Does this ever end?

You might be interested in this:

http://www.clinicaloncology.com/download/Hereditary_breast_cancer.pdf

Hi, Geekyknitter,

I am replying because as I was scanning titles, yours piqued my interest.

If your BRCA tests are negative you might consider setting up a schedule of diligent surveillance and then trying to move on. It sounds like the family fear of cancer might be impacting you, too. Great that you're proactive, just don't let the fear paralyze you. I'm not saying that it is, just would be a shame if it would. 

I was dx in 2010 with no close relatives with breast cx, though a hx of a dad w leukemia and prostate ca and a mom w lung ca. I tested as BRCA neg, but had extended gene sequencing which found a few mutations on the BRCA 2 gene of unknown clinical significance. (No evidence at this time that they cause bc or oc.) I insisted on the full sequencing, even though it was expensive, (at the time) because I am one of 7 cousins (none closer to me than a second cousin) from my maternal grandmother who has had breast or ovarian ca. We were all dx in our mid to late 40s. Yet that same maternal grandmother,her sister, my mom and her sister, all never had BC or OC. Somewhat relevant is that we happen to have lost many relatives in the Holocaust, so we don't have a full family hx of what might have happened. Still, my GC, who specializes in BC of Ashkenazi Jews, feels that my BC isn't genetic and that this may be an odd coincidence. In any case, it didn't impact my treatment.

I believe that my BC has environmental causes for various reasons. This is another thing to look at when seeing family clusters, if everyone lived nearby. 

But end of story is that we all need to be diligent because no one really knows enough about this disease. Even if your father is BRCA +, you have a 50/50 chance of not inheriting the gene. So I would recommend, if it comes back negative, doing all that you can re lifestyle changes to live as defensively anti cancer a life as you can (read david Serbian schreiber's book, 'Anti-Cancer, great book. Simple great healthy way for us ALL, to live) and try to move on and live your life. If, ultimately, you are dx (and of course, hope not) the treatments are probably way better than they were in your great aunts' generation. Good luck!

geeky - I bet the vast majority of us have cancer in our families on both sides or either side. My mother had BC in her late 60s and died 10 years ago but not from BC. Now both my sister and I have BC. My father had lymphoma, my brother had melanoma - he is fine it was 17 years ago, my grandfather on my mothers side had pancreatic cancer and if that isn't enough my mother in law has Alzheimers and her mother had it too. Without subjecting ourselves to THE test we don't know whose genes we inherited except my sister and I obviously had the gene. We both were dx early on and so far, so good. No guarantees of course but the outlook is optimistic. I don't know if we ever get past the fear factor. You are right even if the tests are negative what about the next time? We are forever in the waiting room. I decided because I am the poster person for anxiety anyway I am going to ask my dr for something to take the edge off. BC isn't the only thing any of us is dealing with but it certainly controls our thinking and psyche. We all strive not to let it take over our lives but somehow or another it creeps into our subconscience; how could it now. I am not one of those people who believes if it happens, it happens - my husband is. I have to control or at least be privy to test results like 5 minutes after they do the test. Time does help because your odds of survival do too. It does get better with time. Keep us posted. Diane

geeky, incomplete information stinks. I know.  Hang in there...

The conclusion I've reached, after reading more about breast cancer screening than I ever wanted to, is that the tools we currently have for BC screening absolutely suck.  Mammograms miss too much (especially in dense breasts), and still generate a lot of false positives.  MRIs catch much more, (and still miss some things that mammograms pick up), but they have an extremely high false positive rate.  Ultrasounds are a helpful addition to the other two, especially for dense breasts.  When you do all three for screening annually, you can be pretty certain you're clear, but the likelihood of getting called back for many biopsies is very high.  That's why the USPSTF said that for ordinary risk women, a mammogram every year or two after age 50 is enough - they don't want to find all this stuff in ordinary risk women.  It's too much work, worry, and expense to put hundreds of thousands of women through this process to catch one breast cancer early.

I guess we should be grateful for the tools we have.  Hopefully in our lifetime, they will find one magic imaging tool that can figure it out in one-shot.  A girl can dream...

Hope that your doc says it's all OK.

Hello, 

Just wondering cymom: in which order should the tests get done? Mammo; ultrasound, MRI. Am confused.

Have 10 mm lymph node in armpit - doc says not to worry. Am worried especially I have numerous fatty replaced lymph nodes.

Hate this

Alicki

cymom, 

I have been tested for other mutations in addition to BRCA, both moderate penetrance ones (like CHEK2 1100delC) and low-penetrance ones (for example, risk alleles/variants in PALB2, BRIP, FGFR2, ATM, TP53). It turns out I do actually have MANY low-penetrance risk allelles/SNPs - as in SNPs that have been associated with increased risks of breast cancer in various studies including large genome wide studies. I have many risk variants for example (heterogenous and homogenous) in PALB2, FGFR2, ATM, CASP8 etc and even some variants in the BRCA genes which I assume were not disclosed as they were considered low-risk or unknown risk or whatever. In that article you linked there is for example a referral to 2q35 and 8q24 variants...well, I am homogenous for the risk alleles in EACH of those but as that article points out correctly:

Often, low-penetrance SNPs are located in noncoding regions of the genome (eg, 2q35, 8q24), making it more difficult to identify an associated gene. 

In other words...they don't really know what they may or may not do. My own genetic counselor said as much. Being homogenous for 2q35 and 8q24, each might increase my risk about 1.65, but that in itself does not say much or make me high risk or tell me how they work, or how they work with other SNPs or genes. So, little I can do with that info. Now, they do not a little more about some other SNPs. For example, I have PALB2 risk variants as well and PALB2 is known to be a "partner and localizer of the brca 2 gene" and variants are predicted to be deletrious or cumulative toward risk, but research is still really lacking so there is still little I can do with that information.

