Is my family history normal or suspicious?

Anonymous

I was diagnosed with triple positive IDC a year ago at 28. I tested negative for the BRCA mutation. Since I have only had a unilateral mastectomy, I am worried that I have a different genetic mutation that just hasn't been discovered yet. I have family history, but no history of very young cancer.

Mother - diagnosed with breast cancer at 64

Paternal grandmother - diagnosed with breast cancer at 61

Maternal grandfather's sister - diagnosed with breast cancer at 58

Paternal uncle - diagnosed with prostate cancer at 54

Maternal great-grandmother - died of colon cancer at 69

Maternal aunt - just had pre-cancerous polyps removed from her colon at 57

The other thing is that the two sides of the family that have cancer (my dad's side and my mom's dad's side) are either extremely male-dominated or just really, really small.

So I'm debating whether I should have a preventive mastectomy on my good side and my family history doesn't really point me in either direction. I don't want a second cancer but I have a hard time wrapping my mind around removing a healthy body part too.

Any thoughts?

hyphencollins

Did they do any other testing besides the BRCA? If not, could you get extended panel testing? (Note: I'm not entirely sure what it involves but it was recommended I to me- I was only tested for BRCA initially and will at some point get the extended panel).

Ridley

I have a  considerable amount of cancer in my family as well, but all of the breast cancer was post menopausal until me.  Lots of other types of cancers as well, but with the exception of a couple of first cousins who were diagnosed quite young, all were older than 50.

I tested negative for BRCA as well, but I have to believe there is something genetic going on -- we just don't know what it is yet.

I decided on a bilat mast.  I would have needed a lumpectomy on the "other side" anyway as I had DCIS on that side, and a reduction if I wanted symmetry with my reconstructed breast.  In addition, I found the process very anxiety producing, so I didn't want to go through yearly imaging on the remaining side.  As it turns out, the process continues to be anxiety producing (side effects of tamoxifen resulting in cysts, etc,, etc, etc,), so I'm not sure I gained much on that end.  Maybe I'll feel differently in a few years.

Having said all that, I think I would make the same decision if I had to do it again.

Good luck with your decision -- its a tough one.

Momine

Everybody in my father's family, living or dead, has had cancer unless they managed to get killed by something else at a young age. My dad has had skin and prostate cancer + a precancerous kidney tumor. His sister died of melanoma and his twin brother has had testicular, skin and bladder cancer +precancer of the colon. Their mom died of bladder cancer, one aunt of BC etc etc.

On my mother's side there was no cancer really, but my mother has had ovarian cancer and my mom's sister has stage 4 BC and also had uterine cancer.

My mom and aunt are BRCA negative, but given the above history, it seems to me that there must be some sort of genetic element to all this.

rleepac

I'm waiting on genetic test results because of 75% Jewish ancestry, father had prostate CA, his mom had breast CA and intestinal CA (2 separate primary cancers according to Aunt who is an RN), and my dad's maternal grandfather also had intestinal CA. It will be interesting to see if they 'identify' what the genetic link/mutation is because it seems pretty clearly linked on my dad's side. But it might not be anything they've identified yet so who knows

DiveCat

1 in 3 women, and 1 in 2 men, will get a cancer diagnosis in their lifetime. Cancer itself is not rare. And some families just do have more of it than others (while other families seem plagued with something else, like heart disease). And breast cancer itself, well, the average risk in North America is 1 in 8, with being a woman, and aging, the biggest risk factors. 90% of breast cancer is sporadic, not hereditary linked. What is a red flag is a high number of early onset (pre menopausal) cancers, of a certain cluster of cancer types (like ovarian, breast, bilateral BC, pancreatic), rare cancers (like male breast cancer), and other hereditary signs (some genetic mutations known to increase breast cancer risk for example are also accompanied by excessive freckling, etc).

There may be a genetic link, there may not be. It may be possible to find that mutation, or not (at least not now). It could be ONE mutation, or it could be polygenic.

I don't have a BC diagnosis, but had a bilateral prophylactic mastectomy (I don't call it preventative as sadly it is not a guarantee!). I am from an uninformed BRCA- family, and aside from being BRCA- myself, I have personally also tested negative for about 6-7 other mutations that have clinical recommendations for them. My mother, maternal grandmother, 2 maternal great grandmothers (grandmothers mother and grandfathers mother) have all had BC, 3 of them ending up with metastasic BC, and 3 of them premenopausal. The one who survived later had a metastatic colon cancer diagnosis. I do not have aunts, or even great aunts, so the info is limited in a way. Like you, my family is male dominated. I have no aunts on either side, but a total of nine uncles! My female cousins are all at least 10 years younger than I am in their early 20s. My paternal side has some colon cancer, but no real pattern.

