Negative genetic test results and treatment impacts

[Grandma16]

I was diagnosed with Stage 2a low grade serous carcinoma, had a total hysterectomy and currently receiving frontline Taxol/Carbol treatments. I’ve had 3 treatments with 3 more to go. I had genetic testing of a 43 gene panel and the results were all negative. The geneticist is resubmitting to include additional genes for a total of 81. Has anyone had their genetic tests come back negative? Has that impacted your treatment plans and prognosis? Thank you.

[RonLitBer]

Testing for both 43 and the 81 gene mutations seems a bit low to me. There is a firm in the States that does genetic testing. Their TempusxT test has a list of 596 genes. TempusxO does 1,714 genes and they also have whole genome sequencing. Imagine the cost is high. I am not sure if some of this is over-kill but you can always inquire and see what kind of feedback you get.

tempus.com/genomic-sequencing/

Often a result will use the phrase "variant of uncertain significance" which translates to mean what it says -- they don't know.

I have high grade serous ovarian cancer so it is not surprising that my tumour has a somatic mutation in my TP53 gene. This was not a genetic test but a test of my actual tumour and the mutation is not a germline mutation. But there is no known treatment that gets the p53 protein to work if it is mutated. There are some clinical trials addressing it but they have not been particularly hopeful.

What I am trying to say is that even though someone has a gene mutation it may not have a treatment option that can deal with the mutation.

I would make make sure that the below have been tested as germline mutations which involve a blood test. It is the basic minimum that is now being tested where I live.

ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM*, FANCC, MLH1, MSH2, MSH6, NBN, PALB2, PMS2*, PTEN, RAD51C, RAD51D, STK11, TP53. There are lots more of course especially from a place like Tempus which will do both the genetic test and test your tumour.

Having some types of gene mutations seem to be a positive in terms of treatments that are available. A lot of testing gets done if you are a possible candidate for a clinical trial. These tests are of no charge to you. Unfortunately most clinical trials are designed for high grade serous as it is most prevalent so the low grade trials are harder to come by. I am sure you are aware of this.

Glad to hear you were staged at 2a. That makes a difference.

[Grandma16 in reply to RonLitBer]

Thank you for your info. Of the genes you listed, the only one that wasn’t included was FANCC. InVitae is the company used by the geneticist we were sent to and they did use blood sample. When I see my oncologist, I’ll ask him about getting the larger gene study as well as testing the tumor, if it’s still available. Thanks.

[RonLitBer in reply to Grandma16]

One of the differences between somatic mutations (those found in your tumour) and germ line mutations is that the latter can be passed on to offspring while the former cannot. Even if you test negative for a germ line BRCA mutation a tumour may harbour what is referred to as a "BRCAlike" mutation which may make PARP inhibitors more effective as a treatment option. This is kind of ideal as you cannot pass the mutation on to children but your tumour may respond to an available drug. The other thing about tumours is that they change over time and with treatment.

[thomas62 in reply to RonLitBer]

HiRonLitBer

Your responses are all so interesting to read. A Question; Can a low grader have BRACA'ness in somatic tumour cells? Thank you.

[RonLitBer in reply to thomas62]

That is a good question thomas62. I don't really know but am curious. Do you know?

I was at an educational program recently where the presenter said that mixed tumours are possible and tumours can change from one type to another. I don't remember the specifics.

However, I have read that low grade serous can contain histopathological elements characteristic of other tumours such as endometrioid or clear cell carcinomas. I guess this would be an example of a "mixed tumour".

Most somatic mutations for low grade involve KRAS and BRAF mutations and there are trials for MEK inhibitors that target these which are active and not recruiting at the moment.

clinicaltrials.gov/ct2/show...

clinicaltrials.gov/ct2/show...

Untypical mutations do happen that are typically found in high grade tumours, in low grade serous, low-grade endometrioid, clear cell and mucinous carcinomas. An example is TP53. There are also instances where high grade serous tumours have somatic mutations that happen in low grade serous, low grade endometrioid, clear cell and mucinous tumours.

[thomas62 in reply to RonLitBer]

Wow - it's so complicated isn't it. All I can say is that the medics say my tumours (having had 2 surgeries - one in 2014 and one in 2018) are low grade serous. My first surgery reported low grade serous, areas of borderline and abundant psammona bodies. Also calcification At moment, post my second surgery I am NED and on a hormone inhibitor, Aromasin. I am aware of the BRAF and KRAS in low grade but haven't been tested for these at all. I don't think I have loss of P53 gene!! Please let me (and other low graders) if you come across any further info on my initial question. Thanks again. Gwen x

[RonLitBer in reply to thomas62]

Lovely to hear you are NED on a hormone inhibitor. Long may it last.

