Is my family history normal or suspicious?

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).

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.

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.

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.

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

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?