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Topic: PMS2+ (Lynch) and surgery decisions

Forum: Genetic Testing —

ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53, and mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM)

Posted on: Aug 8, 2021 09:37AM

Jjdrayton wrote:

Hello all,

I was diagnosed with pregnancy associated breast cancer (IDC ER+/PR+/HER-, IIb, Grade 3) in April this year and have almost completed chemo. I haven't been able to do any staging tests due to the pregnancy to confirm there is no Mets. Diagnosed at 40.

Plan was delivery of baby, then lumpectomy with a double reduction to reduce tissue / ensure good margins (and be nicer to my back!) This is scheduled the week of Sept 20th.

I had a genetic panel undertaken for 17 different genes (not sure which, I'm in Canada) and have been diagnosed with Lynch Syndrome with a mutation in PMS2. My genetics counsellor advised that the gene is not associated with BC and theoretically this should not change my treatment plan. I have read some of the research and I know the results are not conclusive at the moment but there are indications that it is a BC gene. I find it a bit of a hard pill to swallow that I'm 40, diagnosed with cancer, but apparently not a type of cancer that is associated my genetic mutation. Medical science grows and changes with new discoveries but I do have to operate within what's known now.

Understanding it's a personal choice and that there are pros and cons to each choice, I'm now reconsidering a double mastectomy to lower the risk of recurrance a little more based on the possibility that PMS2 is a BC gene and my risk of recurrance is higher than originally believed. An additional factor is that my breasts are very very dense and even my confirmed IDC did not show up on a mammogram. I will have screening MRIs but it still makes me nervous. Of course this would mean more surgeries (in addition to what's going to happen to my ovaries/uterus now because of this diagnosis/continues treatment of BC).

Looking for feedback and other personal experience with this mutation. I would welcome "what I would do in your situation". I know there is rarely a clear "correct" choice in this journey but trying to wrap my head around everything.

Thanks

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Aug 8, 2021 12:50PM Aram wrote:

Hi Jjdrayton, I am sorry you are here. I have dense breasts, and even ultrasound missed my cancer. I found it two months later myself. That is why I have decided on double mastectomy from the beginning. Of course later it turned out I have BRCA1 mutation and double mastectomy was recommended. Even without BRCA1, I was planning on BMX just because of dense breasts.

Dx at 40, BRCA1 Dx 2/5/2021, IDC, Left, 1cm, Grade 3, ER-/PR-, HER2+ (IHC) Dx 2/5/2021, IDC, Left, 3cm, Grade 3, ER-/PR-, HER2+ (IHC) Chemotherapy 3/9/2021 AC + T (Taxol) Targeted Therapy 6/1/2021 Herceptin (trastuzumab) Targeted Therapy 6/2/2021 Perjeta (pertuzumab) Surgery 10/6/2021 Mastectomy: Left; Prophylactic mastectomy: Right; Reconstruction (left); Reconstruction (right)
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Aug 8, 2021 04:25PM Rambros wrote:

sorry to read you’re going through all of this while pregnant, must be very tough. I have a variant of undermined significance on PMS2 (from my paternal side) and both my mother & grandmother had breast cancer. Since I was diagnosed young (36) and had breast cancer on both sides of the family I opted for BMX. If you’re not sure about what to do I’d recommend going as planned and think about it over time. You can always have a BMX down the line (though reconstruction will be tougher after lumpectomy & radiation).

Dx 10/8/2014, IDC, Left, 3cm, Stage IIB, Grade 3, 1/10 nodes, ER+/PR+, HER2- (FISH) Surgery 11/17/2014 Mastectomy: Left; Prophylactic mastectomy: Right Chemotherapy 1/6/2015 AC + T (Taxol) Hormonal Therapy Femara (letrozole) Hormonal Therapy Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone), Zoladex (goserelin) Surgery Prophylactic ovary removal Radiation Therapy Lymph nodes, Chest wall
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Aug 8, 2021 04:48PM - edited Aug 8, 2021 05:13PM by ShetlandPony

Hey, Jjdrayton, fellow Lynch person here. I have an MSH6 mutation. And a premenopausal breast cancer diagnosis. I believe that eventually the connection will be considered proven.

The main thing I want to say (other than dang!) is that since the data on Lynch and breast cancer so far is "mixed", it is very unlikely a physician will advise you to take any action based on a possible connection of Lynch with breast cancer. So we are on our own.

I asked a doctor who is actively involved in researching Lynch as breast cancer, about extra breast surveillance for family members with the mutation (but no bc diagnosis). The doctor said, "I don' t think there is enough novel and compelling evidence in 2020 to warrant any practice changes. (I believe there is a link, as did Henry Lynch.) There currently are no formal guidelines for MSH6 carriers as evidence for risk association is deemed insufficient." I asked my genetic counselor to run my question by the team at my own institution, and the team said there is "not sufficient evidence to perform enhanced [breast] surveillance for MSH6 carriers."