I have read that borderline tumours are precursors of ovarian low-grade serous carcinomas.

They usually do an initial test on your tumour from your first debulking which determined that you were low grade. Wonder if they still have some of that tumour. I would also wonder if they kept some tumour from your second debulking. I know that tumours can change especially if you have had treatment in between the surgeries so the second sample would be closer to where your tumour was at when they removed it (at least this is true for high grade).

The other mutation for low grade although not as frequent as BRAF and KRAS is PIK3CA. Seems to be most common in clear cell followed by endometrioid but low grade can have it too (5% in s study from 2006). Even high grade serous but in less than 1% of patients apparently (study from 2011).

As well, somatic mutations in PTEN are also possible in low grade. Mucinous seems to have the highest proportion of this mutation with low grade somewhat less than mucinous (about 20% in a study from 2008). It is less than 1% in high grade serous (study from 2011).

Seems like the most common ‘actionable’ alterations with potential for small molecule targeted therapy are in the PIK3CA/PTEN and KRAS/BRAF signalling pathways.

I never really thought of BRCAness in regard to low grade.

I have done a bit of reading and since somatic BRCAness seems to be tied to good responses to platinum chemotherapy and PARP inhibitors you would think that BRCAness is not connected to low grade (since the response it not very good to platinum chemotherapy). This would mean that PARP inhibitor responses would not apply either. Generally, ovarian cancer arising in BRCA 1 and 2 mutation carriers is high grade serous ovarian cancer.

So my question to you is do low grade serous patients get tested for germ line BRCA 1&2? Perhaps low grade does not have BRCA mutations or perhaps in lower numbers than those with high grade serous? This would explain one possibility why chemotherapy and PARPs would not work. But high grade people without BRCA 1&2 (germ line or somatic) do tend to respond to chemotherapy and some to PARPs.

So you see my dilemma. Can't figure it out for the moment. Would love some to help out here if possible.

[thomas62 in reply to RonLitBer]

Hi RonLitBer,

Thanks for your further message. Some answers to your questions: Post both surgeries I was told low grade serous so I assume they only got this info from testing my tumour. Post my first surgery I had genetic testing for BRAC1 and 2 and it was found to be negative. I do understand your reasoning as to why low graders wouldn't respond to parp inhibitors in relation to chemo response. However, whilst it is well known that low graders don't respond well to chemo this doesn't necessarily mean that the response is zero! So, would this still leave a question mark over a response to PARPs? Hoping you and your family had a peaceful and enjoyable Christmas Day.

Gwen xx

[RonLitBer in reply to thomas62]

Your BRCA test was likely a blood test for germline mutations.

Results for PARP inhibitors is available on the site below for which I have supplied a link. It does not distinguish between low grade and high grade because responses are measured according to other criteria.

clearityfoundation.org/for-...

[thomas62 in reply to RonLitBer]

Hi RonLitBer,

I have looked at the Clearity Foundation and yes, it does not distinguish between low grade and high grade. I think it says that non-BRCA patients can benefit from Parps in combination or with an immunotherpy. So perhaps low graders might benefit! Are low graders likely to have HRD? (homologous recombination deficiency). Any response appreciated. Thank you. Gwen

[RonLitBer in reply to thomas62]

I really can't speak to low grade specifically. HRD does include germline and somatic (in the tumour) BRCA mutations. I dug out an old clinical trial that I was tested for. This is the trial:

clinicaltrials.gov/ct2/show...

I was tested for the following gene mutations in regard to homologous recombination repair deficiency:

ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L.

Response to immunotherapy has not been particularly good in ovarian cancer. Combinations are holding out more hope. Don't have a distinction in regard to low grade.

[RonLitBer in reply to thomas62]

I have also done a search of clinical trials specifically for low grade ovarian cancer. I don't see anything for PARP inhibitors although you will have to google some of the drugs to see what they are.

clinicaltrials.gov/ct2/resu...

Not all are applicable to low grade as it picks up the word "low" and provides results for that.

There really does not seem to be much available.