A maternal male cousin also had early prostate cancer. Prostate cancer itself is not rare and risk gets higher with aging but he way quite young. I have done additional testing that shows certain variations that have been linked to BC, but are not certain and have no clinical recommendations. I was given about a 38-40% lifetime risk assessment by 3 different genetic counsellors based however on family history and uninformed negative BRCA-status. The most they can tell me at this point is it seems clear there is "something", but they can't say what, or whether it could be a single mutation, or the result of a bunch of different inherited genes and how they play together.

It can be frustrating to not know, for me and for those I love, and in my case I just eventually decided I needed to make decisions based on what I DO know and what felt right. I felt a bit like the canary in the coal mine as I am oldest of my siblings/generation in my family. I hope some clarity does come to my family though at some point.

Girl53

DiveCat: Just read your post with great interest. Our situations sound somewhat similar, except I was just diagnosed with BC Monday.

I would also describe my extended family as probably BRCA- but uninformed. Here's what I know so far:

*My mother had an aggressive breast cancer 20 years ago and is living after treatment.

*My paternal grandmother was diagnosed in her mid 60s and died of metastatic disease at 79.

*Great aunts on both parents' sides who died of breast cancer (one before age 40, I think, and another at 52).

*Paternal great aunt who died of ovarian cancer at 64, and a maternal cousin now living with this cancer.

*Two other maternal cousins have also had BC, both diagnosed between 40-50, and both living after treatment.

*Maternal great aunt who never smoked died of throat cancer in old age

*Maternal great greatparents died of stomach and esophogeal cancer, respectively, in old age

*Maternal grandmother had lung cancer in old age (not sure if she died of it)

*Maternal grandfather died of cancer in his early 60s (not sure yet what kind).

I'm not knowledgeable enough yet to know if this is a significant family history of breast or other cancers, but it feels (and has looked) pretty scary. Also, I lost my wonderful first husband to a brain tumor when he was 43 (I am now happily remarried at 53), and my twin sister's husband is dealing with probably-metastatic melanoma whose origin hasn't been identified.

As a woman now dx'd with BC -- and with LCIS and what I believe is strong family history -- I am considering a PBM. Feel sad and scared and so uncertain. But the cancer shadows I have lived with all my life are getting too much for me, I think. Am planning to seek at least two other opinions, in addition to BS (and get gene test), before deciding. My internist has already told me that, if she were in my shoes, she'd have the surgery.

Have you felt peace with your choice? I am new here and will read more of your posts. Thanks a lot.

SummerAngel

I think it's definitely a good idea to talk to a genetic counselor. They can analyze your family history and then decide whether more testing would be a good idea. That could help you make up your mind.

When I was first diagnosed I didn't think there was any significant family history, but they did the BRCA testing right away because I was 45 (negative result). I then saw a genetic counselor and based on the information I had gathered from my parents she did the extended testing. (Result was one variation of unknown significance.) My paternal side has very few women, but this is how that side looks:

Me: Bilateral BC at 45.

Paternal first cousin (I have 6 female cousins, this cousin has one sister): BC at 41

Paternal aunt (my only aunt): BC at 78

Paternal great-grandmother: BC at 45, died from it at 47

For the genetic counselor the important points were that 3 out of 4 of us had BC in our 40's, I have bilateral BC, and there are so few women on that side.

Girl53

Made an interesting discovery today in tracking down family history of BC for geneticist. My paternal grandfather's sister died of BC at age 52; learned today from out-of-state cousin that THREE of great aunt's daughters got BC...two died of it in their 60s/70s and one was treated successfully. Great aunt's only son had a daughter who got BC and participated in a University of Iowa event for women who inherited BC predisposition from father's side of family. The older sister of cousin I spoke to today had a PBM years ago.

Don't like the way this is looking, what with my mother and paternal grandmother both having BC, etc. I've got it coming from both sides of the tree! Does this seem to others that, even if BRCA-, there is something genetic going on here?

BarredOwl

Hi:

Many of you who have had BRCA testing likely met with a Genetic Counselor, or if not, you can request a referral to one (confirm insurance coverage). A Genetic Counselor is probably the best person to consult for a formal assessment of your current family history and for advice about further genetic testing (e.g., multigene panel testing). The assessment of family history is a scientific endeavor, and a counselor should be up to date about the various hereditary cancer syndromes and genes. They can also discuss with you the pros and cons of wider genetic testing. Among the cons, some multigene panels may include genes which lack of consensus practice guidelines for dealing with deleterious mutations, there may be no effective screening and/or risk management options for some cancer types associated with certain genes, less studied genes tend to have a larger number of variants of unknown significance, and there may be some genes for which there is very limited information about the level of risk associated with a pathogenic mutation (e.g., estimated risk is based on a single or few variants).

Here is some information about the challenges in assessing family histories and some results of a recent study regarding the frequency of other mutations in BRCA negative patients and seeming lack of an effect of age at diagnosis on prevalence.

NCI PDQ states:

"The accuracy and completeness of family histories must be taken into account when they are used to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. . . Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve, therefore it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)"

Here is a recent study in which the study group was largely women who lacked BRCA1/2 mutations. Some findings of interest are highlighted below (the complete article is now behind a paywall):

http://oncology.jamanetwork.com/article.aspx?artic...