Some of these variants show odds ratios of only 1.05 or so, some of them are more like 2.0. There are some "approaches" that take certain of these variants and kind of "add them up" to end up with an odds ratio of closer to 4.0...but that is still not a widely accepted practice. Some of these variants are fairly common in certain populations (so many others carry them as well without necessarily a higher risk of breast cancer), while others are quite rare. It is clear that looking at my results I have MANY low-penetrance variants. The problem is...what can I do with this info? Not a heck of a lot. What are the odds they will have studies of people with variants JUST like mine...in my combination, that can lead to any definitive guidelines? Not good Even on an individual SNP basis there are no clinical guidelines in that case for them. Like I said, many of them are very common in certain populations. Many of them still lack a lot of research into them either as a whole or applicable populations. Honestly, none of my medical providers...even the genetics experts...really care ALL that much about this info, they prefer to go by the empirical data (meaning my family history). I have the info, but it's not something that is "worth much" or that can give a whole lot of answers. So really, it just kind of is stuck somewhere in my hard drive on a spreadsheet.

You will see that in the link you posted they conclude the low-penetrance section (and even the moderate penetrance one) by saying pretty much this - evaluation of these low-penetrance variations is not standard clinical practice, and management of those with them is still to be based on estimated risk and certain risk models (like Tyrer-Cuzick). This is exactly my own experience. My risk assessment is based PURELY on my family history and certain other personal factors (such as age at menarche, whether I have had children and when, etc). Interpretation of these kind of results is still behind the actual ability to test for it, as there is still too much unknown.

For me, having this "knowledge" of these variations then does little more than confirm, like my genetic counselors suggested, there are polygenic things going on (if not an unknown mutation) and there may be a cumulative thing at play where many of these low-penetrance risk alleles kind of just, well, together have more of an impact. Am I fairly certain that in my family it is likely these low-penetrance variations are at play in our horrible cancer history given there is no known BRCA-mutation? Yes, and if not that, then there is something else going on like an undiscovered mutation, but still...can't do much with the info. My other family members can't go to their doctors and ask to be tested for these variants because I have them either, it is just not standard practice. 

I TOTALLY understand the "need to know" and to explain why your family is the way it is and so on...so, I am only telling you all this to make sure you know the limitations of this information, and to expect some resistance to testing for them, or little "hype" about it even if you do have any variants. Maybe ONE day it will change and there will be more known about them, but the focus really is still more on "high penetrance" mutations (or finding the next high-penetrance mutation) and not so much on these moderate or low-penetrance mutations. The polygenic side just does not seem to captivate quite the audience that high-penetrance mutations do at this point

Yeah, I get wanting the information...I know for me I hunted for answers to my family's "curse", and I certainly can understand wanting to test for CHEK2 or something if your family profile fits, but the problem is most of the low-penetrance SNP variants tell you little. Everyone has variants in their DNA, and we have millions of places where variants can occur! Some are harmful, some have no effect, some are unknown...some just mean you will have blue eyes. An odds ratio of 1.25 in a small population study that is similar to your ancestry for example may mean your own risk is still quite low, and there may be protective variations also involved! Or unknown variants in mutations that need to exist as well. Variants can be very common...so if 50% of people have a variant, you can't develop guidelines that would say they are all higher risk. Because they aren't! There are many, many studies out there, including GWAS studies, but these variants tend to confer very little additional risk on their own so aren't considered high risk. They also are not commonly tested for excepting in research. Even if they do a Polish study that finds a variant gives an odd ratio of 1.5...you still would not fall into a high risk category on that alone, and it would say little about how the variant affects your family which may has its own unique makeup...including potentially protective genes. We see that even in BRCA+ families some have high rates of cancer, and some have little...they can't say an 87% risk applies to ALL BRCA+ women anymore. There is so much more at play than the mutation alone. It is also near impossible to get a group of people who would all share the SAME variants, particularly if you go outside a family!

Most guidelines are not based ONLY on one study, or one population. I am not in US, but the guidelines that apply where I live factor in MANY studies and research.

I think some GCs are better than others when it comes to hereditary cancer issues. For example, my GC was interested in my Icelandic descent and this is a specific question on the testing forms where I live as it has been found that that there is a founder BRCA mutation in those with Icelandic ancestry. My Northern European ancestry was also of interest to the GC to consider CHEK2. She is also very interested in the research field and the issue of low-penetrance variants so did have a lot of information for me.

If you have a family history though, even without a known mutation, there should still be clinical guidelines that apply to you? The same high risk guidelines in effect where I live that apply to BRCA+ persons are applied by my medical providers to me, excepting the ovarian screening and recommendations as there is no ovarian cancer in my family. All the high risk screening and options for breast cancer are applied to me since my risk assessment puts me in a high risk category. Everyone accepts that there are probably polygenic factors at play, and they don't need the particulars of what SNPs I have. They actually rely on one of Dr. Narod's studies of BRCA- families with 3 close relatives/2 under 50 with breast cancer dx's. That takes prevalence over knowing there is a variant that might increase my risk 1.25-1.65...or that I have several that may or may not play into it. So yeah, my point is you can do the testing for low-penetrance variants, maybe, but in practice it won't really "settle" anything for you or warrant anyone using them instead of your known family history because there is just way too much uncertainty out there about them still (and likely will be for a while). For me anyway, at this point, my family experience is convincing enough to know something is going on, and to make decisions without a specific "answer" to "why".

Another option is to look at BROCA testing through University of Washington, as it tests something like 40 (?) genes that have associations to breast cancer. Just be aware again some of these have no clinical guidelines but may help you find some answers (or raise new ones!)