Li Fraumeni Syndrome

Hi,

My sister (aged 32) is undergoing BC treatment (Left Breast Stage IIA +++), as her mother too had BC (expired at age 38), when my sister got diagnosed with BC, our MO advised us to have a Genetic Testing done for BRCA 1/2 and TP53.

As per the her Genetic testing report, she has TP53 germline mutation and because of that, MO informed us that she has LFS. We never herd about this LFS and after Genetic Counselling, we got to know that there is no cure for this syndrome. We were informed that she is exposed to not only Breast Cancer but some 5-6 more cancers. This news has shaken us completely (we are yet to disclose it to her, we will do it once she is done with her Chemo).

Because of LFS doctors have decided not to give her Radiation therapy as she has only 1/16 positive nodes with clear margin and no vascular invasion.

I am very worried because of this LFS, previously it was 1 cancer now we have 5-6 haunting us all life. I have few questions related to LFS, it would be great if anyone of you can answer to give us some clarity:

1. We are told that Life Expectancy of LFS patients is 45 years, is it true?

2. Chances of Second Cancer is around 20%, it is correct?

3. My sister and her mother didn't had any childhood cancers, does this mean that my sister's daughter (3 years old), if positive of TP53 (which has 50% chance), will be exposed to BC only or she also can have other childhood cancers, even though her mum and grand-mum didn't had any.

4. What are the chances of my sister developing any other cancer apart from BC. Considering she had this mutation from Childhood and no cancer apart from BC has developed till now.

5. Will the chances of subsequent cancer decrease or increase with age.

Thanks in advance for the support.

I stumbled upon this exact topic last night. I was going over my medical records, and I found something I don't understand: when I was first diagnosed they did expanded panel genetic testing through Counsyl, and I was TP53 negative. A year and a half later we did FoundationOne testing on an actual tumor specimen from my recurrence, and that was TP53 positive.

So what does this mean? Do I have Li Fraumeni syndrome? Do I not have the mutation, but my cancer does? I read that maybe 1/3 of breast cancers have this mutation, but is that different than having the mutation before you even get cancer?

My heart goes out to your sister and your family. I was diagnosed at 32 also. I think Lula gives great advice - be proactive about screening and risk reduction. I'm so glad her cancer was found early, and it sounds like her doctors are being thorough. Wishing the best for all of you.

Hi lekker, thank you for that explanation. I had squamous cell carcinoma of my skin when I was 28, and then BC at 32. I attributed the skin cancer to too much sunshine as a child, but when I also got BC I really started to wonder... why two cancers so young? Anyway, thanks again.

Hi All,

Thanks for all your responses, its nice to see support in difficult time.

I was surfing through some websites to gain information on LFS and got to know that there are few criteria to define presence of LFS:

Criteria 1 - Classic Li-Fraumeni syndrome (LFS) is defined by presence of all of the following criteria:

• A proband with a sarcoma diagnosed before age 45 years
• A first-degree relative with any cancer before age 45 years
• A first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age

Criteria 2 -

• Proband with a tumor belonging to the LFS tumor spectrum (e.g. soft tissue sarcoma, osteosarcoma, brain tumor, pre-menopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least one first- or second-degree relative with a LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; OR
• Proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
• Proband with adrenocortical carcinoma or choroid plexus tumor, regardless of family history.

One of the trials shows that 92%-95% of individuals who tested positive for germline TP53 pathogenic variants met the revised Chompret criteria for LFS (Criteria 1). What about remaining 5-7% who are tested positive of Germine TP53 mutation but don't meet the Chompret Criteria.??

My sister doesn't meet Criteria 1 & 2, though she is tested positive of Germline TP53 Mutation. Does she has LFS??? In our family history only my sister and her mother had BC and no one else. We don't know whether her mother had TP53 mutation or not as she wasn't tested. My sister's mother has 2 Brothers and they don't have any Cancer nor their kids (total 4 kids).

We met 2 Genetics doctor:

Doctor 1 - "She has mutation and this classify LFS criteria though considering family doesn't have Cancer history (only mother had BC and no other 1 or 2 degree relative had cancer), he feels chances of other cancer are less"

Doctor 2 - "She only has mutation and mere TP53 germline mutation doesn't mean you have LFS. Chompret Criteria needs to be fulfilled (which is not fulfilled in my sister's case) and considering the family history she doesn't feel there is LFS risk."

We are very confused and don't know which doctor to believe. Does testing positive of TP53 mutation means you have LFS or positive testing needs to be accompanied with fulfillment of Chompret Criteria???

Mother's brother and their children all are free from Cancer (Brother's age 58 years and Children's age approx. 30-32 years).

Hi Lula,

Thanks for replying. My sister is positive of germline through blood testing. Yes, I agree she can be the first one to have mutation and thus we wont be able to fulfill the criteria. Is this a good news that its not running in hereditary or its the same?

Hi Lula, thanks for the information. She has mutation in variant P.Arg175His exon 5. Is mutation in this variant associated with any specific cancers? Or variant doesn’t matter and risk is same irrespective of variant.

Hi Lula, thanks for the reply. As my sister is going though treatment, she doesn't get much time to read about it and we are also telling her slowly about what it means so that she doesn't get panic.

We are trying to figure out what cancers are associated with her mutation (c.524G>A p.(Arg175His) exon 5), it will help us in some manner.

Also, we have been told about some study where Metformin (medicine to cure Type II diabetes), has been found to have tumor suppressing effect. Do you have any idea about it?

on the Metformin...there’s a theory that high insulin levels (often found in overweight/obese individuals who have insulin resistance and/or those with type 2 diabetes) increase tumor cell proliferation. Scientists are looking at various anti-diabetic agents to see if they have a favorable impact on tumor cell proliferation. Metformin is the first med theyve looked at in this capacity. Metformin works by suppressing excess glucose release from the liver and to a lesser extent helps sensitize the cells in the body to the insulin that the body is making. Reducing excess glucose release from the liver lowers the amount of insulin the body makes in response and sensitizing the cells to the insulin increases its cellular uptake so it’s not lingering in the bloodstream. There is a low risk of hypoglycemia (low blood sugar) with it, some people experience a little weight loss, and better blood sugars. They biggest side effects are GI related: nausea, upset stomach, cramping, diarrhea. If you start with the generic and the side effects are miserable, try switching to the name brand as the side effects are less. Or just start out with name brand.