[thomas62 in reply to RonLitBer]

Hi RonLitBer

I keep trying to get some positive info. on low grade but, as you say there isn't a lot out there. Thank you so much for the info. you have given me. All the very best to you and yours for 2019.

[RonLitBer in reply to thomas62]

The best to you and your family for the New Year as well. If I come across anything I will let you know.

[Grandma16 in reply to RonLitBer]

Thank you for all of your information. The company that ran my genetic testing was using my blood sample. I reviewed my pathology report from my surgery and it appears most of the tumor samples have been saved. Should the tumor samples be tested to have a complete analysis that might be helpful in treatment options? Thank you.

[RonLitBer in reply to Grandma16]

Yes, I think that is worth looking into. The blood test tested germline mutations. Those that are passed on through hereditary.

Testing your tumour will give you results for somatic mutations. They are called somatic due to their occurrence in the somatic (non-reproductive) cells. Since these mutations do not occur in the germ cells, they cannot be passed to offspring.

The most common disease caused by somatic mutated cells is cancer.

[thomas62 in reply to RonLitBer]

Hi again RonLitBer,

Looking for any information again. You refer to the fact that you have a somatic mutation of TP53 gene and that there is no known treatment for p53 protein if it is mutated. A question; I had a blood sample test done through a laboratory called Galkina Laboratory. The results showed I didn't have a problem with the P53 gene itself but that I did with the P53 protein at Intracellular level but not at the Extracellular level! Can you throw any light on this? Again any info appreciated.

[RonLitBer in reply to thomas62]

I would find out from the lab if they tested for TP53 as a somatic mutation. It is rare in low grade. Very high mutation in high grade and in about 50% of all cancers.

[thomas62 in reply to RonLitBer]

HIi again RonLitBer,

I had this blood test done privately in Feb. 2015 via blood test. Presumably I would have to ask my hospital for a tumour sample to be tested! Do you think this would provide me with information I could use regarding my low grade serous. I am currently NED with a CA125 of 14 (at least I was in Oct.last year) following second surgery. Again thank you.

[RonLitBer in reply to thomas62]

I would check with the clinic and see what they did first. I have seen where they use a blood test for TP53 mutation and claim it checks for somatic mutations but I am not sure how this can be done since as far as I know somatic mutations show up in the tumour only and a test of the tumour needs to happen.

[RonLitBer in reply to thomas62]

I looked up the Galkina Laboratory. I am quite truthfully appalled at what I have read. This is a quote from the web about an article by Dr. Galikina-Taylor.

"This article by Dr Olga Galkina-Taylor, an expert on p53 and cancer, and David Broom, MIRCH, a qualified Medical Herbalist, looks at the role of p53 and how damage can lead to cancer. Yet (as they tell you towards the end of the article) a variety of natural bioactive compounds, from resveratrol to fish oils and herbs like sage and ashwagandha, can restore the p53 gene and protein. Dr Galinka-Taylor states that a fully working p53 gene can then stop a cancer in its tracks and cites a number of cancers including breast cancer and lung cancer. So, this could well be a crucial ingredient in an Integrative and Complementary Cancer Programme to defeat your cancer. Judge for yourself:"

quantumhealing.co.za/p53-ge...

None of the things mentioned ie resveratrol, fish oils and herbs like sage and ashwagandha can restore the TP53 gene and thus the proper functioning of its protein. Quite plainly this is utter nonsense. Science has been working on restoring the functioning of TP53 for a long time now and there are clinical trials that are working on it. No successful method has been found to date. If there was a method to do so it would be applicable to about 50% of all cancers and a lot of suffering would be alleviated in this world.

I think you should discuss tumour testing with an actual oncologist.

[thomas62 in reply to RonLitBer]

Thanks so much for this info - much appreciated. It's a big learning curve.

Gwen xx

[Babbey]

Hi there

I too am low grade 3c. Most low grade is genetic negative. While this is positive In terms of not worrying about children and the possibility of passimg to them, it does affect treatment. Not as many drugs are available for negative brca people and many clinical trials are oooking for brca positive people. Question of funding. There is a low grade trial currently running 🏃‍♀️ n the us for low grade brca negative.

I’m two years ago m and doing great! Wishing you health and strength!

D

[thomas62 in reply to Babbey]

Hi Babbey, Can I ask which trial you are referring to. I am low grade3b. 5 years on from diagnosis. Thank you.