As you may know, in the United States (and other countries have similar bodies) the National Comprehensive Cancer Network aka NCCN regularly convenes a panel of experts to make evidence-based recommendations for testing, treatment, etc. No physician is going to gainsay current guidelines. Not going to happen. Now, I do believe in the value of evidence-based medicine. But, science moves slowly, and I think sometimes there is preliminary evidence or clues that are good enough to influence an individual person about their own care. Sometimes the stakes are high enough to push the boundaries.

Is that the case with your surgery decision? I don't know, but I think I might ask the genetics counselor, surgeon, and medical oncologist something like this: I understand we do not have enough evidence for a connection of PMS2 and breast cancer. If you knew that a woman with a similar history to mine had a mutation that *was* proven to confer, let's say a 27% risk of breast cancer, how would that affect the treatment plan for her? Is that a big enough figure that you would you advise single or double mastectomy? Or enhanced surveillance with MRI and mammograms alternating every six months? Some mutations such as BRCA carry a risk high enough to recommend mastectomy. What about lower-risk gene mutations? How do we think about those numbers?

Let me tell you, anyone in my family who has the mutation will get enhanced screening, one way or another! It turns out to be a matter of age plus one-side family history that qualified one of them, and both-sides family history that qualified another. The youngest one has not tested yet. They will be offered screening younger than usual based simply on family history, but if they test positive for the mutation I will insist they start even earlier, I don't care how coy the doctors are about their precious data. (And the fourth living person with the mutation had post-menopausal breast cancer.)

I assume you have read this paper and the relevant ones listed in the notes?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138356/

In the above study, "The prevalence of breast cancer differed based on mutation type (p=0.0043), as 27% of women with a PMS2 mutation were diagnosed with breast cancer, compared to 3%, 4%, and 9% in MLH1, MSH2, and MSH6 patients. The average age at diagnosis for women with a PMS2 mutation was 46.7 years."

Also see this one which implicates PMS2 and MSH6:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051923/?report=reader


Please keep in touch if you are able. I'm so sorry cancer is interfering with what should be simply a time of joy for you.

2011 Stage I ITCs sn, premenopausal, Oncotype 16. 2014 Stage IV mets breast,liver. TaxolNEAD. Ibrance+letrozole 2yrs. Fas+afinitor nope. XelodaNEAD 2yrs. Eribulin,Doxil nope. SUMMIT FaslodexHerceptinNeratinib for Her2mut NEAD Dx 2011, ILC, 1cm, Stage IA, Grade 1, 0/1 nodes, ER+/PR+, HER2- Dx 2014, ILC, 2cm, Stage IV, metastasized to liver/other, Grade 2, ER+/PR+, HER2- Hormonal Therapy Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Radiation Therapy Whole-breast: Breast Surgery Lumpectomy
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Aug 9, 2021 08:39AM Jjdrayton wrote:

Good morning!

Thank you all for the considered responses and support. It really is appreciated. Every time I think I have a handle on a plan it goes a little sideways :)

Thanks so much Aram and Rambros for sharing your decisions and advice. It is really helpful to see what triggered people's choices and will definitely help inform mine.

ShetlandPony - your thoughts echo mine exactly in terms of belief the link will eventually be proven, but I really appreciate the advice to ask in a hypothetical about the patient with an extra 27% risk - I agree that none of my Dr's are going to go against the current accepted guidance, but it is my choice in the end either way and I agree that individual treatment plans can sometimes be influenced by preliminary data! The way you framed the question is perfect to help me get the info I need with my oncologist and surgeon. Thanks also for sharing the studies. Indeed those are the ones that particularly influenced my concern.

I'll keep you all posted.


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Aug 9, 2021 03:45PM redhead403 wrote:

Hi! I had the variant of that gene for lynch syndrome. It was brushed off to be honest. In my family, all of my brothers and father had prostate cancer. My paternal and maternal aunts had breast cancer along with my mother. I have an aunt who died in the 1950's or 60's of something abdominal cancer. Cousin had prostate cancer and I had an uncle who had esophageal or gastric cancer. I don't know if it is MSH6 but sure sounds like there is something genetic there. I think that some genes have not been discovered yet or the connection to genes haven't been established yet

Surgery 4/16/2019 Lumpectomy: Left Dx 9/9/2019, DCIS/IDC, Left, <1cm, Stage IA, Grade 2, 0/3 nodes, ER+/PR+, HER2- (IHC) Surgery 11/7/2019 Lymph node removal: Sentinel; Mastectomy: Left, Right; Prophylactic mastectomy: Right; Prophylactic ovary removal; Reconstruction (left): Silicone implant; Reconstruction (right): Silicone implant Radiation Therapy 1/6/2020 Whole-breast: Breast
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Aug 9, 2021 04:01PM - edited Aug 9, 2021 04:08PM by ShetlandPony

It sounds like we have a similar bent toward research, JJ!