This trial "prospectively enrolled 1046 individuals who were appropriate candidates for HBOC [hereditary breast and ovarian cancer] evaluation and who lacked BRCA1/2 mutations." Among these, "The vast majority were women, and 83% had a personal history of breast and/or ovarian carcinoma, while only 14% were cancer unaffected. . . . An additional 23 patients referred to our centers and harboring non-BRCA1/2 mutations were enrolled and included in subsequent analyses."

They "carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals." The multigene panels used were: "the 29-gene Hereditary Cancer Syndromes test (Invitae), used at Stanford and MGH, or the 25-gene MyRisk test (Myriad Genetics), used at BIDMC." [MGH, Mass General Hospital and BIDMC, Beth Israel Deaconess Medical Center]

Mutations in other genes were not that common: "Consistent with recently reported findings from other similar cohorts and our group's published work, we found that 3.8% of BRCA1/2mutation-negative individuals (95% CI, 2.8%-5.2%) harbored deleterious mutations in other hereditary cancer predisposition genes."

However, among the group of mutation carriers, the following findings are interest (emphasis added by me):

• "A substantial subset of individuals (20 of 63) were found to have mutations in high-risk genes associated with detailed NCCN consensus management guidelines, and in these instances finding the mutation would always change management (Table 2). Notably, although these individuals had personal and/or family histories consistent with the mutation, many would not have met established gene and/or syndrome-specific testing criteria. Thus, these clinically significant mutations may have been missed by the traditional, focused testing approach. The potential clinical effect of finding these mutations was equally important for patients' family members: testing of additional family members would be recommended in all cases (Table 1)."

• "Notably, among patients with breast cancer, we did not observe an effect of age at diagnosis on the prevalence of breast cancer–associated genes (Figure 1). This situation is quite different from BRCA1/2, the prevalence of which is strongly age dependent, and suggests that diagnosis age is not a reliable indicator of mutation probability when testing for these other genes."

Whether to seek further testing is not an easy question. Good luck to all.

BarredOwl

Girl53

BarredOwl: Thank you for great info. This topic is gripping, whether or not one has a BC dx. It feels so odd, to me, to be affected by "something" I can't see or really understand. (Or at least I'm assuming my family is affected by some genetic syndrome.) Having collected a fair amount of reliable family data, it seems to me we have some major predisposition going on, but so far it's not among family members under 40 years of age.

With knowledge of significant BC on both sides of family -- and at least two cases of ovarian cancer -- do I even need a BRCA test? Would the point be to know whether my or other family members' ovaries might need to be removed? And, as pointed out above, what would many of us do with information about other genes/mutations whose effects we're not sure of, and which we are all but powerless over?

I am still not sure what a rampant family history means now that I have been diagnosed: do I have much higher-than-average risk of recurrence, or of multiple primary breast cancers? Could this lead to conclusion that PBM is better than rads/Tamox/close monitoring?

This probably comes down to making an individual decision that will bring peace of mind. I so don't want to have to make a decision like this.

Girl53

Yet another question...I am all over these boards and hoping you're not getting impatient with me! When get genetic testing, is there any way to know -- if you're someone like me with BC on both sides of family and you test positive --, whether the gene(s) came from father's side or mother's? How would you know which set of relatives to inform if something came back positive?

BarredOwl

Hi Girl53:

I suppose in some reasonably large families, the distribution of kinds of syndrome-associated cancers and/or their distribution among differing degrees of relatives might make one side more likely than the other. In others, with breast and ovarian cancers occurring at similar degrees of relationship on both sides, probably there would be no way to know without actually testing it. All of the questions you are asking are really best addressed by an expert genetic counselor.

For me personally, I felt that BRCA1/2 seem to be the most prevalent high risk mutations, and knowing about it was better than not knowing. Many (but not all) variants of BRCA1/2 and impact on risk have been characterized. There are consensus guidelines for enhanced screening and/or risk reduction measures for BRCA1/2, (although not for all associated cancer types). If I had a pathogenic/deleterious mutation, my family members who chose to be tested, could be either positive or negative. Those who were positive, could choose to commence enhanced breast screening at a minimum. Whether a person would choose screening only, chemo-prevention, or prophylactic mastectomy and/or bilateral salpingo oophorectomy is really a personal risk/benefit analysis. Different people have different "risk tolerances" and would decide the question differently. Age may play in. Factors which affect accuracy of screening, such as breast density, might play in. Some people might want to do everything possible regardless of side effects, while others might look very carefully at the known degree of risk reduction for each action, and weigh that against the likelihood and severity of the side effects of a proposed action. In the end, the full BRCA1/2 came out negative for me. There may be some other known or unknown gene mutation(s) in there (with less of an age-at-diagnosis effect), so I still think about multi-gene panel testing, but the cons noted above give me pause.

BarredOwl