or a recurrence.

The genetic counseling sessions I attended were very thorough and very helpful. We discussed and diagrammed out my family tree in great depth. There was a lot of discussion about that. Then the topic of genes/DNA was covered pretty well I'd say. I felt like I was in a crash course in a high school or college genetics class! There was a lot of time for discussion and questions. I was very pleased with the counseling opportunity and I would highly recommend seeing a genetic counselor if you are thinking about testing. While I did get the impression they were very pro-testing, they also respected my opinions and decisions about going through with testing or not. I'm not sure if you can even have genetic testing done without counseling first. It's a very important component.

I attended genetic counseling sessions with my mother, father and two siblings at Mayo Clinic in Rochester, MN. After those meetings, my mother decided to be tested and it turned out she was BRCA2 positive. She was already two years into her cancer, however, so her initial treatment had already ended. She found out too late actually in hind sight. Immediately after that, doctors there recommended that I get tested as well, although they didn't actually come out and say that...it's a very personal decision. Like I mentioned before, I thought I had a little more time to think things over, but cancer doesn't always follow "the plan."