Be careful with how you interpret the percentages and check with the genetic counselor to make sure you assess your possible risk correctly. You said, "an extra 27% risk" -- based on the Pederson paper, I presume -- but that is not quite right. It is not extra as in 27% more than the general population. All women start with some risk simply because they are women. (For the sake of simplicity I am not including men in our discussion, though we know they can have bc too.) For example, in the paper by Roberts et al, the risk for PMS2 was found to be 37.7% cumulative risk by age 60, BUT that is not compared to a 0% risk in the general population. According to cancer.gov, "Based on current incidence rates, 12.9% of women born in the United States today will develop breast cancer at some time during their lives (1)." From Roberts:

"We found a twofold and threefold increased risk of breast cancer for the women with MSH6 and PMS2 PVs in our cohort, whereas no breast cancer association was observed for MLH1 or MSH2. PVs in MSH6 and PMS2 were found to confer 31.1% and 37.7% cumulative risks for breast cancer by the age of 60 while PVs in MLH1 or MSH2 were found to confer breast cancer risks close to the expected general population risk, 16.1% and 15.5%, respectively."

So now we see why cancer patients should have taken statistics in college, or brush up on it if they did! Pay attention to the meaning of the term "cumulative" and what the ages are. (I will confess that such statistics are slippery to my mind; sometimes I grasp their meaning and sometimes I feel I don't quite have it.)

I thought of other possible ways to phrase your question: At what level of risk of recurrence or new breast cancer do you recommend a patient consider mastectomy vs. lumpectomy? At what level of risk do you recommend prophylactic mastectomy of the healthy breast? Taking into account my bc diagnosis, age, etc. what would be my estimated risk of a second breast cancer in my lifetime? And how would that change if I had a mutation that was known/proven to confer a roughly 30% risk to women in the general population?


2011 Stage I ITCs sn, premenopausal, Oncotype 16. 2014 Stage IV mets breast,liver. TaxolNEAD. Ibrance+letrozole 2yrs. Fas+afinitor nope. XelodaNEAD 2yrs. Eribulin,Doxil nope. SUMMIT FaslodexHerceptinNeratinib for Her2mut NEAD Dx 2011, ILC, 1cm, Stage IA, Grade 1, 0/1 nodes, ER+/PR+, HER2- Dx 2014, ILC, 2cm, Stage IV, metastasized to liver/other, Grade 2, ER+/PR+, HER2- Hormonal Therapy Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Radiation Therapy Whole-breast: Breast Surgery Lumpectomy
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Aug 9, 2021 04:05PM ShetlandPony wrote:

Golly, redhead. Have you or other family members had a cancer genetics counselor go over your family tree of cancer? It could be important for them to know of any mutations that would point to extra surveillance for various cancers.

2011 Stage I ITCs sn, premenopausal, Oncotype 16. 2014 Stage IV mets breast,liver. TaxolNEAD. Ibrance+letrozole 2yrs. Fas+afinitor nope. XelodaNEAD 2yrs. Eribulin,Doxil nope. SUMMIT FaslodexHerceptinNeratinib for Her2mut NEAD Dx 2011, ILC, 1cm, Stage IA, Grade 1, 0/1 nodes, ER+/PR+, HER2- Dx 2014, ILC, 2cm, Stage IV, metastasized to liver/other, Grade 2, ER+/PR+, HER2- Hormonal Therapy Tamoxifen pills (Nolvadex, Apo-Tamox, Tamofen, Tamone) Radiation Therapy Whole-breast: Breast Surgery Lumpectomy
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Aug 9, 2021 08:37PM redhead403 wrote:

Hi again,

Yes I went over it with the physician. That was the only variant and or genetic mutation. I am thinking that there are others undiscovered as of yet

Surgery 4/16/2019 Lumpectomy: Left Dx 9/9/2019, DCIS/IDC, Left, <1cm, Stage IA, Grade 2, 0/3 nodes, ER+/PR+, HER2- (IHC) Surgery 11/7/2019 Lymph node removal: Sentinel; Mastectomy: Left, Right; Prophylactic mastectomy: Right; Prophylactic ovary removal; Reconstruction (left): Silicone implant; Reconstruction (right): Silicone implant Radiation Therapy 1/6/2020 Whole-breast: Breast

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